SEMINARS IN PERINATOLOGY

VOL 32, NO 4 AUGUST 2008

Antenatal Testing: A Re-Evaluation

CAROLINE SIGNORE, MD, MPH, AND CATHERINE Y. SPONG, MD Guest Editors

TABLE OF CONTENTS
Introduction Caroline Signore and Catherine Y. Spong ............................................. 231 232 239 243 Epidemiology of Stillbirth and Fetal Central Nervous System Injury Hamisu M. Salihu ................................................................................... Normal Fetal Physiology and Behavior, and Adaptive Responses with Hypoxemia Chester B. Martin Jr ......................................................................... Fetal Movement Assessment J. Frederik Fren, Alexander E.P. Heazell, Julie Victoria Holm Tveit, Eli Saastad, Ruth C. Fretts, and Vicki Flenady ................... Antenatal Fetal Assessment: Contraction Stress Test, Nonstress Test, Vibroacoustic Stimulation, Amniotic Fluid Volume, Biophysical Prole, and Modied Biophysical ProleAn Overview Lawrence D. Devoe ......................... Fetal Doppler: Umbilical Artery, Middle Cerebral Artery, and Venous System Giancarlo Mari and Farhan Hanif ........................................................... Monitoring of Fetal Well-Being: Role of Uterine Artery Doppler Alessandro Ghidini and Anna Locatelli ................................................... Assessing Cardiac and Neurological Maturation During the Intrauterine Period Curtis L. Lowery, R. B. Govindan, Pamela Murphy, and Hari Eswaran ...... Antenatal Testing: Diabetes Mellitus Michael P. Nageotte ...................................... Antepartum Testing in Patients with Hypertensive Disorders in Pregnancy Roger K. Freeman .............................................................................. Fetal Growth Restriction Jena Miller, Sifa Turan, and Ahmet A. Baschat ................. Antenatal Fetal Assessment: Multifetal GestationAn Overview Lawrence D. Devoe ............................................................................... Amniotic Fluid Abnormalities Christopher R. Harman ........................................... Michael Y. Divon and Noa Feldman-Leidner ......... Postdates and Antenatal Testing

247 253 258 263 269 271 274 281 288 295

Antepartum Testing for Women with Previous Stillbirth

Jonathan W. Weeks ........

301

Management of Decreased Fetal Movements J. Frederik Fren, Julie Victoria Holm Tveit, Eli Saastad, Per E. Brdahl, Babill Stray-Pedersen, Alexander E. P. Heazell, Vicki Flenady, and Ruth C. Fretts ........................................ New Indications for Antepartum Testing: Making the Case for Antepartum Surveillance or Timed Delivery for Women of Advanced Maternal Age Ruth C. Fretts and Ugonna A. Duru ............................................................. Antenatal TestingBenets and Costs Christina M. Scifres and George A. Macones .................................................................................................

307

312 318

Volume 32, Number 4

August 2008

Introduction

ntepartum fetal testing aims to improve perinatal and pregnancy outcome, with the ultimate goal of reducing mortality (fetal death) as well as morbidity, including cerebral palsy and neonatal encephalopathy. Fetal death occurs in 6.4/1000 pregnancies in the US, although it is anticipated that this is an underestimate. In half of these, antepartum risk factors are present and, of these, 25 to 75% may be amenable to prenatal modication. Cerebral palsy affects 2/1000 liveborn infants; neonatal encephalopathy occurs in 1.9 to 3.8 per 1000 births and may result in permanent neurologic disability, as in cerebral palsy. In the vast majority of cases, the neurologic insults resulting in neonatal encephalopathy are felt to arise in the antepartum period, before the onset of labor. Electronic techniques for recording fetal heart rate patterns in labor were developed in the 1950s and were hoped to have great promise for identifying fetuses at risk for injury or death, to allow preventive interventions. Use of intrapartum electronic fetal monitoring (EFM) was widely adopted before rigorous studies assessing its benet were conducted. With its use, the rate of cesarean delivery increased due to intrapartum EFM interpretation; however, the rates of cerebral palsy remained unchanged. Thus, the use of EFM did not confer signicant protection from fetal or newborn morbidity or mortality. Not long after the advent of intrapartum EFM, these technologies were applied to assessments of fetal well-being before labor. With the introduction and increasing sophistication of ultrasound fetal imaging and Doppler blood ow measurement techniques, a fairly wide armamentarium of antepartum fetal tests became available for clinical use. Again, however, the evidence base supporting their use and the recommendation of one modality over another is limited. It is not clear which antenatal testing strategy best reduces perinatal mortality and morbidity.

To review the current state of the art in antenatal fetal assessment and identify areas for further research, a workshop was convened at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) in August 2007. Titled Antenatal Testing: A Reevaluation, the workshop goals included describing indications and testing methodologies that are backed by sufcient evidence, and identifying those conditions and methods for which gaps in knowledge and evidence still exist. Along with cosponsors the NIH Ofce of Rare Diseases, the American College of Obstetricians and Gynecologists, and the American Academy of Pediatrics, the Pregnancy and Perinatology Branch of NICHD invited 20 expert researchers and clinicians to summarize and present the latest evidence regarding a spectrum of issues in antenatal testing:

The epidemiology of antepartum stillbirth and neurological injury Normal fetal physiology and fetal responses to intrauterine insults The technology and utility of existing and emerging fetal assessment methods Maternal and fetal indications for antenatal testing Costs and benets of antenatal testing

This issue of Seminars in Perinatology contains articles based on the presentations given at the Workshop. It is hoped that readers will appreciate the strengths and limitations of the existing evidence regarding antenatal fetal assessment and that the obstetrical and scientic communities will be inspired to develop research protocols that will increase our understanding of the optimal use of antenatal testing for prevention of perinatal morbidity and mortality. Caroline Signore, MD, MPH Catherine Y. Spong, MD Guest Editors

0146-0005/08/$-see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2008.04.001

231

Epidemiology of Stillbirth and Fetal Central Nervous System Injury

Hamisu M. Salihu, MD, PhD
The epidemiology of stillbirth and fetal central nervous system (CNS) injury is described with some emphasis on maternal and feto-placental risk factors. To maximize utility of the discussion and because it also represents the classical manifestation of fetal CNS injury, we have selected cerebral palsy (CP) to illustrate the epidemiologic aspects of injury to the fetal CNS in general. While trends in stillbirth rates have modestly decreased over time, those of CP seem to be increasing. Interestingly, both stillbirth and CP share traditional as well as emerging risk factors lending credence to the hypothesis that fetuses that would previously have been stillborn are increasingly surviving albeit with some form of morbidity. The existence of shared risk factors also suggests that in some cases of stillbirth fetal CNS injury precedes the in utero fetal demise. Pregnant women bearing these risk indicators represent potential candidates for appropriate and tailored protocols for antenatal fetal testing. Semin Perinatol 32:232-238 2008 Elsevier Inc. All rights reserved. KEYWORDS epidemiology, stillbirth, cerebral palsy, risk factors

tillbirth complicates about 1 in every 1000 viable pregnancies,1,2 although rates vary across populations and within population strata and rises with increase in fetal number.3 Worldwide, the World Health Organization estimates about 4 million stillbirths annually, and this is likely an underestimate because a signicant proportion of home stillbirth deliveries in developing settings go unrecorded.4 While the epidemiology of stillbirth as a discrete entity has been described and poorly understood factors of risk have been highlighted,5 the interconnectedness between fetal mortality (stillbirth) and fetal morbidity in those fetuses that have sustained injuries but escaped death remains understudied. This is important because a recent theory has postulated a common pathway shared by processes leading to both stillbirth, delayed death during infancy, and residual morbidity.6 Additional evidence also supports the view that in certain cases of stillbirth fetal central nervous system (CNS) injury preceded the in utero fetal demise.7 It is therefore logical and
Department of Obstetrics and Gynecology, and Department of Epidemiology and Biostatistics, University of South Florida, Tampa, FL. This work was partially supported through a Young Clinical Scientist Award to Dr. Hamisu Salihu by the Flight Attendant Medical Research Institute (FAMRI). The funding agency did not play any role in any aspect of the study. Address reprint requests to Hamisu Salihu, MD, PhD, COPH, 13201 Bruce B. Downs Blvd., MDC 56, Tampa, FL 33612-3805. E-mail: hamisu. salihu@gmail.com

more useful to examine stillbirth and fetal morbidity under the same conceptual framework since prevention strategies are likely to be shared. In this article, we seek to discuss the epidemiology of stillbirth and fetal CNS injuries with some emphasis on risk factors, especially the emerging factors.

Epidemiology
Denitions
Stillbirth is dened as in utero fetal death at 20 weeks of gestation. Fetal central nervous system injuries encompass a variety of clinical (eg, cerebral palsy, epilepsy, etc) and pathophysiologic syndromes (eg, periventricular leukomalacia, intraventricular hemorrhage, neonatal stroke, etc) and it will be well beyond the scope of this endeavor to discuss each and every entity. Cerebral palsy (CP) is the most common of all fetal CNS injuries. It is the most common diagnosis among referred cases for pediatric rehabilitation.8 It also encompasses the other clinical and pathophysiologic syndromes. For instance, 20 to 40% of children with CP suffer from epileptic episodes.9,10 Because CP represents the classical manifestation of fetal CNS injury, we discuss this clinical entity to illustrate the epidemiologic aspects of injury to the fetal brain in general. To this end, we dene CP as a group of nonprogressive, but often changing, motor impairment syndromes secondary to lesions or injuries of the brain arising at any time during brain development.

232

0146-0005/08/$-see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2008.04.002

Epidemiology of stillbirth and fetal CNS injury

9 8 Fetal mortality rate/1000 7 6 5 4 3 2 1 0
19 91 19 92 19 94 19 96 19 90 199 3 19 97 19 95 19 99 20 00 199 8

233

Total Early Late

Year

Figure 1 Trends for total, early, and late stillbirth in the United States from 1990-2000 (constructed from the NCHS public access data les). (Color version of gure is available online.)

Prevalence and Trends

About half of all perinatal deaths (from 20 weeks of gestation to age 1 year) occur in utero.11 Approximately, 25,000 stillbirths on average are recorded annually in the US, and this is about 10 times as high as deaths from sudden infant death syndrome.12 Whereas rates of total stillbirths declined considerably and consistently from 1950 to 1990, only modest decreases in total stillbirths have occurred subsequently and these have remained barely noticeable as a result of corresponding increases in early stillbirths (Fig. 1). The contrasting increases versus decreases in trends for early and late stillbirths, respectively, are indicative of the positive impact of advancement in perinatal technologies over the years on fetal survival at later rather than earlier gestational ages.13 In contrast to stillbirth the prevalence of CP has been climbing from about 1.5/1000 live births in the 1960s to about 2.5/ 1000 in the 1990s.14-18 The rise in the prevalence of CP has been attributed to the increased survival of low birth weight and preterm infants. Low birth weight newborns now contribute about 50% of all cases of CP and just over half of the most severe cases, whereas in the 1960s they accounted for one-third of all CP cases and only one-sixth of the most severe.18 The rapid rise in survival of infants with extremely low birth weight values might also have contributed to the increase in CP cases over time. Salihu and coworkers examined the birth rate and survival of previable infants (dened as birth weight within the range 200499 g) in the US comparing two cohorts, 1985 to 1988 versus 1995 to 1999.19 The authors noted a 100% rise in the birth rate of previable fetuses between the two periods (from 60.6 per 106 live births to 131.9 per 106 live births). Survival beyond the neonatal period among these babies also increased considerably by about 50% between the two periods (from 12.0 to 17.4%). Using modeling approaches, the investigators predicted that by the year 2010 about one of four of these babies will be a survivor. The rate of CP rises exponentially with falling birth weight:

1.1/1000 for birth weights 2500 g; 11.5/1000 for birth weights 1500 to 2499 g; 77/1000 for birth weights 1000 to 1499 g; and 90/1000 for birth weights 1000 g.20,21 It is therefore logical that given the aforementioned projected rise in survival of previable fetuses (who without intervention would have been stillborn), the current increase in CP should be expected to persist into the future. In a similar pattern the positive trend in the prevalence of CP correlates with the increase in the proportion of preterm live births and their survival. In a recent population-based cohort study, Vincer and coworkers noted that infant mortality among very preterm infants decreased by about 55% between 1993 and 2002.22 Simultaneously, the CP rates among very preterm births increased by about 125% (from 44.4/1000 to 100.0/1000). Without the current improvement and advances in perinatal technology, most of these babies would have either been stillborn or been early neonatal deaths. Paradoxically, while the use of intrapartum fetal monitoring technology has signicantly prevented unexpected intrapartum stillbirth, the expected positive impact of this technology on CP has not materialized. Clinical trials have noted a signicant increase in CP among preterm infants followed during labor with electronic monitoring.23 This has led some to question whether in fact these already-injured preterm infants would have simply died in utero but for the fetal monitoring,24 a good example of unavoidable and unintentional conversion of mortality into morbidity.

Risk Factors for Stillbirth and Fetal CNS Injury

Maternal Factors
Maternal Age Maternal age has consistently been associated with stillbirth in singleton pregnancies. The relationship between stillbirth

234 and maternal age is U-shaped with elevated risks at the two extremes of reproductive age. The risk of stillbirth increases with advancing maternal age in a dose-dependent pattern.25 One obvious underlying cause is the greater-than-expected rates for fetal stillbirth-related anomalies among older women.26 The increased incidence of medical complications with aging is also a factor. With advancing age, infertility sets in and the use of Assisted Reproductive Technology to bear children increases in a dose-effect fashion: 4.3, 18.3, 40, and 65% among young (20-29 years old), mature (30-39 years old), very mature (40-49 years old), and older mothers ( 50 years old), respectively.25 Low maternal age is also a risk factor for stillbirth. In a most comprehensive study of stillbirth among pediatric gravidas (mothers aged 10-14 years), the authors observed elevated risk for stillbirth in this group with increase in fetal number.27 The suspected pathways among pediatric mothers are, however, different from those described for older gravidas. Biologic immaturity, factors linked to preterm delivery, and unfavorable social environments are the suggested pathways for in utero fetal demise among pediatric mothers.27 While the risk of stillbirth climbs with increase in fetal number among teenagers,28 it decreases with ascending fetal number among older mothers.25 Maternal age also seems to be a risk factor for fetal CNS injury. Similar to the case for stillbirth, the relationship between maternal age and CP follows a U-shaped distribution. The risk for CP has been reported to be signicantly greater among teen mothers as well as those mothers advanced for age.29 The risk for CP was estimated to be 30, 20, and 40% greater among teen ( 19 years), mature (35-39 years), and very mature mothers ( 40 years).29 Parity The association between parity and stillbirth follows a trajectory similar to that noted for maternal age and stillbirth. The risk of stillbirth is U-shaped with higher risk levels among nulliparous30 and extremely parous mothers.31 In a most detailed study among multiparous women categorized into moderately parous (1-4 previous live births), highly parous (5-9 previous live births), very highly parous (10-14 previous live births), and extremely parous ( 15 previous live births), the risk of stillbirth climbed progressively with increasing parity.31 Further analyses among the extremely parous group broken down into 15, 16, 17, and 18 previous live births conrmed the dose effect relationship between parity and stillbirth. The mechanism of stillbirth among highly parous women is explained by the phenomenon of uterine exhaustion because of persistent organ overuse.31 Fetal CNS injury seems to be associated with parity in a U-shaped pattern as well, although data in this regard is not as consistent as for stillbirth. In a recent population-based analyses covering 2303 infants born in Sweden with a diagnosis of CP compared with 1.6 million controls, the investigators observed a 20% higher likelihood for CP among infants of primiparous women (OR 1.2; 95% condence interval 1.1-1.3).29 In a review analyses, the rate of CP among infants of women with parity 3 was found to be signicantly greater than expected.32 These ndings are ad-

H.M. Salihu
ditional evidence suggesting a common shared pathway for stillbirth and fetal CNS injury. Obesity The relationship between gradations of obesity and in utero fetal demise was recently clearly demonstrated in a large population-wide study covering more than 1.5 million deliveries in the United States.33 In doing so the authors categorized obese mothers into the three typical obesity subclasses, namely, class I (BMI 30.0-34.9); class II (BMI 35.039.9), and extreme obesity (BMI 40). Overall, obese mothers were about 40% more likely to experience stillbirth as compared with nonobese gravidas (Hazards ratio 1.4; 95% CI 1.3-1.5). The investigators also noted that the risk for stillbirth increased in a monotonic fashion with ascending obesity class (P 0.01). Perhaps the most striking and unique nding of the study was the pronounced risk for stillbirth among black obese mothers when compared with their white counterparts. Equally intriguing is that the black disadvantage in stillbirth widened signicantly with increase in BMI, with the greatest blackwhite difference observed among extremely obese mothers. A number of hypotheses has been advanced to explain the adverse fetal outcomes associated with maternal obesity. It is well established that obese women are at elevated risk for gestational diabetes mellitus and hypertensive disorders.3 However, even in the absence of these complications, the heightened risk for adverse birth outcomes among obese women still persists.34,35 As compared with thinner women obese mothers are less likely to perceive fetal kick counts so that in case of diminished fetal movements preceding fetal demise thinner women are more likely to perceive the difference and seek prompt medical care.3 Obese gravidas tend to have hyperlipidemia, which suppresses prostacyclin secretion while enhancing peroxidase production.36 This imbalance favors vasoconstriction and platelet aggregation, processes that impede the maternalfetal circulation, hampering normal fetal growth and development. As compared with nonobese mothers, obese pregnant women experience more extended periods of snoring during sleep with more frequent apnea-hypoxia incidents, leading to prolonged episodes of oxygen desaturation.37 This could reduce blood ow to the fetus leading to fetal compromise and greater likelihood of in utero fetal demise. It is well established that maternal obesity is related to fetal macrosomia and shoulder dystocia, which could lead to fetal injuries and fetal distress at birth.38,39 Shoulder dystocia and obstetric maneuvers for shoulder release have been associated with increased incidence of peripartal asphyxia and subsequent cerebral palsy.40 Race/Ethnicity The most pronounced disparity in stillbirth across racial/ ethnic groups is that between blacks and whites, especially among singleton births. For unknown probably biologic reasons, the blackwhite gap in stillbirth risk narrows with increase in fetal number in a dose-dependent fashion.41 Several hypotheses have been advanced to explain blackwhite stillbirth gap including disparity in socio-economic status, access

Epidemiology of stillbirth and fetal CNS injury

to quality care, preponderance of hypertensive disorders among black mothers, and other obstetric complications. A recent study is also suggestive that the high rate of obesity among black women could be contributory to the black white disparity in stillbirth rates.33 Similar to the ndings in stillbirth, black infant survivors are more likely to develop CP later in life than their white counterparts.42 When these racial differences are examined over time, the blackwhite gap appears stable but persistent. Studies of CP by race are relatively few and explanations for blackwhite CP prevalence differentials have not yet been sufciently explored. Prenatal Smoking There is evidence linking prenatal smoking and stillbirth, although the causal relationship between prenatal smoking and adverse birth outcomes is frequently confounded by other maternal characteristics including race, socio-economic status, as well as other unknown or immeasurable exposures that could potentially impact and modify the uterine environment. Further, gene environment interaction is an important variable that inuences fetal response to the toxic effects of in utero tobacco exposure.43 However, the quantication of genetobacco smoke effects is mostly not measured in case-control study designs because of lack of relevant data, especially, at the population level. The risk of CP is about 20% greater among infants of smoking mothers as compared with those of nonsmoking gravidas.29 Such an association is biologically plausible since prenatal smoking has also been associated with neuro-cognitive abnormalities including reduced intelligence in the offspring.44 Synthesizing from the literature, it is possible that a number of tobacco toxins could induce fetal CNS injuries leading to brain cell decit, impaired synaptic conguration, or failure of migration of neurons,45,46 processes that are linked to subsequent development of CP. Medical Conditions Hypertension and diabetes mellitus are the most important medical conditions associated with stillbirth. Over the years, effective and aggressive management protocols have reduced the previously high levels of stillbirth rate attributable to these conditions to rates that are modestly above population levels.47 It appears that the elevated risk for stillbirth associated with hypertensive disorders is mainly accounted for by preeclampsia/eclampsia rather than chronic hypertension.2 Other medical conditions associated with elevated risk for stillbirth include systemic lupus erythromatosis,48 thrombo-

235 philias,49 high hemoglobin concentration,50 and thyroid disease.51 Similar to stillbirth, maternal medical conditions in pregnancy inuence the development of fetal CNS injuries. The risk of newborn encephalopathy (a precursor for subsequent CP) is elevated 2-fold, 6-fold, and 10-fold among infants born to women with hypertension, severe preeclampsia, and thyroid disease, respectively.52 Infants of pregnant women with diagnosed type 2 diabetes have a 100% higher likelihood for CP as compared with controls.29 There is some evidence linking thrombophilia in the mother or child to the development of perinatal stroke and subsequent cerebral palsy.53,54 Infertility and Assisted Reproduction Technology (ART) Infertility per se is a risk factor for stillbirth. Spontaneous pregnancies in untreated infertile women may be at higher risk for perinatal mortality than spontaneous pregnancies in fertile women.55 About 1% of all babies and 18% of multiple births born in the United States result from ART,56 and recently, the procedure has become a focus of increasing study. The risk of stillbirth among ART-conceived singleton births is more than double that for spontaneously conceived singletons.57 However, ART-conceived twins bear risks for adverse birth outcomes comparable to those of their spontaneously conceived counterparts.58 It is likely that the greater-thanexpected rates of derived singletons (resulting from early vanishing of a co-twin) among ART-conceived singleton gestations might be contributory to these ndings. Similar to the ndings in stillbirth, the risk for neurological impairment in ART-conceived children is about four times that of naturally conceived children (OR 3.7; 95% CI 2.0-6.6).59 In tandem with comparable ndings in stillbirth, the elevated risk for neurological complications is conned to singletons only while twins of both ART and natural conceptions bear similar risk levels. Table 1 offers the pathway through which ART could cause CP among vulnerable fetuses by comparing prematurity versus in utero growth perturbation.60 Although the exact pathways remain poorly understood, some aspects of the processes involved during ART or an underlying disorder linked to the infertility of couples receiving fertility treatments could to some extent explain the elevated risks for stillbirth and fetal CNS injury among ARTconceived infants.

Table 1 Exploratory Pathway for the Association Between IVF-ICSI and Fetal CNS Injury (cerebral palsy) Preterm IVF singleton Non-IVF singleton IVF twin Non-IVF twin 6.5% 3.7% 40% 33.3%

P Value
<0.0001 0.004

Very Preterm 1.8% 0.8% 9.5% 8.2%

P Value
<0.0001 0.02

SGA 4.4% 3.2% 16.0% 16.0%

P Value
<0.0001 0.6

Reprinted with permission from Hvidtjrn and coworkers.60

236

H.M. Salihu
Table 2 Twinning and Incidence of Cerebral Palsy Twin Phenotype Twins versus singletons In utero partial reduction Neonatal partial reduction CP of co-twina Growth discordanceb
aThe bNo

Recurrence of Stillbirth and Fetal CNS Injury

The risk for a subsequent stillbirth in a woman whose previous pregnancy ended in a stillbirth increases by 2- to 10fold.61,62 Even among women of low baseline risk, prior stillbirth event elevates the risk for a subsequent stillbirth by at least fourfold.63 History of stillbirth confers greater risk for subsequent early (fetal death between 20 and 28 weeks) than for late stillbirth (fetal death at 29 weeks) [hazards ratio (HR) 10.3; 95% CI 6.1 to 17.2 versus HR 2.5; 95% CI 1.0 to 6.0]; and for intrapartum (HR 12.2; 95% CI 4.5-33.3) than for antepartum (HR 4.2; 95% CI 2.3-7.7) stillbirth. In a similar fashion, the risk for CP recurrence in a subsequent pregnancy increases vefold,64 about the same magnitude as for stillbirth recurrence.64 While persistent maternal conditions in subsequent pregnancies might be an explanation, the contribution of these factors do not sufciently explain stillbirth or fetal CNS morbidity recurrence. A recent theory offers an alternative and more convincing biologic pathway based on molecular event memory mechanisms to explain this recurrence.6 The theory provides a framework that bears the potential for possible future intervention to prevent stillbirth and fetal CNS morbidity recurrence.

Rate of CP (per 1000) 5.9 versus 1.8 (4-fold increase) 47 versus 4.8 (10-fold increase) 63 versus 4.8 (11-fold increase) 118 versus 5.9 (20-fold increase) 7.7 versus 4.9 (60% greater risk)

P Value
<0.0001 <0.0001 <0.0001 <0.0001 >0.05

greatest risk for CP among twins. difference between the smaller and the larger twin. Adapted from Scher and coworkers.66

Feto-Placental Factors
Multiple Pregnancy On average, the proportion of multiple births has increased over the previous decades mostly as a result of a shift to the right of the maternal age distribution of pregnant women as well as the increasing use of articial reproduction technology for the treatment of infertility. Multiples now account for 3% of all births but 10% of all stillbirths.2 The risk for stillbirth increases in a dose-dependent pattern with increase in fetal number.3 Similarly, the rate of fetal CNS injury increases with multiple gestation. In a study encompassing 705 twin pairs (1410 twins), 96 sets of triplets (287 triplets excluding one infant death), and 7 sets of quadruplets (27 quadruplets excluding one infant death), Yokoyama and coworkers65 observed an increasing trend of CP with rising fetal number in utero: 9/1000, 31/1000, and 111/1000 among twins, triplets, and quadruplets, respectively. Further, the risk for at least one child having a CP within a multiple cluster also correlated positively with fetal number: 15/1000; 80/1000, and 429/ 1000 twin, triplet, and quadruplet clusters, respectively. Most of the data on CP in multiples have been conducted among twins only. The risk of CP in twins has also been shown to be a function of the twin cluster phenotype as summarized in Table 2, with the greatest risk associated with the co-twin of an affected twin sibling.66 Fetal Gender Sex of the fetus is associated with the occurrence of both stillbirth and CP. The sexual difference in stillbirth has been observed in different populations and is therefore unlikely to be artifactual.67,68 It has been postulated that this sexual dif-

ference might be mediated by physiologic variation at the level of the maternal response to the conceptus, at the placenta, or may be as a result of sexual differences in fetal physiology.69-72 However, the exact mechanism still remains unclear. Similarly, fetal CNS injury comprising CP and related developmental disorders are more common in males than in females. Most recently pooled data explain the disparity to be due to the greater vulnerability of the male fetus to white matter injury and intraventricular hemorrhage.73 Sex differences in hormonal inuences on neuro-protection against hypoxia-ischemic injuries and gender-based intrinsic differences in cell death pathways of growing neurons have been postulated as likely reasons for greater risk of CP among male infants.73 Other feto-placental risk factors for stillbirth and fetal CNS injury include infection,74,75 congenital malformations,76,77 cord anomalies,78-80 and placental abnormalities.81,82

Unexplained Stillbirth and Fetal CNS Injury

Approximately half of all stillbirths remain unexplained, and the proportion of this category of stillbirth increases with gestational age.5,83 Identied risk factors for unexplained stillbirth include unappreciated fetal growth restriction, postdates, advanced maternal age, suboptimal education attainment, primiparity and multiparity ( 3), and the presence of cord loops.84-86 Similarly, a signicant proportion of cases of cerebral palsy remain unexplained, although the increasing use of sophisticated neuro-imaging techniques have improved elucidation of pathologic pathways and timing of occurrence of fetal CNS injury.77

Conclusion
While the rate of stillbirth is modestly declining, that of cerebral palsy, a consequence of fetal CNS injury, seems to be on the rise. The increasing survival of infants who in the past would have been stillborn partly explains the rising trend. A growing number of emerging risk factors for both stillbirth and cerebral palsy are being uncovered. Pregnant women

Epidemiology of stillbirth and fetal CNS injury

bearing these risk indicators represent potential candidates for appropriate and tailored protocols for antenatal fetal testing.

237
26. Fretts RC, Usher RH: Fetal deaths in women in the older reproductive age group. Contemp Rev Obstetr Gynecol 9:173-179, 1997 27. Salihu HM, Ekundayo OJ, Kristensen S, et al: Childhood pregnancy (10-14 years old) and risk of stillbirth in singletons and twins. J Pediatr 148:522-526, 2006 28. Alexander MR, Salihu HM, Dwight RJ: Survival of triplets born to United States teenagers. Am J Obstet Gynecol 191:2097-2102, 2004 29. Thorngren-Jernick K, Herbst A: Perinatal factors associated with cerebral palsy in children born in Sweden. Obstet Gynecol 108:1499-1505, 2006 30. Bai J, Wong F, Bauman A, et al: Parity and pregnancy outcomes. Am J Obstet Gynecol 186:274-278, 2002 31. Aliyu MH, Salihu HM, Keith LG, et al: Extreme parity and risk of stillbirth. Obstet Gynecol 106:446-453, 2005 32. Topp M, Langhoff-Roos J, Uldall P: Preterm birth and cerebral palsy. Predictive value of pregnancy complications, mode of delivery, and Apgar scores. Acta Obstet Gynecol Scand 76:843-848, 1997 33. Salihu HM, Dunlop A-L, Alio AP, et al: Extreme obesity and risk of stillbirth among black and white gravidas. Obstet Gynecol 110:552557, 2007 34. Kristensen J, Vestergaard M, Wisborg K, et al: Pre-pregnancy weight and the risk of stillbirth and neonatal death. BJOG 112:403-408, 2005 35. Cnattingius S, Bergstrom R, Lipworth L, et al: Prepregnancy weight and the risk of adverse pregnancy outcomes. N Engl J Med 338:147-152, 1998 36. Stone JL, Lockwood CJ, Berkowitz GS, et al: Risk factors for severe preeclampsia. Obstet Gynecol 83:357-361, 1994 37. Maasilta P, Bachour A, Teramo K, et al: Sleep-related disordered breathing during pregnancy in obese women. Chest 120:1448-1454, 2001 38. Usha Kiran TS, Hemmadi S, Bethel J, et al: Outcome of pregnancy in a woman with an increased body mass index. BJOG 112:768-772, 2005 39. Cedergren MI: Maternal obesity and risk of adverse pregnancy outcome. Obstet Gynecol 103:219-224, 2004 40. Iffy L, Veradi V, Jakobovits A: Common intrapartum denominators of shoulder dystocia Zentrabl Gynecol 116:33-37, 1994 41. Salihu HM, Kinniburgh BA, Aliyu MH, et al: Racial disparity in stillbirth among singleton, twin and triplet gestations in the United States. Obstet Gynecol 104:734-740, 2004 42. Bhasin TK, Brocksen S, Avchen RN, et al: Prevalence of four developmental disabilities among children aged 8 yearsMetropolitan Atlanta Developmental Disabilities Surveillance Program, 1996 and 2000. MMWR Surveill Summ 55:1-9, 2006 43. Wang X, Zuckerman B, Pearson C, et al: Maternal cigarette smoking, metabolic gene polymorphism, and infant birth weight. JAMA 287: 195-202, 2002 44. Yolton K, Dietrich K, Auinger P, et al: Exposure to environmental tobacco smoke and cognitive abilities among US children and adolescents. Environ Health Perspect 113:98-103, 2005 45. Volpe JJ: Overview: normal and abnormal human brain development. Ment Retard Dev Disabil Res Rev 6:1-5, 2000 46. Adams J, Barone S, LaMantia A, et al: Workshop to identify critical windows of exposure for childrens health: Neurobehavioral work group summary. Environ Health Perspect 108:533-544, 2000 (suppl 3) 47. Smulian JC, Ananth CV, Vintzileos AM, et al: Fetal deaths in the United States: inuence of high-risk conditions and implications for management. Obstet Gynecol 100:1183-1189, 2002 48. Simpson LL: Maternal medical disease: risk of antepartum fetal death. Semin Perinatol 26:42-50, 2002 49. Brenner B, Hoffman R, Blumenfeld Z, et al: Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost 83:693-697, 2000 50. Stephansson O, Dickman PW, Johansson A, et al: Maternal hemoglobin concentration during pregnancy and risk of stillbirth. JAMA 284:26112617, 2000 51. Simpson LL: Maternal medical disease: risk of antepartum fetal death. Semin Perinatol 26:42-50, 2002 52. Badawi W, Kurinczuk JJ, Keogh JM, et al: Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ 317:1549-1553, 1998

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1. Martin JA, Hoyert DL: The national fetal death le. Semin Perinatol 26:3-11, 2002 2. Goldenberg RL, Kirby R, Culhane JF: Stillbirth: a review. J Matern Fetal Med 16:79-94, 2004 3. Salihu HM, Aliyu MH, Rouse DJ, et al: Potentially preventable excess mortality among higher-order multiples. Obstet Gynecol 102:679-684, 2003 4. Mcclure EM, Nalubamba-Phiri M, Goldenberg RL: Stillbirth in developing countries. Int J Gynecol Obstet 94:82-90, 2006 5. Fretts RC: Etiology and prevention of stillbirth. Am J Obstet Gynecol 193:1923-1935, 2005 6. Salihu HM: Fetal loss repetition. Event memory hypothesis. Med Hypotheses 70:567-571, 2008 7. Sims ME, Turkel SB, Halterman G, et al: Brain injury and intrauterine death. Am J Obstet Gynecol 151:721-723, 1985 8. Odding E, Roebroeck ME, Stam HJ: The epidemiology of cerebral palsy: incidence, impairments and risk factors. Disabil Rehabil 28: 183-191, 2006 9. Carlsson M, Hagberg G, Olsson I: Clinical and aetiological aspects of epilepsy in children and cerebral palsy. Dev Med Child Neurol 45:371376, 2003 10. Bruck I, Antonuik SA, Spessatto A, et al: Epilepsy in children with cerebral palsy. Arq Neuropsiquiatr 59:35-39, 2001 11. Centers for Disease Control and Prevention: Racial/Ethnic trends in fetal mortalityUnited States, 1990-2000. MMWR Morb Mortal Wkly Rep 53:529-532, 2004 12. Centers for Disease Control and Prevention: National Center on Birth Defects and Developmental Disabilities. Available at: http://www. cdc.gov/ncbddd/bd/stillbirths.htm. Accessed July, 2007 13. Cnattingius S, Stephansson O: The epidemiology of stillbirth. Semin Perinatol 26:25-30, 2002 14. Pharoah PO, Cooke T, Johnson MA, et al: Epidemiology of cerebral palsy in England and Scotland, 1984-9. Arch Dis Child Fetal Neonatal Ed 79:F21-F25, 1998 15. Anonymous: The Scottish low birthweight study: I. Survival, growth, neuromotor and sensory impairment. Arch Dis Child 67:675-681, 1992 16. Evans P, Elliott M, Alberman E, et al: Prevalence and disabilities in 4 to 8 year olds with cerebral palsy. Arch Dis Child 60:940-945, 1985 17. Nordmark E, Hagglund G, Lagergren J: Cerebral palsy in southern Sweden I. Prevalence and clinical features. Acta Paediatr 90:12711276, 2001 18. Colver AF, Gibson M, Hey EN, et al: Increasing rates of cerebral palsy across the severity spectrum in north-east England 1964-1993. The North of England Collaborative Cerebral Palsy Survey. Arch Dis Child Neonatal Ed 83:F7-F12, 2000 19. Salihu HM, Emusus D, Aliyu ZY, et al: Survival of pre-viable infants in the United States. Wien Klin Wochenschr 117:324-332, 2005 20. Liu JM, Li S, Lin Q, et al: Prevalence of cerebral palsy in China. Int J Epidemiol 28:949-954, 1999 21. Winter S, Autry A, Boyle C, et al: Trends in the prevalence of cerebral palsy in a population-based study. Pediatrics 110:1220-1225, 2002 22. Vincer MJ, Allen AC, Joseph KS, et al: Increasing prevalence of cerebral palsy among very preterm infants: a population-based study. Pediatrics 118:e1621-e1626, 2006 23. Shy NE, Luthy DA, Bennett FC, et al: Effects of electronic fetal heart rate monitoring as compared with periodic auscultation on the neurologic development of premature infants. N Engl J Med 322:588-593, 1990 24. Clark SL, Hankins GDV: Temporal and demographic trends in cerebral palsyfact and ction. Am J Obstet Gynecol 188:628-633, 2003 25. Salihu HM, Shumpert MN, Slay M, et al: Childbearing beyond maternal age 50 and fetal outcomes in the United States. Obstet Gynecol 102: 1006-1014, 2003

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53. Nelson KB: Thrombophilias, perinatal stroke, and cerebral palsy. Clin Obstet Gynecol 49:875-884, 2006 54. Gunther G, Junker R, Strater R, et al: Symptomatic ischemic stroke in fullterm neonates: role of acquired and genetic prothrombotic risk factors. Stroke 31:2437-2441, 2000 55. Allen VM, Wilson RD, Cheung A: Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC); Reproductive Endocrinology Infertility Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC). Pregnancy outcomes after assisted reproductive technology. J Obstet Gynaecol Can 28:220-250, 2006 56. Wright VC, Chang J, Jeng G, et al: Assisted reproductive technology surveillanceUnited States, 2003. MMWR Surveill Summ 55:1-22, 2006 57. Jackson RA, Gibson KA, Wu YW, et al: Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol 103: 551-563, 2004 58. Helmerhorst FM, Perquin DA, Donker D, et al: Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ 328:261-265, 2004 59. Strmberg B, Dahlquist G, Ericson A, et al: Neurological sequelae in children born after in vitro fertilisation: a population-based study. Lancet 359:461-465, 2002 60. Hvidtjrn D, Grove J, Schendel DE, et al: Cerebral palsy among children born after in vitro fertilization: the role of preterm deliverya population-based, cohort study. Pediatrics 118:475-482, 2006 61. Greenwood R, Samms-Vaughan M, Golding J, et al: Past obstetric history and risk of perinatal death in Jamaica. Paediatr Perinat Epidemiol 8:40-53, 1994 (suppl 1) 62. Samueloff A, Xenakis EM, Berkus MD, et al: Recurrent stillbirth: significance and characteristics. J Reprod Med 38:883-886, 1993 63. Stillbirth recurrence in a population of relatively low-risk mothers. Paediatr Perinat Epidemiol 21:24-30, 2007 (suppl 1) 64. Hemminki K, Li X, Sundquist K, et al: High familial risks for cerebral palsy implicate partial heritable aetiology. Paediatr Perinat Epidemiol 21:235-241, 2007 65. Yokoyama Y, Shimizu T, Hayakawa K: Prevalence of cerebral palsy in twins, triplets and quadruplets. Int J Epidemiol 24:934-938, 1995 66. Scher AI, Petterson B, Blair E, et al: The risk of mortality or cerebral palsy in twins: a collaborative population-based study. Pediatr Res 52:671-681, 2002 67. Gadow EC, Castilla EE, Lopez Camelo J, et al: Stillbirth rate and associated risk factors among 869 750 Latin American hospital births 19821986. Int J Gynaecol Obstet 35:209-214, 1991 68. Smith GCS: Sex, birth weight, and risk of stillbirth in Scotland, 19801996. Am J Epidemiol 151:614-619, 2000

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69. Rivers JP, Crawford MA: Maternal nutrition and the sex ratio at birth. Nature 252:297-298, 1974 70. Ayromlooi J, Essman WB: Sex differences in fetal sheep adrenal steroidogenesis. Int J Gynaecol Obstet 17:3-5, 1978 71. Padbury JF, Hobel CJ, Lam RW, et al: Sex differences in lung and adrenal neurosympathetic development in rabbits. Am J Obstet Gynecol 141:199-204, 1981 72. Montano MM, Wang MH, Vom Saal SF: Sex differences in plasma corticosterone in mouse fetuses are mediated by differential placental transport from the mother and eliminated by maternal adrenalectomy or stress. J Reprod Fertil 99:283-290, 1993 73. Johnston MV, Hagberg H: Sex and the pathogenesis of cerebral palsy. Dev Med Child Neurol 49:74-78, 2007 74. Goldenberg RL, Thompson C: The infectious origins of stillbirth. Am J Obstet Gynecol 189:861-873, 2003 75. Wu YW, Escobar GJ, Grether JK, et al: Chorioamnionitis and cerebral palsy in term and near-term infants. JAMA 290:2677-2684, 2003 76. Wapner RJ, Lewis D: Genetics and metabolic causes of stillbirth. Semin Perinatol 26:70-74, 2002 77. Blair E, Al Asedy F, Badawi N, et al: Is cerebral palsy associated with birth defects other than cerebral defects? Dev Med Child Neurol 49: 252-258, 2007 78. Airas U, Heinonen S: Clinical signicance of true umbilical knots: a population-based analysis. Am J Perinatol 19:127-132, 2002 79. Collins JH: Umbilical cord accidents: human studies. Semin Perinatol 26:79-82, 2002 80. Redline RW: Clinical and pathological umbilical cord abnormalities in fetal thrombotic vasculopathy. Hum Pathol 35:1494-1498, 2004 81. Adelson P, Spurrett B, Trudinger B, et al: A New South Wales population-based study of stillbirths weighing 2,500 g or more. Aust NZ J Obstet Gynaecol 33:166-173, 1993 82. Redline RW, Wilson-Costello D, Borawski E, et al: Placental lesions associated with neurologic impairment and cerebral palsy in very lowbirth-weight infants. Arch Pathol Lab Med. 122:1091-1098, 1998 83. Fretts RC, Boyd ME, Usher RH, et al: The changing pattern of fetal death, 1961-1988. Obstet Gynecol 79:35-39, 1992 84. Huang DY, Usher RH, Kramer MS, et al: Determinants of unexplained antepartum fetal deaths. Obstet Gynecol 95:215-221, 2000 85. Cnattingius S, Haglund B, Kramer MS: Differences in late fetal death rates in association with determinants of small for gestational age fetuses: population based cohort study. BMJ 316:1483-1487, 1998 86. Divon MY, Haglund B, Nisell H, et al: Fetal and neonatal mortality in the postterm pregnancy: the impact of gestational age and fetal growth restriction. Am J Obstet Gynecol 178:726-731, 1998

Normal Fetal Physiology and Behavior, and Adaptive Responses with Hypoxemia
Chester B. Martin Jr, MD
The principal objective of antenatal testing is to detect fetal hypoxia before the fetus has suffered lasting harm. This article summarizes some of the mechanisms by which fetal oxygen consumption is maintained under normal conditions, and adaptations that occur in response to hypoxemia. Alterations in the fetal heart rate are prominent in the fetal response to hypoxemia and are the basis of some methods of antenatal testing. The principal mechanisms underlying these fetal heart rate changes are described. Adaptations in the distribution of blood ow that permit the fetus to deal with reduced oxygen levels are summarized. Developmental trends in fetal motility and behavior are outlined, and also how these are modied by fetal growth retardation and maternal diabetes. Fetal movements are suppressed during acute hypoxemia, but with gradually developing hypoxemia, normal movement patterns may continue until the fetus becomes acidemic. This may limit the use of these biophysical variables in antenatal testing. Semin Perinatol 32:239-242 2008 Elsevier Inc. All rights reserved. KEYWORDS fetus:physiology, hypoxemia, movements, behavior, well-being

he principal objective of most antenatal testing is to detect fetal hypoxemia before the fetus has suffered lasting harm or even death. Normal fetal physiology involves several adaptations that permit the fetus to achieve a level of O2 consumption similar to that in extrauterine life despite relatively low O2 tensions in fetal blood. Under normal conditions, in fact, O2 delivery to fetal tissues exceeds metabolic needs. Other adaptations occur in the fetal heart rate, the distribution of the fetal blood ow, and also fetal motility and behavior when fetal O2 levels are reduced. Most of these operate to favor fetal survival, at least when the insult is limited in severity and duration. Many of these latter adaptations can be detected clinically and can be useful in assessment of fetal well-being.

Adaptations that Contribute to Normal Fetal Oxygenation

The most important mechanism sustaining fetal O2 consumption at levels similar to those in extrauterine life is the

Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, School of Medicine and Public Health, University of WisconsinMadison, Madison, WI. Address reprint requests to Chester B. Martin Jr, MD, Division of MaternalFetal Medicine, 6 Center, Meriter Hospital, 202 South Park Street, Madison, WI 53715. E-mail: cbmartin@wisc.edu

maintenance of high blood ow rates in fetal tissues. These high ow rates are the result of the high fetal cardiac output250 to 300 mL/kg/min compared with approximately 75 mL/kg/min in a resting adult. Important contributors to the high fetal cardiac output are the high fetal heart rate and the central shunting that allows the fetal ventricles to work largely in parallel rather than in series. Central intracardiac shunting also directs the best fetal blood umbilical vein blood bypassing the fetal liver via the ductus venosus through the foramen ovale to the left heart for preferential distribution to the brain and myocardium. Other factors frequently cited in maintaining fetal oxygenation include high fetal hemoglobin concentrations and the O2 dissociation curve of fetal erythrocytes. The former applies mainly in late pregnancy. The higher O2 afnity of fetal erythrocytes, while favoring O2 loading in the placenta, operates in the other direction in fetal tissues. Changes in the fetal circulation play an important role in the fetal adaptation to hypoxemia. The changes include changes in the fetal heart rate and redistribution of the fetal cardiac output. The fetal cardiac output does not change during hypoxemia in the absence of signicant acidemia. In an intact fetus, the initial fetal heart rate response to sudden hypoxemia is slowing and increased variability. This is a chemoreceptor response mediated by the vagus nerve. As the hypoxemia is prolonged to 30 to 60 minutes, there is a gradual return of the heart rate toward or even above prehy239

0146-0005/08/$-see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2008.04.003

240 poxemic levels. This is the result of increasing levels of circulating epinephrine and norepinephrine, plus modulation of vagal activity by endogenous opiates.1 Although the gradual development of fetal tachycardia without preceding fetal heart rate slowing occurs clinically in some complicated pregnancies, tachycardia as an initial response to hypoxemia has not often been observed experimentally, perhaps because the rate of reduction of O2 tension has been too rapid. This explanation is supported by the observations of Nijland and associates: in a group of fetuses where the maternal fraction of inspired (FI) O2 was reduced very gradually, the fetal heart rate increased without an initial slowing.2 The role of the arterial chemoreceptors in the fetal circulatory response to acute hypoxemia has been demonstrated in experiments comparing the changes in fetal heart rate, blood pressure, and blood ow in the carotid and femoral arteries between intact fetuses and those subjected to carotid sinus denervation.3 In the intact fetuses, acute hypoxemia caused an abrupt fall in both fetal heart rate and femoral artery blood ow. The carotid sinus-denervated fetuses, on the other hand, showed no signicant change in fetal heart rate and only a gradual fall in femoral blood ow during the hour of hypoxemiaan effect of circulating vasoactive agents. Both groups showed a gradual rise in blood pressure and rather similar increases in carotid artery blood ow indicating local (brain blood ow) and circulating humoral (catecholamines, other vasoactive substances) mechanisms in those responses. Similar reex mechanisms are involved in the fetal heart rate response to phasic hypoxia produced by uterine contractions. This was investigated by the use of autonomic blocking agents in fetal sheep.4 Phasic hypoxemia was produced by 1-minute occlusions of the uterine blood ow, repeated every 3 minutes. This produced late fetal heart rate decelerations. Administration of atropine converted the decelerations to late accelerations, demonstrating an adrenergic sympathetic response normally masked by the vagal cardiodecelerator effect. This adrenergic component is important in supporting the fetal heart rate during hypoxemia, since hypoxemia during beta-adrenergic blockade results in profound slowing of the fetal heart rate and circulatory collapse. Simultaneous blockade with atropine, phentolamine, and propranolol eliminated the fetal heart rate responses to the phasic hypoxemia in nonacidemic fetuses. On the other hand, when a fetus was made severely acidemic (pH 6.96) by repeated periodic occlusions combined with sustained partial reduction of uterine blood ow, administration of atropine had no effect on the depth and duration of the late decelerations, demonstrating that under these conditions the decelerations were due to direct hypoxic depression of myocardial chronotropism. Some early observations in human fetuses showed that atropine reduced the amplitude of type 2 dips (late decelerations) but did not eliminate them.5 Thus, reex mechanisms are also involved in late decelerations in human fetuses. It is likely that late decelerations are largely reex at rst occurrence and progressively the result of cardiac depression with increasing hypoxia and acidosis.

C.B. Martin

Hypoxemia and Fetal Blood Flow Distribution

Most investigators have found no change in fetal cardiac output with hypoxemia, despite the initial decrease in fetal heart rate. The fetal circulation, however, responds to hypoxemia by redistribution of blood ow in favor of some organs and away from others (centralization of the circulation). This is accomplished by reex (mainly adrenergic), local (eg, nitric oxide, prostaglandins), and humoral (eg, catecholamines, angiotensin, vasopressin, serotonin) mechanisms. Those fetal organs showing increased blood ow during hypoxemia are brain, heart, and adrenals.6 In the brain, the increased ow per 100 g tissue was greatest for the brainstem and smallest for the cerebral hemispheres, with the cerebellum being intermediate. Despite the increased ow rates, O2 delivery to the cerebrum and cerebellum was decreased at the lowest O2 contents. The increases in blood ow to the myocardium and adrenals with hypoxemia were greater per 100 g tissue than those to any of the brain divisions. O2 delivery to the myocardium was maintained over the range of O2 content studied. Blood ow to most other fetal organs eg, kidney, spleen, pancreas, intestine, and carcass (skin and muscle)tended to remain relatively constant during mild hypoxemia and to decrease progressively as O2 content fell below about 1.5 mmol/L, or approximately 50 to 60% of the normal levels. In consequence, O2 delivery to those organs decreased progressively with decreasing O2 contents.6 Blood ow to the fetal lungs decreased rapidly and markedly below an O2 content of about 4 mmol/L, with little further change at lower O2 levels.6 Most investigators have found no change in fetal placental blood ow with hypoxemia. Studies in fetal sheep have demonstrated that the fetus can sustain its protective circulatory adjustments during prolonged hypoxemia (4 hours to 4 days) in the absence of progressive metabolic acidemia.7-10 Fetal O2 consumption is maintained and O2 delivery to the fetal brain is sufcient for metabolic requirements. With the development of progressive metabolic acidosis, these protective adaptations begin to fail, and at pH levels below 7.0 both whole fetal and cerebral O2 consumption fall substantially.7,10 That a similar pattern of blood ow redistribution occurs in hypoxemic human fetuses can be inferred from the brain and heart sparing seen in asymmetrical fetal growth retardation and from the pattern of organ damage following intrapartum asphyxia. Changes in blood ow patterns can also be detected in human fetuses by means of Doppler ultrasound. This will be discussed later in this seminar.

Fetal Motility and Behavior

Alternating periods of rest and activity can be observed in human fetuses from the time of just detectable movements until term.11,12 In general, normal fetuses spend two to three times as much time in activity than in rest. Before 20 weeks,

Normal fetal physiology and behavior

periods of absent movements are generally short, 6 minutes or less, but from 32 to 40 weeks the longest duration of absent movements in a cohort of healthy fetuses increased from 15.5 to 37 minutes.12 These developmental trends should be kept in mind during ultrasound examinations and when performing biophysical proles and antenatal cardiotocograms (nonstress tests). For example, a 35- to 40-minute period of fetal inactivity can be normal at 40 weeks but is probably not normal at 32 weeks and earlier. Fetal motilities are linked. For example, during epochs when the fetus is making body movements, it is also more likely to exhibit breathing and eye movements. It is also more likely to show a reactive fetal heart rate pattern with increased variability and accelerations. This linkage increases with increasing gestational age, especially after 36 weeks. Fetal breathing movements are about twice as likely to be present during epochs when the fetal heart rate pattern is reactive than during nonreactive periods.13 Late in the third trimester36 to 38 weeks in fetuses of normal multiparas and 38 to 40 weeks in healthy nulliparas fetal body movements, eye movements, and fetal heart rate patterns become even more tightly linked with the emergence of fetal behavioral states.12,14 Behavioral states are combinations of particular conditions of variables that are stable in time and recur. These combinations can be observed before states emerge, but to accept the presence of states there must be temporal stability of the combinations and simultaneous change of the state variables at state transitions. The emergence of fetal behavioral states is disturbed in growthretarded fetuses and fetuses of even well-controlled diabetic gravidas.15,16 From the standpoint of antenatal testing, the most obvious indication that behavioral states have not developed in late pregnancy is interruption of periods of fetal quiescence by brief bouts of fetal body movements. Fetal brain function can be assessed by observation of fetal motility, fetal behavior, and fetal heart rate variability. Opportunities include observation of the variety and vigor of fetal movements during ultrasound examinations or biophysical proles as well as antenatal cardiotocography. Healthy fetuses exhibit a varied repertoire of vigorous movements, whereas sick fetuses are more likely to show sluggish and stereotyped movements.

241 change in the biophysical variables until the fetuses began to develop metabolic acidemia.23 Thus, observation of fetal breathing and body movements during a biophysical prole does not guarantee that the fetus is not hypoxemic. Fetal heart rate accelerations are highly associated with fetal movements, but neuromuscular blockade with gallamine in fetal sheep only reduced the incidence of accelerations by 36%, with no change in their amplitude or duration.24 Therefore, the majority of fetal heart rate accelerations occur as a result of central nervous system output rather than as a consequence of fetal movements. The occurrence of fetal heart rate accelerations during cardiotocography is generally considered reassuring. However, during the course of fetal deterioration in chronically instrumented rhesus monkeys, fetal heart rate accelerations were still present at the onset of late fetal heart rate decelerations. At this time the fetal pO2 was decreased, but the pH was not. When fetal heart rate accelerations disappeared, the fetal pO2 had decreased further and metabolic acidemia was present.25 In fetal sheep, prolonged hypoxemia in the absence of acidemia led to an initial increase in the number of fetal heart rate accelerations, but after 12 hours the fetal heart rate had returned to normal patterns indistinguishable from those of normoxic fetuses.26 A reactive nonstress test, therefore, also does not rule out fetal hypoxemia. Thus, a provocative test such as the contraction stress test may detect developing fetal hypoxemia earlier than tests that depend on the biophysical variables of fetal movements and heart rate accelerations. Once acidemia has developed, the rate of fetal deterioration can accelerate. Lowering the pH shifts the oxyhemoglobin dissociation curve to the right, reducing O2-carrying capacity and aggravating the hypoxemia. In diabetic gravidas, moreover, hyperglycemia favors increased fetal lactate production, thus amplifying the acidemia. Deepening acidosis can lead eventually to circulatory failure and fetal death. This sequence is probably responsible for many unexplained stillbirths following apparently normal antenatal testing.

References
1. LaGamma EF, Itskovitz J, Rudolph AM: Effects of naloxone on fetal circulatory responses to hypoxemia. Am J Obstet Gynecol 143:933940, 1982 2. Nijland R, Jongsma HW, Nijhuis JG, et al: Arterial oxygen saturation in relation to metabolic acidosis in fetal lambs. Am J Obstet Gynecol 172:810-819, 1995 3. Giussani DA, McGarrigle HH, Spencer JA, et al: Effect of carotid denervation on plasma vasopressin levels during acute hypoxia in the lategestation fetal sheep. J Physiol 477:81-87, 1994 4. Martin CB Jr, de Haan J, van der Wildt B, et al: Mechanisms of late decelerations in the fetal heart rate: a study with autonomic blocking agents in fetal lambs. Eur J Obstet Gynecol Reprod Biol 9:361-373, 1979 5. Mendez-Bauer C, Poseiro JJ, Arellano-Hernndez G, et al: Effects of atropine on the heart rate of the human fetus during labor. Am J Obstet Gynecol 85:1033-1053, 1963 6. Peeters LLH, Sheldon RE, Jones MD Jr, et al: Blood ow to fetal organs as a function of arterial oxygen content. Am J Obstet Gynecol 135:637646, 1979 7. Rurak DW, Richardson BS, Patrick JE, et al: Oxygen consumption in the fetal lamb during sustained hypoxemia with progressive acidemia. Am J Physiol 258:R1108-R1115, 1990

Effects of Hypoxemia on Fetal Motility and Behavior

During acute hypoxemia produced experimentally in fetal sheep, the fetus powers down: Fetal movements, including trunk, limb, breathing, and eye movements, are suppressed, thus reducing fetal O2 needs, and the electrocortical activity pattern switches to a high-voltage synchronized one associated with lower O2 uptake.17-20 More prolonged observation, however, has demonstrated that the decrease in biophysical activity in response to moderate hypoxemia shows adaptation with return to normal levels after several hours despite continuing hypoxemia.21,22 Also, when fetal hypoxia was induced very gradually over 4 days, there was no signicant

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8. Rurak DW, Richardson BS, Patrick JE, et al: Blood ow and oxygen delivery to fetal organs and tissues during sustained hypoxemia. Am J Physiol 258:R1116-R1122, 1990 9. Bocking AD, White SE, Homan J, et al: Oxygen consumption is maintained in fetal sheep during prolonged hypoxaemia. J Dev Physiol 17: 169-174, 1992 10. Richardson BS, Rurak D, Patrick JE, et al: Cerebral oxidative metabolism during sustained hypoxaemia in fetal sheep. J Dev Physiol 11:3743, 1989 11. de Vries JI, Visser GHA, Prechtl HFR: The emergence of fetal behaviour. II. Quantitative aspects. Early Hum Dev 12:99-120, 1985 12. Nijhuis JG, Prechtl HFR, Martin CB Jr, et al: Are there behavioural states in the human fetus? Early Hum Dev 6:177-195, 1982 13. van Vliet MAT, Martin CB Jr, Nijhuis JG, et al: The relationship between fetal activity and behavioral states and fetal breathing movements in normal and growth-retarded fetuses. Am J Obstet Gynecol 153:582588, 1985 14. van Vliet MAT, Martin CB Jr, Nihjuis JG, et al: Behavioural states in the fetuses of nulliparous women. Early Hum Dev 12:121-135, 1985 15. van Vliet MAT, Martin CB Jr, Nihjuis JG, et al: Behavioral states in growth-retarded human fetuses. Early Hum Dev 12:183-197, 1985 16. Mulder EHJ, Visser GHA, Bekedam DJ, et al: Emergence of behavioural states in the fetuses of type-1 diabetic women. Early Hum Dev 15:231252, 1987 17. Boddy K, Dawes GS, Fisher R, et al: Foetal respiratory movements, electrocortical activity and cardiovascular responses to hypoxaemia and hypercapnia in sheep. J Physiol 243:599-618, 1974

C.B. Martin
18. Natale R, Clewlow F, Dawes GS: Measurement of fetal forelimb movements in the lamb in utero. Am J Obstet Gynecol 140:545-551, 1981 19. Bocking AD, Harding R: Effects of reduced uterine blood ow on electrocortical activity, breathing and skeletal muscle activity in fetal sheep. Am J Obstet Gynecol 154:655-662, 1986 20. Richardson BS, Patrick JE, Abdulijabbar H: Cerebral oxidative metabolism in fetal sheep: relationship to electrocortical activity state. Am J Obstet Gynecol 153:426-431, 1985 21. Koos BJ, Kitanaka T, Matsuda K, et al: Fetal breathing adaptation to prolonged hypoxaemia in sheep. J Dev Physiol 10:161-166, 1988 22. Bocking AD, Gagnon R, Milne KM, et al: Behavioral activity during prolonged hypoxemia in fetal sheep. J Appl Physiol 65:2420-2426, 1988 23. Richardson BS, Carmichael L, Homan J, et al: Electrocortical activity, electroocular activity, and breathing movements in fetal sheep with prolonged and graded hypoxemia. Am J Obstet Gynecol 167:553-558, 1992 24. Bocking AD, Harding R, Wickham PJ: Relationship between accelerations and decelerations in heart rate and skeletal muscle activity in fetal sheep. J Dev Physiol 1:47-54, 1985 25. Murata Y, Martin CB Jr, Ikenoue T, et al: Fetal heart rate accelerations and late decelerations during the course of intrauterine death in chronically catheterized rhesus monkeys. Am J Obstet Gynecol 144:218-223, 1982 26. Bocking AD, White S, Gagnon R, et al: Effect of prolonged hypoxemia on fetal heart rate accelerations and decelerations in sheep. Am J Obstet Gynecol 161:722-727, 1989

Fetal Movement Assessment

J. Frederik Fren, MD, PhD,*, Alexander E.P. Heazell, MBChB(Hons), Julie Victoria Holm Tveit, MD, Eli Saastad, RN, Rm, MSc,*, Ruth C. Fretts, MD, MPH, and Vicki Flenady, RN, Rm, MMedSc
Maternal perception of fetal movements is the oldest and most commonly used method to assess fetal well-being. While almost all pregnant women adhere to it, organized screening by fetal movements has seen variable popularity among health professionals. Early results of screening were promising and fetal movement counting is the only antepartum testing method that has shown effect in reducing mortality in a randomized controlled trial comparing testing versus no testing. Although awareness of fetal movements is associated with improved perinatal outcomes, the quest to dene a quantitative alarm limit to dene decreased fetal movements has so far been unsuccessful, and the use of most such limits developed for fetal movement counting should be discouraged. Semin Perinatol 32:243-246 2008 Elsevier Inc. All rights reserved. KEYWORDS fetal movement, fetal monitoring, methods, stillbirth

Fetal Movements as a Sign of Fetal Well-Being

aternal perception of fetal movements (FM) is the oldest and most commonly used method to assess fetal well-being.1 In most communities today, it is performed as unstructured screening to which almost all pregnant women adhere. Among women who have delivered a live-born baby, more than 99% agreed with the statement that it was important to them to feel the baby move every day.2 When they screen themselves as positive for decreased fetal movements (DFM), most will present their concerns to their health care provider with the expectation of further evaluations.
*Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway. Brigham and Womens Hospital, Division of Maternal-Fetal Medicine, Harvard Medical School, Boston, MA. Maternal and Fetal Health Research Group, University of Manchester, Manchester, UK. Department of Obstetrics and Gynecology, and Center for Perinatal Research, Rikshospitalet-Radiumhospitalet, Universty of Oslo, Oslo, Norway. Akershus University College, Lillestrm, Norway. Centre for Clinical Studies, Mater Mothers Hospital, School of Medicine, University of Queensland, Brisbane, Australia. This work was supported in part by The Norwegian Research Council, The Norwegian Womens Public Health Association, The Norwegian Medical Association, and Unexpected Child Death Society of Norway. Address reprint requests to J. Frederik Fren, MD, PhD, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo, Norway. E-mail: frederik.froen@fhi.no

There is little doubt that normal FM are a highly specic indicator of fetal viability, and conversely, as we discuss elsewhere in this issue of Seminars in Perinatology, that women presenting with DFM are at increased risk of perinatal complications, specically, stillbirth, fetal growth restriction, and associated conditions. Despite the popularity among women, formal or organized screening of FM has seen very variable popularity among health professionals through the last decades.1 One in six Australian obstetricians and one in three UK obstetricians believe screening of FM is of no benet,3 and many contemporary guidelines for antenatal care actively discourage the use of formal fetal movement counting (FMC).4,5 The purpose of FMC may be broadly divided into two understandings: on one hand, it may be an organized effort to promote awareness among pregnant women and ensure vigilance to FM on a daily basis, and thus, to support the ongoing screening by subjective perceptions of DFM. Alternatively, a more formal approach to FMC is to implement a structured chart together with specied quantitative alarm limits, or denitions of DFM. If these alarm limits are reached, women are expected to present their concerns regarding DFM to their health care provider. This latter approach to FMC was expected not only to bring along the improved awareness of FM but also to substitute fallible subjective maternal perceptions with objective measures of DFM. Neither of the two implementations of FMC would introduce a new screening but only attempt to improve the value of the existing self-screening performed by pregnant women. Although the latter un243

0146-0005/08/$-see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2008.04.004

244 derstanding of formal FMC has been favored in research, the design of the research undertaken has purposely or accidentally been unable to separate these two effects. In this article we aimed to review the effects of FMC in stillbirth prevention and to discuss which aspects of FMC may be benecial and which are probably not.

J.F. Fren et al
were not supposed to count FM, must have led to signicant contamination between the groups. Overall, perinatal mortality decreased during their study period, falling to 2.8/1000 compared with 4/1000 before the intervention. In the cluster-randomized trial, the mean time participants used to count their requested 10 FM was 162 minutes, and the alarm limit for when to contact health professionals was absence of FM for 1 day or less than 10 FM in 10 hours for two consecutive days. Only 60% of women were compliant with daily counting, and one in two compliant to the alarm limits among the 8.4% that reported DFM.14 In comparison, Moore and Piacquadio reported the same year that the mean time to count to 10 was 20 minutes with a compliance to counting of 94%, and 15.5% of women reported DFM. In their study, women were instructed to present for further evaluations if they had not perceived 10 FM within 2 hours.7 This evokes the next question: are these two interventions at all comparable? It is unlikely that both of these methodologies are equally suitable for screening purposes in total populations.

Studies of Stillbirth Prevention by Fetal Movement Counting

There have only been two studies in total populations (all pregnancies) and two studies in mixed low-risk and high-risk populations evaluating the effect of FMC for all versus no FMC. In the total population studies, both were conducted as prospective cohorts with a control period followed by an intervention period. In 1986, Westgate and Jamieson in New Zealand reported a relative risk of stillbirth of 0.76 (0.551.04), and 0.56 (0.35-0.90) for stillbirths perceived as avoidable.6 In 1989, Moore and Piacquadio in the US reported the rst part of their study, and in 1990, the nal results, with the equivalent risks as 0.42 (0.23-0.76) and 0.25 (0.07-0.88).7,8 The two studies in mixed populations were both conducted in single institutions. In 1983, Neldam in Denmark published the nal results of his randomized controlled trial9,10 as part of his PhD thesis from 1986.11 He reported a relative risk of stillbirth, and of avoidable stillbirths, of 0.25 (0.07-0.88) and 0.27 (0.08-0.93), respectively. This is, in fact, the only randomized controlled trial to date of antepartum testing of any kind versus no testing that has reported reduced mortality. However, as the randomization procedure was based on the mothers initial booking number (even or odd numbers), some investigators nd the study methodologically awed.12 We postulate that the probability of manipulation of the sequence in which pregnant women were referred and booked for antenatal care at the National Hospital of Copenhagen to be exceedingly small. In 1985 Lobb and coworkers in the UK reported the comparison of two units at Liverpool Maternity Hospital with competing protocols based on a preexisting difference in protocol, and the unit advocating FMC had the relative risks of 0.92 (0.6-1.35) and 0.86 (0.49-1.52).13 Yet, such encouraging results from cohort studies of whole populations and a randomized controlled trial have been overshadowed by negative ndings from a study that deserves further discussion. In 1989 Grant and coworkers published a large cluster-randomized controlled trial comparing FMC in a total population versus FMC only for risk pregnancies in the same population.14 They found no effect of their intervention. Although this was not a study of FMC compared with no FMC, it is without doubt the most referenced and inuential1 publication on FMC and is often misinterpreted as evidence against FMC in guidelines for antepartum care.4,5 The use of FMC in both arms of the study (for all versus for risk pregnancies), as well as the use of within hospital clusters, in which pregnant women in the same community were either urged to perform FMC or informed in writing about their inclusion in a FMC study in which they

Methods and Alarm Limits for Maternal Fetal Movement Counting

The concept of maternal FMC in the third trimester is based on the presumption that maternal perception of FM accurately reects fetal activity or at least gross fetal body or limb movements. A range of methodologies from piezo-electric crystals to ultrasound scanning have been used for objective measures of FM, but every method has its limitations and a gold standard is difcult to dene. In comparison with the ultrasound, the mean proportion of FM perceived by the mother ranges from 37 to 88%,15-23 and in comparison with other methodologies from 39 to 90%16,21,24-27; strong generalized FM were perceived in the higher end of this scale. With respect to generalized FM, there is close agreement between maternal and objective measures of FM, increasing with the number of fetal parts contributing to it.17-19,23 The one common factor in these studies is that maternal perception of FM was recorded while the mother was lying down and focusing on FM. This is the only situation in which we know that maternal perception of FM has a fair to good correlation with actual fetal activity. Outside such a setting, both the actual frequency of FM as well as the mothers ability to perceive them is affected by many factors such as maternal position,28,29 activity and exercise,28,30,31 stress,32-34 blood sugar,35,36 caffeine consumption,37 smoking,38 and obviously whether she pays attention to FM or not. Maternal counting while lying down and focusing on FM, preferably at a time of day when she knows that the baby is usually active, is thus the only method known to be a valid approximation to actual fetal activity. Counting while focusing on FM is also the only way women intuitively will perform FMC if they are concerned for DFM. Any alarm limits, or denitions of DFM, associated with such FMC should

Fetal movement assessment

therefore be based on data from studies of focused counting in a population equivalent to the one being screened. Many denitions of DFM to be used in conjunction with formal FMC have been proposed, ranging from total absence of FM for a whole day39,40 to less than 10 FM in 2 hours,7 based on time to count ranging from 12 hours41 to a median of 15 minutes.42 Most of the early DFM denitions were based on the data from Daily Movement Counts,41 in which small groups of high-risk women in hospital were required to note FM through both rest and activities through 12 hours, although later versions reduced these to shorter or repeated intervals. The limits calculated from these materials were not primarily developed for screening purposes but were simply cutoff limits identifying death and severe morbidity in highrisk patients with an average fetal mortality of 5%.39,40,43,44 In 1976 and 1977 Pearson published the new concept of Count to 10 or Cardiff method.44,45 This was initially based on Daily Movement Counts as well, and this count as you go method was used in the large randomized controlled trial from 1989 explaining the extreme alarm limits and long mean time to count to 10 in this study compared with the mean time to count to 10 in focused counting of approximately 20 minutes.7,46,47 The only denition of DFM based on focused counting data from a total population, and then subsequently tested as a screening tool in focused formal FMC in a total population, is the rule of 10 FM within 2 hours from the study by Moore and Piacquadio.7 In their study, this reected approximately 5 SD from the mean and corresponds approximately to the 95th percentile from Valentin and coworkers.47 This is currently the recommended method for FMC by the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists.48 With a short time needed to perform counting for normal pregnancies, it has the highest compliance and acceptance rates.46 While 10 FM within 2 hours seems to be the only validated denition of DFM for focused counting, our surveys from Norway, UK, and Australia indicate that this denition has little support among obstetricians. The most highly approved denitions of DFM are 10 movements in 10 hours or other limits derived from the obsolete Daily Movement Counts.3,49 If women perform focused counting, such limits represent extreme deviations from normality, and adhering to them may cause more harm than good. Although the four studies comparing formal FMC versus no counting, including a randomized controlled trial, strongly suggested benet, none of them have actually demonstrated that their denition of DFM was benecial. None of these studies prevented women from presenting with their own subjective perception of DFM, and the benecial effects reported may have resulted from a combination of high awareness and maternal common sense in terms of dening DFM. Indeed, the fact that FMC versus no counting seems to be benecial irrespective of the chosen denition of DFM would support the hypothesis that benet was derived from increased maternal vigilance regarding FM. When awareness, vigilance, and fetal movement counting is to be promoted, we have suggested that a maternal perception of signicant and

245 sustained reduction in fetal activity should remain the main denition of DFM. Any alarm limits, as 10 FM in 2 hours, should only be for guidance as a rule of thumb.

Any Future for Formal Fetal Movement Counting?

While self-screened women who present with concerns for DFM do manage to identify a high-risk population, the ongoing fetal movement screening overall still achieves limited success. An important limitation to the efcacy of screening using FM may be substandard management of mothers concerns for DFM, as we discuss elsewhere in this issue of Seminars in Perinatology. Currently, far too many women do not seem to appreciate the importance of fetal activity, and stillbirths are often preceded by long periods of decreased or absent FM.50,51 Promoting awareness by recommending women to count FM on a daily basis has been associated with signicant benets, and the full potential of this has yet to be seen. On the other hand, formal FM counting with a dened quantitative limit for when women should be subjected to further evaluation of fetal well-being cannot be recommended at this time. Such a single limit, that would be better than a maternal perception of DFM, probably does not exist due to too large interpersonal variations.52 Even the currently best available quantitative denition of DFM, 10 FM in 2 hours, may be of little benet as a screening tool. From a total population in Norway, we have collected 1200 FM charts where the mother has indicated the daily time to count to 10 at a convenient time of day, starting with the rst perceived FM. By this method, the mean time to count to 10 is less than 10 minutes. The limit of 10 FM in 2 hours in the preterm period of the third trimester is indeed associated with odds ratios of 5.5 (P 0.001), 3.0 (P 0.024), and 2.4 (P 0.057) for preterm birth, emergency cesarean section, and a birth weight centile below 10, respectively. However, the sensitivity of this indicator in predicting such events is as low as 12, 7, and 6%, respectively, and the area under the curve remains insignicant in receiver operating characteristic curves. For future FMC screening methodologies to exploit the full potential of maternal perceptions of FM as a sign of fetal well-being, signicant research efforts must be put into the understanding of which changes in perceived fetal activity are associated with good and adverse outcomes of pregnancy.

References
1. Fren JF: A kick from withinfetal movement counting and the cancelled progress in antenatal care. J Perinat Med 32:13-24, 2004 2. Saastad E, Ahlborg T, Fren JF: Maternal awareness towards fetal activity associated with SGA. J Midwifery Womens Health 2008 (in press) 3. Heazell AE, Green M, Wright C, et al: Midwives and obstetricians knowledge and management of women presenting with decreased fetal movements. Acta Obstet Gynecol Scand 87:331-339, 2008 4. National Collaborating Centre for Womens and Childrens Health: Antenatal CareRoutine Care for the Healthy Pregnant Woman (ed 2). London, UK, RCOG Press, 2008

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5. Klovning, A, Backe B, Eide BI, et al: Sosial- og Helsedirektoratet. Retningslinjer for svangerskapsomsorgen. Oslo, Sosial- og Helsedirektoratet, 2005 6. Westgate J, Jamieson M: Stillbirths and fetal movements. NZ Med J 99:114-116, 1986 7. Moore TR, Piacquadio K: A prospective evaluation of fetal movement screening to reduce the incidence of antepartum fetal death. Am J Obstet Gynecol 160:1075-1080, 1989 8. Moore TR, Piacquadio K: Reply to Study results vary in count-to-10 method of fetal movement screening. Am J Obstet Gynecol 163:264265, 1990 9. Neldam S: Fetal movements as an indicator of fetal well-being. Lancet 1:1222-1224, 1980 10. Neldam S: Fetal movements as an indicator of fetal well-being. Dan Med Bull 30:274-278, 1983 11. Neldam S: Fetal movements as an indicator of fetal well-being. University of Copenhagen, 1986 12. Mangesi L, Hofmeyr GJ: Fetal movement counting for assessment of fetal well-being. Cochrane Database of Systematic Reviews (Issue 1), 2007 13. Lobb MO, Beazley JM, Haddad NG: A controlled study of daily fetal movement counts in the prevention of stillbirths. J Obstet Gynaecol 6:87-91, 1985 14. Grant A, Valentin L, Elbourne D, et al: Routine formal fetal movement counting and risk of antepartum late death in normally formed singletons. Lancet 2:345-349, 1989 15. Gettinger A, Roberts AB, Campbell S: Comparison between subjective and ultrasound assessments of fetal movement. BMJ 2:88-90, 1978 16. Valentin L, Marsal K, Lindstrom K: Recording of foetal movements: a comparison of three methods. J Med Eng Technol 10:239-247, 1986 17. Hertogs K, Roberts AB, Cooper D, et al: Maternal perception of fetal motor activity. BMJ 2:1183-1185, 1979 18. Rayburn WF: Clinical signicance of perceptible fetal motion. Am J Obstet Gynecol 138:210-212, 1980 19. Schmidt W, Cseh I, Hara K, et al: Maternal perception of fetal movements and real-time ultrasound ndings. J Perinat Med 12:313-318, 1984 20. Schmidt W, Cseh I, Hara K, et al: Maternal perception, tocodynamometric ndings and real-time ultrasound assessment of total fetal activity. Int J Gynaecol Obstet 22:85-90, 1984 21. Sorokin Y, Pillay S, Dierker LJ, et al: A comparison between maternal, tocodynamometric, and real-time ultrasonographic assessments of fetal movement. Am J Obstet Gynecol 140:456-460, 1981 22. Neldam S, Jessen P: Fetal movements registered by the pregnant woman correlated to retrospective estimations of fetal movements from cardiotocographic tracings. Am J Obstet Gynecol 136:1051-1054, 1980 23. Prenzlau P, Bayer H, Hoffmann H: [Fetal movement patterns in the external cardiotocography and their interpretation by simultaneous ultrasound observation]. Zentralbl Gynakol 105:972-976, 1983 24. Ehrstrom C: Fetal movement monitoring in normal and high-risk pregnancy. Acta Obstetr Gynecol Scand Suppl 1-32, 1979 25. Sadovsky E, Mahler Y, Polishuk WZ, et al: Correlation between electromagnetic recording and maternal assessment of fetal movement. Lancet 1:1141-1143, 1973 26. Sadovsky E, Polishuk WZ, Yaffe H, et al: Fetal movements recorder, use and indications. Int J Gynaecol Obstet 15:20-24, 1977 27. Johnson TRB, Jordan ET, Paine LL: Doppler recordings of fetal movement. 2. Comparison with maternal perception. Obstet Gynecol 76:4243, 1990 28. Cito G, Luisi S, Mezzesimi A, et al: Maternal position during non-stress test and fetal heart rate patterns. Acta Obstet Gynecol Scand 84:335338, 2005

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29. Minors DS, Waterhouse JM: The effect of maternal posture, meals and time of day on fetal movements. Br J Obstet Gynaecol 86:717-723, 1979 30. Manders MA, Sonder GJ, Mulder EJ, et al: The effects of maternal exercise on fetal heart rate and movement patterns. Early Hum Dev 48:237-247, 1997 31. Winn HN, Hess O, Goldstein I, et al: Fetal responses to maternal exercise effect on fetal breathing and body movement. Am J Perinatol 11:263-266, 1994 32. DiPietro JA, Costigan KA, Gurewitsch ED: Fetal response to induced maternal stress. Early Hum Dev 74:125-138, 2003 33. Sjostrom K, Valentin L, Thelin T, et al: Maternal anxiety in late pregnancy: effect on fetal movements and fetal heart rate. Early Hum Dev 67:87-100, 2002 34. Groome LJ, Swiber MJ, Bentz LS, et al: Maternal anxiety during pregnancy: effect on fetal behavior at 38 to 40 weeks of gestation. J Dev Behav Pediatr 16:391-396, 1995 35. Eller DP, Stramm SL, Newman RB: The effect of maternal intravenous glucose-administration on fetal activity. Am J Obstet Gynecol 167: 1071-1074, 1992 36. Gelman SR, Spellacy WN, Wood S, et al: Fetal movements and ultrasound: effect of maternal intravenous glucose administration. Am J Obstet Gynecol 137:459-461, 1980 37. Devoe LD, Murray C, Youssif A, et al: Maternal caffeine consumption and fetal behavior in normal 3rd-trimester pregnancy. Am J Obstet Gynecol 168:1105-1112, 1993 38. Graca LM, Cardoso CG, Clode N, et al: Acute effects of maternal cigarette smoking on fetal heart rate and fetal body movements felt by the mother. J Perinat Med 19:385-390, 1991 39. Leader LR, Baillie P, Van Schalkwyk DJ: Fetal movements and fetal outcome: a prospective study. Obstet Gynecol 57:431-436, 1981 40. Sadovsky E, Ohel G, Havazeleth H, et al: The denition and the significance of decreased fetal movements. Acta Obstet Gynecol Scand 62(5): 409-413, 1983 41. Sadovsky E, Yaffe H: Daily fetal movement recording and fetal prognosis. Obstet Gynecol 41:845-850, 1973 42. Valentin L, Marsal K: Fetal movement in the third trimester of normal pregnancy. Early Hum Dev 14:295-306, 1986 43. Liston RM, Cohen AW, Mennuti MT, et al: Antepartum fetal evaluation by maternal perception of fetal movement. Obstet Gynecol 60:424426, 1982 44. Pearson JF, Weaver JB: Fetal activity and fetal well-being: an evaluation. BMJ 1:1305-1307, 1976 45. Pearson JF: Fetal movementsa new approach to antenatal care. Nursing Mirror Midwives J 144:49-51, 1977 46. Smith CV, Davis SA, Rayburn WF: Patients acceptance of monitoring fetal movement. A randomized comparison of charting techniques. J Reprod Med 37:144-146, 1992 47. Valentin L, Lofgren O, Marsal K, et al: Subjective recording of fetal movements. I. Limits and acceptability in normal pregnancies. Acta Obstet Gynecol Scand 63:223-228, 1984 48. Gilstrap LC, Oh W: Guidelines for Perinatal Care. Washington, DC, AAP and ACOG, 2002 49. Saastad E, Fren JF: [Reduced fetal movements clinical management, recommendations and information]. Tidsskr Nor Laegeforen 125: 2627-2630, 2005 50. Fren JF, Arnestad M, Frey K, et al: Risk factors for sudden intrauterine unexplained death: epidemiologic characteristics of singleton cases in Oslo, Norway, 1986-1995. Am J Obstet Gynecol 184:694-702, 2001 51. Maleckiene L, Nadisauskiene R, Bergstrom S: Socio-economic, demographic and obstetric risk factors for late fetal death of unknown etiology in Lithuania: a case-referent study. Acta Obstet Gynecol Scand 80:321-325, 2001 52. Valentin L: Fetal movements in late pregnancy. Detection of fetal jeopardy by objective recording and by maternal counting. University of Lund, 1986

Antenatal Fetal Assessment: Contraction Stress Test, Nonstress Test, Vibroacoustic Stimulation, Amniotic Fluid Volume, Biophysical Prole, and Modied Biophysical ProleAn Overview
Lawrence D. Devoe, MD
Antenatal fetal assessment was introduced into the United States in the 1970s. The initial antepartum test, the oxytocin challenge test, later renamed as the contraction stress test, became the gold standard for fetal surveillance. Its labor intensive requirements and contraindications made it inapplicable to some high-risk pregnancies. Other testing schemes were developed subsequently, the nonstress test and its alternative, vibroacoustic stimulation, the semiquantitative assessment of amniotic uid volume, the biophysical prole and its modied version, the modied biophysical prole. This article is a brief critical review of these testing methods and focuses on the following: (1) physiologic bases; (2) testing methodologies; (3) supportive evidence from randomized controlled and observational trials; and (4) areas needing further investigation. Semin Perinatol 32:247-252 2008 Elsevier Inc. All rights reserved. KEYWORDS antepartum testing, contraction stress test, nonstress test, amniotic uid, biophysical prole

he modern era of fetal assessment was ushered in by the use of continuous electronic fetal monitoring (EFM) during the labors of near-term patients. Intrapartum fetal heart rate (FHR) patterns were correlated with neonatal outcomes and specic FHR patterns emerged that provided surrogate measures of fetal oxygenation. A consensus was reached eventually on those patterns predictive of adequate fetal oxygenation or of fetal hypoxia and acidosis.1 Intrapartum EFM ndings led to the initial fetal assessment test that was used in the United States, the oxytocin challenge test (OCT).2 The increasing use of obstetric ultrasonography led to other fetal surveillance methods such as the biophysical prole (BPP). The goals of fetal assessment are to identify fetuses that are well oxygenated or at risk for hypoxia and to enable appropriate intervention so that perinatal mortality and morbidity can be prevented or reduced. This article will describe the basis for these assessment tests, review the evidence support-

ing their use, and indicate areas of concern and opportunities for further research.

Contraction Stress Test

The contraction stress test (CST), formerly known as the OCT, was introduced in the early 1970s.2 It was based on intrapartum observations that linked recurrent late FHR decelerations with fetal hypoxemia. Previous studies3 had shown that as fetal arterial pO2 fell below 20 mm Hg, most uterine contractions would generate a late FHR deceleration. The underlying mechanism for this event is a bradycardic response to transient systemic hypertension provoked by a reduction in arterial oxygen levels. As developed by Freeman and colleagues,4 the CST was performed with intravenous oxytocin until at least three moderate or strong contractions per 10 minutes were generated in a 20-minute window. Later, maternal nipple stimulation was substituted for intravenous oxytocin. Except for a possibly higher risk of uterine hyperstimulation, the nipple stimulation test has performed similarly to the standard CST.5,6 Test classication is as follows: Negative: No late or signicant variable decelerations Positive: Late decelerations with at least 50% of contractions 247

Section of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta, GA. Address reprint requests to Lawrence D. Devoe, MD, Department of Obstetrics and Gynecology, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912. E-mail: ldevoe@mail.mcg.edu

0146-0005/08/$-see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2008.04.005

248 Suspicious: Intermittent late or variable decelerations Hyperstimulation: Decelerations with contractions 90 seconds duration or 2-minute frequency Unsatisfactory: Fewer than three contractions per 10 minutes or an uninterpretable tracing A positive CST could result from maternal conditions (cardiorespiratory disorders, hypovolemia, uterine hyperstimulation) or fetal conditions (placental insufciency, umbilical cord compression). Variable decelerations prompt ultrasound evaluation of the amniotic uid volume and umbilical cord localization.7 Equivocal tests are usually repeated within 24 hours unless other indications for delivery are present. Management of preterm pregnancies with positive CST results require individualization based on the presence or absence of reactivity and fetal maturity.8 Nonreactive positive CSTs correlate well with fetal growth restriction, increased incidence of late decelerations in labor, and low 5-minute Apgar scores.9 In a prospective observational cohort study, Freeman and coworkers noted a very low rate of false-negative tests, ie, risk of fetal death within 1 week of a negative CST.10 False-positive rates, ie, delivery of an unaffected infant after a positive CST, have been estimated at approximately 30%.9 Few direct comparisons of the CST with other testing methods such as the nonstress test (NST) or BPP have been obtained through prospective observational studies.11-13

L.D. Devoe
accelerations. The criteria for nonreactivity varied initially.18 Current test criteria typically consider an NST to be reactive if there are two accelerations exceeding 15 beats per minute amplitude and 15 seconds duration in a 20-minute window for term pregnancies and 10 beats per minute amplitude and 10 seconds duration for gestational ages below 32 weeks.9 Nonreactivity may be associated with three differing scenarios which fail to meet reactivity criteria, progressing from the presence of accelerations of inadequate amplitude or frequency through the absence of accelerations in the presence of fetal movements (uncoupling) to the complete absence of accelerations and fetal movements. This uncoupling phenomenon has been well characterized by several groups.19,20 Nonreactivity may be associated with prolonged fetal sleep states, immaturity, maternal ingestion of sedatives, and fetal cardiac or neurologic anomalies. Cumulative studies of NST performance suggest a false-negative rate of 0.3% within 1 week of a reactive NST and a false-positive rate of 50%.18 There have been four randomized controlled trials, containing fewer than 1500 patients in which study groups received NSTs and control groups received standard care.21 A meta-analysis did not show use of the NST reduced rates of perinatal death or neonatal seizures. Two prospective trials have compared the NST to the CST.11,12 Freeman and colleagues, reporting on more than 6000 patients,11 found that the CST provided better prediction of fetal health (false-negative rate of 0.4/1000) than the NST (false-negative rate of 3.2/1000); however, this study was heavily weighted toward the CST as a primary method by a 3:1 ratio. Devoe and coworkers studied nearly 1300 patients who received either twice-weekly NSTs or weekly CSTs.12 No perinatal deaths were reported within 1 week of either a negative CST or reactive NST.

Summary
The CST was the rst important antepartum assessment test used in the United States. It has been used less often after other biophysical testing modalities were introduced, eg, the NST, the BPP, and Doppler velocimetry. Most supportive evidence for use of the CST is based on Level II-2 and II-3 data. It is associated with a very low false-negative rate of estimated at 0.04% (Level II-1) evidence and false-positive rate estimated at 30% (Level II-3).

Vibroacoustic Stimulation (VAS)

A variation on the standard NST evolved during the 1980s and was based on previous observations that sound and vibratory stimuli could elicit changes in FHR baseline.22 Brief exposure to a vibroacoustic signal (producing 82 decibels at 1 meter in air) has been shown to reduce testing time and the incidence of false nonreactive NSTs in otherwise healthy fetuses.22 This response is present throughout the third trimester and results in a typical increase in FHR baseline within 10 seconds of at least 10 bpm for at least 180 seconds.23,24 A positive response is dened as the rapid occurrence of a qualifying acceleration following VAS. While data are limited, fetal exposure to VAS does not appear to be associated with adverse long-term effects on child development.25 Positive (reactive) VAS tests appeared comparable to standard reactive NSTs26 and negative CSTs.27 Perinatal outcomes following positive VAS appear to be similar to those associated with reactive NSTs, while testing time was shorter with VAS.28 A meta-analysis of the trials comparing VAS and NST conrmed that the incidence of nonreactive tests and test duration were reduced. Testing efcacy could not be established due to the limited sample sizes enrolled.29

The Nonstress Test

It was noted that the presence of FHR accelerations modied the signicance of an apparently positive CST14 and usually resulted in the delivery of nonhypoxic infants. The presence of two accelerations in a 20-minute window predicted a negative CST in most cases and formed the basis for the most widely used test reactivity criteria.15 Other investigators16,17 studied resting antepartum FHR baseline tracings and showed that the presence of accelerations was associated with a low likelihood of fetal compromise, while their absence increased the risk of adverse perinatal outcomes (hypoxia, acidosis, growth restriction, placental insufciency, and anomalies). The conventions of the NST evolved during a number of studies performed during the late 1970s and early 1980s as summarized by Devoe.18 NST reactivity occurs through an autonomic neural linkage between peripheral fetal activity and midbrain cardioregulatory centers, which strengthens as the fetus matures. At term, nearly 90% of fetal movements elicit reactive

Antenatal fetal assessment

249 cient if AFI exceeds 8 cm, while twice weekly testing should apply to pregnancies in which AFI is below 5 cm. More rigorous assessment of AFV as an independent predictor of perinatal outcome is limited. Few studies have compared the relative merits of either MVP or AFI for predicting adverse perinatal outcome. Chauhan and coworkers44 surveyed 18 studies with more than 10,000 patients. A criterion of AFI 5 cm predicted a 2.2-fold increased risk for cesarean delivery and a 5.5-fold increased risk for 5-minute Apgar score below 3. In a prospective trial of BPP using either MVP or AFI, Magann and colleagues45 found that MVP yielded a lower frequency of oligohydramnios and equivalent prediction of cesarean delivery for fetal distress. These investigators also compared three criteria for oligohydramnios: AFI 5 cm and two nomograms for AFI below the 5th percentile for gestational age.39 None of these criteria effectively predicted the risk of cesarean delivery for fetal distress, 5-minute Apgar score below 3, umbilical artery pH 7.00, or birth weight below the 5th percentile.

Summary
Level I evidence supporting the NSTs use comes from limited trials performed in an early era of antepartum testing. Most supportive data come from case control trials (Level II-2) or retrospective cohort analyses (Level II-3). Compared with the CST, most available evidence (Level II-3) suggests that the NST has higher false-negative and false-positive rates. The rate of false nonreactivity can be reduced by VAS, extending the observation period beyond 20 minutes to account for fetal sleep states,30 and using gestational age-specic criteria for preterm gestations.31 A recent overview suggests that use of the NST in antepartum care of high-risk patients is associated with an apparent reduction in stillbirths (Level II-2, Level II-3).32

Amniotic Fluid Volume (AFV) Assessment

AFV evaluation began in the early 1980s but has rarely been used as a sole fetal assessment method. AFV uctuations tend to occur more gradually than do the other dynamic measures of fetal status; therefore, AFV assessment has been used to reect a chronic measure of the intrauterine environment.33 In the third trimester, AFV is the byproduct of fetal urination, gastrointestinal motility, tracheal efux, and amniotic membrane transfer to and from fetal and maternal water compartments. The historic gold standard for AFV measurement uses dye-dilution determinations obtained through amniocentesis, an approach not feasible for repeated measurements during pregnancy. Semiquantitative estimates of AFV using ultrasound measurements of AF pockets became part of BPP testing in the early 1980s.34 Two common approaches for estimating AFV have evolved: maximum vertical pocket (MVP) and amniotic uid index (AFI).35 Nomograms for semiquantitative AFV have been developed also for the course of normal pregnancy.36 Both MVP and AFI have been correlated with actual AFV as measured with dye dilution.37 These estimates of AFV tend to correlate well with actual AFV within the normal range but over- and underestimate the extremes of AFV, oligohydramnios, and polyhydramnios, respectively. With this understanding, AFI and MVP have been used as markers for intrauterine condition rather than as measures of actual AFV. Although MVP was the initial method of assessing AFV,38 Rutherford and coworkers developed the four-quadrant AFI35 and this method has achieved ascendancy in current practice. Alternative schemes using gestational-age nomograms have also been studied.39 Early observational studies correlated adverse perinatal outcomes with MVPs 2 cm and showed increased risks of congenital anomalies, fetal growth restriction, and perinatal death.40 Although a number of adverse conditions can reduce AFV, prolonged gestation exceeding 41 or 42 weeks has been the best studied of these indications for AFV assessment.41 Using a criterion of AFI above or below 8 cm, studies by Lagrew and coworkers42 and Wing and coworkers43 suggest that at less than 41 weeks gestation, weekly testing is suf-

Summary
Varying thresholds and standards have been used for semiquantitative AFV estimation. The best data (Level II-2 and II-3) suggest that MVP and AFI are similar predictors of adverse perinatal outcomes but neither is an effective sole observation for fetal assessment.

Fetal Biophysical Prole

The BPP was developed in the early 1980s as evaluation of AFV and fetal breathing, body, and reex movements could be obtained with real-time ultrasound systems. Manning and coworkers34 reported on a multiple parameter fetal testing scheme that combined a standard NST with real-time ultrasound observation of fetal breathing, body movements, reex activity, and AFV estimation. The BPP was assigned a score ranging from 0 to 10 based on the criteria established for each parameter: (1) Nonstress test, reactive or nonreactive; (2) fetal breath movements, present or absent for 30 seconds; (3) fetal body movements, present or absent; (4) fetal reex movements, present or absent; (5) AFV, above threshold for oligohydramnios. It was proposed that either acute hypoxia (NST, breathing, or movement) or chronic hypoxia (reex activity, AFV) could alter each parameter predictably. Vintzileos and coworkers46 hypothesized that hypoxia affect the neurologic centers responsible for biophysical behavior in an order inverse to the timing of their maturation. Subsequent observations by this group were consistent with this hypothesis.47 Based on the observations of Manning,48 score has been correlated with the risk of intrauterine asphyxia or death and recommended clinical response obtained from two decades of observation (Level II-3).49-52 This series of nearly 90,000 patients suggests that the BPP has a false-negative rate of 0.6/1000, based on a weekly interval between normal tests. The BPP has a false-positive rate of approximately 50%.53

250 Timing of the initiation of the BPP has varied, although most data come from testing after 30 weeks gestation.54 A weekly testing interval has been recommended following a normal BPP score9; however, prospective trials to support this approach are lacking. Consequently, individualization of testing intervals for specic high-risk conditions has been recommended.48 Rigorous trials of the efcacy of biophysical testing have been limited and compared the full BPP to the NST alone.2 Meta-analysis of these trials55 does not show that use of the BPP signicantly reduced perinatal mortality or morbidities. Nageotte and coworkers56 compared the BPP to the CST for primary surveillance and found the BPP to provide comparable performance with fewer interventions. This study was not powered to address the prevention of perinatal death.

L.D. Devoe
Table 1 Test IndicationsPregnancies at Highest Risk for Intrauterine Asphyxia Obstetric Postdates Growth retardation Previous stillbirth Decreased fetal movement Pregnancy-induced hypertension Premature rupture of membranes Discordant twins (20%) Cholestasis of pregnancy Rh-isoimmunization Oligohydramnios (5 cm) Polyhydramnios (24 cm) Medical Diabetes Chronic hypertension Cardiac disease Renal disease Thyroid disease SLE Thrombophilias

Summary
There is considerable Level II-2 and Level II-3 evidence to support the BPP as an alternative to the CST or NST for primary fetal surveillance. The BPP appears to have falsenegative rates similar to those of the CST, although direct comparisons are very limited. Putative advantages of full BPP testing are its noninvasiveness, potential for observation of fetal anatomy, and parameters that reect acute and chronic responses to fetal hypoxia. Conversely, it requires more operator skill and time than does the NST or AFV assessment alone.

the MBPP and CST were similar.13 The largest observational series was reported by Miller and coworkers54on more than 15,000 patients undergoing more than 50,000 MBPPs. Their false-negative rate was 0.8/1000; their false-positive rate was 60%.

Summary
Level II-2 and Level II-3 evidence suggest that the MBPP has efcacy similar to the CST and full BPP. More rigorous prospective and adequately powered trials are still lacking.

Modied Biophysical Prole

Given the relative labor-intensiveness of the standard BPP, interest in developing a simpler screening test grew during the 1980s. Termed the modied BPP (MBPP), this scheme took advantage of two biophysical parameters for reecting acute fetal oxygenation and acid-base balance (NST) and chronic fetal oxygenation (AFV). The NST is believed to be the rst parameter usually affected by hypoxia,49 while AFV decreases gradually when perfusion to the brain and heart is increased and renal blood ow is reduced. This model, consistent with the pathophysiology of fetal growth restriction, was supported by Manning and coworkers, who showed a geometric increase in fetal death as single MVP measurements declined from 2.0 cm.57 The standards for reactivity and AFV estimation in the MBPP are similar to those of the full BPP. The MBPP has become increasingly popular with surprisingly little objective data on its efcacy. An early study of postdates pregnancy compared the MBPP to standard FHR testing, followed by the addition of fetal movement elements of the full BPP, and nally the addition of AFV estimation.58 The addition of AFV estimation appeared to make the greatest improvement in test efcacy. In this study, the MBPP compared favorably to the CST as a primary screening test. Eden and colleagues59 supported the use of the MBPP as a primary screening test with the full BPP as a backup test. In a retrospective evaluation, of the false-negative rates of the MBPP and the CST, Nageotte and coworkers showed that false-negative rates of

General Testing Considerations: Areas of Concern

Indications for Testing
Table 1 lists indications commonly recommended for antenatal fetal surveillance.8 Although it is assumed that antepartum tests will have similar value in for all indications in determining the risk of adverse perinatal outcome, Kontopoulos and Vintzileos have questioned this assumption.60 Devoe and coworkers tested 1000 consecutive patients with common high-risk indications: hypertension, diabetes mellitus, postdatism, and suspected fetal growth restriction.61 Screening performance varied with test indication, being best for patients with hypertension and fetal growth restriction and worst for postdates pregnancies. As individual tests, the NST and Doppler velocimetry performed better than did AFV assessment for each of these conditions.

Timing of Testing Initiation

Most data on efcacy of antepartum surveillance methods have been obtained in near term pregnancies with fewer data as gestational age decreases. The largest studies cited in this article have limited numbers of fetuses 32 weeks gestation. As for a false-positive test resulting in iatrogenic prematurity, this risk must be weighed against the risk of delaying delivery of a compromised infant. Miller and colleagues54 addressed this issue in their retrospective survey of MBPP testing. Their data showed that all fetal deaths could have been avoided if testing had started at 28 weeks gestation rather than 32 weeks. However, there was a 1.5% rate of iatrogenic prema-

Antenatal fetal assessment

Table 2 Quality of Evidence and Strength of Recommendations for Antepartum Test Methods Test Contraction stress test Nonstress test Vibroacoustic stimulation Amniotic uid volume Assessment (MVP, AFI) Biophysical prole Level of Evidence II-2 II-2 II-1 II-2 II-3 II-2

251

Recommendation for Primary Screening in High-Risk Patients B C C B

Level of evidence: I, at least one adequate randomized controlled trial; II-1, well-designed nonrandomized controlled trial; II-2, well-designed cohort or case-control trial; II-3, multiple time series reported. Strength of recommendation: A, good evidence to support recommendation; B, fair evidence to support recommendation; C, insufcient evidence to support or reject recommendation.

turity for a false-positive test, and 20% of these infants had complications due to prematurity. More data are needed to address the reliability of antepartum testing and the toll exacted for test-based interventions in gestations below 32 weeks.

Selection of Testing Method

A summary of the tests examined in this article is presented in Table 2. The criteria for level of evidence and strength of recommendations are based on those recommended by the US Preventive Services Task Force. None of these tests are well supported by the most rigorous trials expected for evaluation of screening, diagnostic, or therapeutic interventions. While there is no evidence to support these tests for use in low-risk pregnancies, there is only fair evidence to justify their use as recommended in high-risk pregnancies.

Conclusions
Antepartum fetal surveillance has entered its fourth decade and millions of fetuses have been evaluated with at least one antenatal test during this time period. Although the use of biophysical testing schemes to screen high-risk pregnancies has become routine, they have evolved with limited highquality scientic data. Serious questions remain open at present. What is the best initial testing approach for high-risk pregnancies? What is the optimal timing of test initiation and how should high-risk conditions affect test initiation? How often should antenatal tests be repeated if not completely normal and reassuring? How should test indications inuence the testing method chosen and how might that method affect the likelihood of adverse outcome? How should antenatal testing in the fetus between 24 and 32 weeks gestational age be best conducted? These questions must be answered if the best application of antenatal surveillance techniques is to be accomplished.

References
1. National Institute of Child Health and Human Development Research Planning Workshop: Electronic fetal heart rate monitoring. research guidelines for interpretation. Am J Obstet Gynecol 177:1385-1390, 1997 2. Ray M, Freeman RK, Pine S, et al: Clinical experience with the oxytocin challenge test. Am J Obstet Gynecol 114:1-9, 1972

3. Pose SV, Castillo JB, Mora-Rojas EO, et al: Test of fetal tolerance to induced uterine contractions for the diagnosis of chronic fetal distress. Proc 8th Meeting PAHO Washington 185:96-104, 1969 4. Freeman RK, Anderson G, Dorchester W: A prospective multi-institutional study of antepartum fetal heart rate monitoring. I. Risk of perinatal mortality and morbidity according to antepartum test results. Am J Obstet Gynecol 143:771-777, 1982 5. Capeless EL, Mann LI: Use of breast stimulation for antepartum stress testing. Obstet Gynecol 64:641-645, 1984 6. Palmer SM, Martin JN, Moreland ML, et al: Contraction stress test by nipple stimulation: efcacy and safety. South Med J 79:1102-1105, 1986 7. Devoe LD: Antepartum and intrapartum fetal assessment. Obstetr Gynecol Clin 26:535-556, 1999 8. American College of Obstetricians and Gynecologists (ACOG): Antepartum fetal surveillance (Practice Bulletin No. 9). Washington, DC, 1999 9. Lagrew DC: The contraction stress test. Clin Obstet Gynecol 38(1):1125, 1995 10. Freeman RK, Anderson G, Dorchester W: A prospective multi-institutional study of antepartum fetal heart rate monitoring. I. Risk of perinatal mortality and morbidity according to antepartum test results. Am J Obstet Gynecol 143:771-777, 1982 11. Freeman RK, Anderson G, Dorchester W: A prospective multi-institutional study of antepartum fetal heart rate monitoring. II. Contractions stress test versus nonstress test for primary surveillance. Am J Obstet Gynecol 143:778-781, 1982 12. Devoe LD, Morrison J, Martin J, et al: A prospective comparative study of the extended nonstress test and nipple stimulation contraction stress test. Am J Obstet Gynecol 157:531-537, 1987 13. Nageotte MP, Towers CV, Asrat T, et al: The value of a negative antepartum test: contraction stress test and modied biophysical prole. Obstet Gynecol 84(2):231-234, 1976 14. Trierweiler M, Freeman R, James J: Baseline fetal heart rate characteristics as an indicator of fetal status during the antepartum period. Am J Obstet Gynecol 125:618-623, 1976 15. Everston LR, Gauthier RJ, Schifrin BS, et al: Antepartum fetal heart rate testing. I. Evolution of the nonstress test. Am J Obstet Gynecol 133:2933, 1979 16. Lee CY, DiLoreto PC, OLane JM: A study of fetal heart rate acceleration patterns. Obstet Gynecol 45:142-146, 1975 17. Rochard F, Schifrin BS, Goupil F, et al: Nonstressed fetal heart rate monitoring in the antepartum period. Am J Obstet Gynecol 126:699706, 1976 18. Devoe LD: The nonstress test, in Eden RD, Boehm FH (eds): Assessment and Care of the Fetus: Physiologic, Clinical and Medicolegal Principles. East Norwalk, CT, Appleton and Lange, 1990, pp 365-383 19. Baser I, Johnson TR, Paine LL: Coupling of fetal movement and fetal heart rate accelerations as an indicator of fetal health. Obstet Gynecol 80(1):62-66, 1992

252
20. Visser GH, Bekedam DJ, Ribbert LS: Changes in antepartum heart rate patterns with progressive deterioration of the fetal condition. I. J Biomed Comput 25(4):239-246, 1990 21. Pattison N, McCowan L: Cardiotocography for antepartum fetal assessment. Cochrane Database of Systematic Reviews 1999. Issue 1. Art No. CD001068. DOI:10.1002/14651858 22. Smith CV, Phelan JP, Broussard PM, et al: Fetal acoustic stimulation testing: a retrospective analysis of the fetal acoustic stimulation test. Am J Obstet Gynecol 153:567-568, 1985 23. Smith CV: Vibroacoustic stimulation. Clin Obstet Gynecol 38:68-77, 1995 24. Devoe LD, Gardner P, Arnold P, et al: The effects of vibroacoustic stimulation baseline fetal heart rate in term pregnancy. Am J Obstet Gynecol 160:1086-1090, 1989 25. Nyman M, Barr M, Westgren M: A four-year follow-up of hearing and development in children exposed in utero to vibro-acoustic stimulation. Br J Obstet Gynaecol 99:685-688, 1992 26. Marden D, McDufe RS, Allen R, et al: A randomized controlled trial of a new fetal acoustic stimulation test for fetal well-being. Am J Obstet Gynecol 176:1386-1388, 1997 27. Read JA, Miller FC: Fetal heart rate accelerations in response to acoustic stimulation as a measure of fetal well-being. Am J Obstet Gynecol 129:512-517, 1977 28. Smith CV, Phelan JP, Platt LD, et al: Fetal acoustic stimulation testing. II. A randomized clinical comparison with the nonstress test. Am J Obstet Gynecol 155:131-134, 1986 29. Tan KH, Smyth R: Fetal vibroacoustic stimulation for the facilitation of tests of fetal wellbeing. Cochrane Database of Systematic Reviews 2001. Issue 1. Art. No. CD002963. DOI:10.1002/14651858 30. Ware DJ, Devoe LD: The nonstress test: reassessment of the gold standard. Clin Perinatol 21(4):779-796, 1994 31. Castillo RA, Devoe LD, Arthur M, et al: The preterm nonstress test: effects of gestational age and length of study. Am J Obstet Gynecol 160:172-175, 1989 32. Devoe LD, Jones CR: Nonstress test: evidence-based use in high-risk pregnancy. Clin Obstetr 45(4):986-992, 2002 33. Vintzileos AM, Campbell WA, Ingardia CJ, et al: The fetal biophysical prole and its predictive value. Obstet Gynecol 62(3):271-278, 1983 34. Manning FA, Platt LD, Sipos L: Antepartum fetal evaluation: development of a fetal biophysical prole. Am J Obstet Gynecol 136:787-795, 1980 35. Rutherford SE, Phelan JP, Smith CV, et al: The four quadrant assessment of amniotic uid volume: an adjunct to antepartum fetal heart rate testing. Obstet Gynecol 70:353-357, 1987 36. Moore TR, Cayle JF: The amniotic uid index in normal human pregnancy. Am J Obstet Gynecol 162:1040-1049, 1990 37. Croom CS, Banias BB, Ramos-Santos E, et al: Do semiquantitative amniotic uid indices reect actual volume? Am J Obstet Gynecol 167: 995-999, 1992 38. Manning FA, Baskett TF, Morrison I, et al: Fetal biophysical prole scoring: a prospective study in 1184 high-risk patients. Am J Obstet Gynecol 140:289-294, 1981 39. Johnson JM, Chauhan SP, Ennen CS, et al: A comparison of 3 criteria of oligohydramnios in identifying peripartum complications: a secondary analysis. Am J Obstet Gynecol 197:207-209, 2007 40. Chamberlain PF, Manning FA, Morrison I, et al: Ultrasound evaluation of amniotic uid volume. I. The relationship of marginal and decreased amniotic uid to perinatal outcome. Am J Obstet Gynecol 150:245249, 1984

L.D. Devoe
41. Phelan JP, Platt LD, Yeh S-Z, et al: The role of ultrasound assessment of amniotic uid in the management of postdates pregnancy. Am J Obstet Gynecol 151:304-308, 1985 42. Lagrew DC, Pircon RA, Nageotte M, et al: How frequently should amniotic uid index be repeated? Am J Obstet Gynecol 167:11291133, 1992 43. Wing DA, Fishman A, Gonzalez C, et al: How frequently should the amniotic uid index be performed during the course of antepartum testing? Am J Obstet Gynecol 174:33-36, 1996 44. Chauhan SP, Sanderson M, Hendrix NW, et al: Perinatal outcome and amniotic uid: a meta-analysis. Am J Obstet Gynecol 181:1473-1478, 1999 45. Magann EF, Doherty DA, Field K, et al: Biophysical prole with amniotic uid assessments. Obstet Gynecol 104:5-10, 2004 46. Vintzileos AM, Campbell WA, Ingardia CJ, et al: The fetal biophysical prole and its predictive value. Obstet Gynecol 62:271-278, 1983 47. Vintzileos AM, Knuppel RA: Multiple parameter biophysical testing in the prediction of fetal acid-base status. Clin Perinatol 21:823-848, 1994 48. Manning FA: Dynamic ultrasound-based fetal assessment: the fetal biophysical prole score. Clin Obstet Gynecol 38:26-44, 1995 49. Manning FA, Morrison I, Harman CR, et al: The abnormal fetal biophysical prole score. V. Predictive accuracy according to score composition. Am J Obstet Gynecol 162:918-924, 1990 50. Manning FA, Harman CR, Morrison I, et al: Fetal assessment based on fetal biophysical prole scoring. IV. An analysis of perinatal morbidity and mortality. Am J Obstet Gynecol 162:703-709, 1990 51. Manning FA, Harman CR, Morrison I, et al: Fetal assessment based on fetal biophysical prole scoring. III. Positive predictive accuracy of the very abnormal test (biophysical score 0). Am J Obstet Gynecol 162: 398-402, 1990 52. Dayal AK, Manning FA, Berck DJ, et al: Fetal death after normal biophysical prole score: an eighteen year experience. Am J Obstet Gynecol 181:1231-1236, 1999 53. Manning FA: Fetal biophysical prole. Obstet Gynecol Clin North Am 26:557-577, 1999 54. Miller DA, Rabello YA, Paul RH: The modied biophysical prole: antepartum testing in the 1990s. Am J Obstet Gynecol 174:812-817, 1996 55. Alrevic Z, Neilson JP: Biophysical prole for fetal assessment in high risk pregnancies. Cochrane Database of Systematic Reviews 1996, Issue 2. CD000038. DOI:10.1002/14751858 56. Nageotte MP, Towers CV, Asrat T, et al: Perinatal outcome with the modied biophysical prole. Am J Obstet Gynecol 170:1672-1676, 1994 57. Manning FA, Hill LM, Platt LD: Qualitative amniotic uid volume determination by ultrasound: antepartum detection of intrauterine growth retardation. Am J Obstet Gynecol 139:254-258, 1985 58. Eden RD, Gergely RZ, Schifrin BS, et al: Comparison of antepartum testing schemes for the management of the postdate pregnancy. Am J Obstet Gynecol 144:683-692, 1982 59. Eden RD, Seifert LS, Kodack LD, et al: A modied biophysical prole for antenatal fetal surveillance. Obstet Gynecol 71:356-359, 1988 60. Kontopoulos EV, Vintzileos AM: Condition-specic antepartum fetal testing. Am J Obstet Gynecol 191:1546-1551, 2004 61. Devoe L, Gardner P, Dear C, et al: The diagnostic value of concurrent nonstress testing, amniotic uid measurement and Doppler velocimetry in screening a general high risk population. Am J Obstet Gynecol 163:1040-1047, 1990

Fetal Doppler: Umbilical Artery, Middle Cerebral Artery, and Venous System
Giancarlo Mari, MD,* and Farhan Hanif, MD
One of the most important applications of Doppler ultrasonography in obstetrics is the detection of fetal anemia in pregnancies complicated by either red-cell alloimmunization or by other causes of fetal anemia. Doppler of the umbilical artery also has prognostic value in pregnancies affected by twintwin transfusion syndrome undergoing in-utero intervention. Another potential major application is the use of Doppler ultrasound in the management of intrauterine-growth-restricted fetuses. At the present time, there is no single test that appears superior to the other available tests for timing the delivery of the growthrestricted fetus. Therefore, the decision to deliver a fetus, especially at <32 weeks, remains mostly based on empirical management. Doppler may provide a more reliable and systematic basis for timing these deliveries. This review emphasizes the three following concepts: (a) normal and abnormal Doppler of the umbilical artery, middle cerebral artery, mitral and tricuspid valves, umbilical vein, and ductus venosus; (b) some clinical applications of Doppler sonography in obstetrics; and (c) potential future research of Doppler in obstetrics. Semin Perinatol 32:253-257 2008 Elsevier Inc. All rights reserved. KEYWORDS feat anemia, IUGR, Doppler, ductus venosus, middle cerebral artery

Umbilical Artery

Middle Cerebral Artery

Angle-independent indices differ among the different cerebral arteries.5 The middle cerebral artery is the most studied cerebral artery because (a) it is easy to sample; (b) it provides information on the cerebral blood ow in normal and IUGR fetuses; and (c) it can be sampled at an angle of 0 between the ultrasound beam and the direction of the blood ow.6 Therefore, for the middle cerebral artery we are able to determine angle-independent indices (the most used is the pulsatility index) and also the real velocity of blood ow. In IUGR fetuses there is a redistribution of the blood ow from the fetal periphery to the brain. This phenomenon is called the brain-sparing effect.7

mbilical artery angle independent indices (pulsatility index or systolic/diastolic (S/D) ratio) decrease with advancing gestation because of a decreased placental vascular resistance, which physiologically occurs with advancing gestation.1,2 In pathologic conditions, such as in intrauterinegrowth-restricted (IUGR) fetuses, the umbilical artery waveforms change and the angle-independent indices become abnormal (values above their reference ranges). These changes reect an increased placental vascular resistance.2 Giles and coworkers demonstrated that the number of placental arteries per high power eld is decreased in cases of abnormal umbilical artery Doppler.3 Only in pregnancies with suspected intrauterine growth restriction and/or hypertensive disease of pregnancy does the use of umbilical artery Doppler reduce the number of perinatal deaths and unnecessary obstetric interventions.4

Umbilical Vein
After 15 weeks gestation, the umbilical vein normally has a continuous blood ow but becomes pulsatile in pathological cases, such as in IUGR and hydropic fetuses.8 For the umbilical vein we use a qualitative assessment: continuous versus pulsatile blood ow.

*Tennessee Maternal Fetal Medicine Institute, Memphis, TN. Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI. Address reprint requests to Giancarlo Mari, MD, Director of Tennessee Maternal Fetal Medicine Institute, Director MFM and Vice Chairman Ob/ Gyn, UTHSC, 853 Jefferson Avenue Rout E-102, Memphis, TN 381032807. E-mail: gmari@utmem.edu

Atrioventricular Valves
The atrioventricular valves (mitral and tricuspid) are characterized by two peaksthe E wave that corresponds to the 253

0146-0005/08/$-see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2008.04.007

254

G. Mari and F. Hanif

Hemodynamically, these phases reect the rapid chronologic change in pressure gradients between the umbilical vein and the right atrium. In appropriate-for-gestational-age fetuses, there is forward ow at the ductus venosus, and the pulsatility index for veins (S-D/a) decreases with advancing gestation. However, in IUGR fetuses, the pulsatility index increases, and in the most severe cases, there is a wave reversed ow.

Figure 1 Flow velocity waveforms of the ductus venosus. S systole; D 1st phase of the diastole corresponding to the passive rapid lling of the ventricles; a 2nd phase of the diastole corresponding to the atrial contraction. (Color version of gure is available online.)

Three Clinical Applications of Doppler Sonography in Obstetrics

Diagnosis of Fetal Anemia
The middle cerebral artery (MCA) can be insonated at an angle of 0 between the ultrasound beam and the direction of the blood ow and, consequently, the real velocity of the blood ow can be determined.6 The lowest intra- and interobserver variability is obtained when the MCA proximal to the transducer is sampled soon after its origin from the internal carotid artery, without the use of an angle corrector, by using a 1- to 2-mm sample volume.13 A peak systolic velocity (PSV) above 1.50 MoM (Fig. 2), in fetuses at risk for anemia, has a sensitivity for detecting anemia of 100% (CI: 86-100%) in red cell alloimmunization cases as well as in other cases of anemia.14-16 The false-positive rate is 12%, but this percentage may decrease when serial MCA values are obtained.17 In fetuses at risk for anemia because of red cell alloimmunization, we use the curve reported in Figure 3 in the following way. We initially perform three exams, 1 week apart, and then obtain the regression line of the three points. If the curve is to the right side of the dotted line, we perform the next

rapid lling of the ventricles and the A wave that corresponds to the atrial contraction. The A wave is taller than the E wave,9,10 which may suggest that atrial contraction is important in the fetus, and is associated with stiffness of fetal cardiac chambers. With advancing gestation, the E/A ratio increases. By contrast, after birth, and also in the adult, the E wave is taller than the A wave. In fact, in the adult, 85% of the blood passes from the atria to the ventricles during the rst part of the diastole. In IUGR fetuses the two waves become abnormal (the E/A ratio increases) and, in the most severe cases, there is tricuspid and mitral regurgitation.11

Ductus Venosus
Ductus venosus waveforms are characterized by two peaks, the S and D, followed by a nadir, the a wave (Fig. 1).12

Figure 2 Peak velocity of systolic blood ow in the middle cerebral artery with advancing gestation. The solid curve indicates the median peak systolic velocity in the middle cerebral artery, and the dotted curve indicate 1.5 multiples of the median. (Modied from Mari and colleagues.14)

Fetal Doppler

255 amnioreduction or laser therapy.22,23 The MCA PSV is also another parameter of choice that allows the diagnosis of fetal anemia and indicates the need for transfusions in the recipient following laser therapy.24

Intrauterine Growth Restriction

Most of the studies that report on IUGR have not differentiated between constitutionally and pathologically small fetuses. Additionally, studies on the pathogenesis of IUGR have been limited by the concept that IUGR fetuses represent a homogeneous group. This has created some confusion and has hampered our understanding of the mechanisms that are at the basis of IUGR. We use the term small for gestational age for those small fetuses with no maternal pathology and with normal umbilical artery and middle cerebral artery Doppler results. In contrast, growth-restricted fetuses are small fetuses with a recognizable maternal pathology or an abnormal umbilical or middle cerebral artery Doppler. When no maternal pathology is present but there is an abnormal fetal Doppler, we dene small fetuses as idiopathic IUGR fetuses.25,26

Figure 3 Average regression line for nonanemic fetuses (dotted line, y 17.28 1.99x); mildly anemic fetuses (thin line, y 53.54 4.17x), and severely anemic fetuses (thick line, y 76.82 5.26x). (Reprinted with permission.17)

MCA Doppler examination between 2 and 4 weeks. For example, if a patient with an anti-D titer of 1:256 is seen at 17 weeks gestation, and her previous pregnancies have not been complicated by fetal anemia, and the regression line of her rst three exams is to the right side of the dotted line, we perform the next examination in 4 weeks. However, if the values are between the dotted line and one of the continuous lines, the next examination is performed in 2 weeks. Finally, if the regression line is to the left of one of the continuous lines, and the MCA PSV is below 1.50 MoM, we perform the next examination every 2 to 3 days. After 34 weeks gestation, if we use the 1.50 MoM as the cutoff point, we nd that the number of false positives increases. Therefore we look at serial MCA values rather than at one single value. We deliver our patients at risk for fetal anemia at 38 to 39 weeks gestation. In 1997, we reported that the accuracy of the MCA PSV was at least as good as that of the delta OD450 in the diagnosis of fetal anemia. (We also noted that the MCA PSV had an important advantage in that it is noninvasive.)18 The accuracy of the MCA PSV was conrmed by Pereira and coworkers19 in a retrospective studythe same approach we used. More recently, a multicenter prospective study has determined that the MCA PSV is actually more reliable than the delta OD 450 in the diagnosis of fetal anemia,20 which has led the American College of Obstetrics and Gynecology to report that the MCA PSV is an excellent tool for the diagnosis of fetal anemia in the hands of trained people.21 Retrospective studies have suggested that the MCA PSV can be used for timing the subsequent transfusions, but a randomized trial should be performed to conrm this.

Placental Insufciency and Idiopathic IUGR Fetuses

The concept that placental insufciency is THE cause of IUGR is a source of confusion. We believe that placental insufciency is not THE cause of the problem but is rather the consequence of a disease process that often we do not understand.25 We agree with Assali, who dened placental insufciency as an umbrella that covers our ignorance in terms of etiology and pathogenesis of the utero-placental chronic dysfunction (from Bruno Salvadori, personal communication). We have recently reported that placental insufciency is a symptom and it can be compared with the fever seen in patients with bacterial pneumonia.25 As with pneumonia, there are many agents that could cause it; similarly, with placental insufciency there may be many underlying causes. If we use an antipyretic in patients with bacterial pneumonia, the fever will temporarily subside; however, to treat the entire condition it is necessary to use antibiotics to target the specic etiologic factor. Similarly, with IUGR, we often view the problem from the wrong directionas a consequence of placental insufciencyand we therefore believe that we should treat the placental insufciency. In reality we should nd and treat the specic cause of placental insufciency. The optimal management, however, would be the prevention of IUGR fetuses. In many IUGR fetuses there is an underlying maternal pathology, eg, chronic hypertension or advanced stage diabetes mellitus, at the basis of placental insufciency. In other IUGR cases there is not an identiable cause of placental insufciency; these are the cases that we dene as idiopathic IUGR fetuses.25,26

TwinTwin Transfusion Syndrome

Doppler measurements of the umbilical artery are excellent prognostic parameters to assess patients with twintwin transfusion syndrome. Twintwin transfusion syndrome patients with absent end-diastolic velocity have a worse prognosis than patients with forward end-diastolic velocity at the umbilical artery in one of the twins, when the twins undergo

What Is New in IUGR Research?

We and others have reported a temporal sequence in the cardiovascular system of IUGR fetuses.26-29 We have also re-

256 ported that the MCA PSV is increased in IUGR fetuses and that this increase predicts perinatal mortality more accurately than the MCA pulsatility index.30 In addition, there is a correlation between the MCA PSV and a low pO2 and high pCO2 in IUGR fetuses.31 Recently, there has been much interest in nding a method to decide when to deliver the IUGR fetus. It has been hypothesized that an abnormal ductus venosus Doppler would be an indication for delivery. Although this could be an indication for delivery after 32 weeks, we do not believe that ductus venosus reversed ow (DVRF) is an indication for delivery early in the third trimester in all cases of IUGR fetuses. This is based on our recent reports that, for each week the fetus remains in utero between 25 and 29 weeks, there is a decreased perinatal mortality of 48%,32 and that the majority of fetuses with DVRF are not acidemic.33 Therefore, the main goal would be to differentiate between those fetuses with DVRF that require early intervention from those for which delivery can be delayed. We believe that undertaking a randomized study to determine the optimal timing of delivery of the growth-restricted fetus is premature, because at the current time, there is no study that has demonstrated differentiation among the different IUGR fetuses. Without this information, the results of a randomized study could lead to the adoption of a awed test to determine the optimal timing for delivery of the growthrestricted fetus. We do not wish to make the mistake of possibly adopting a test determined to be the best in such a trial before the full range of observational and randomized studies to evaluate all tests in normal and at risk and diseased pregnancies has been completed. To do so would duplicate the history and ensuing controversies of adoption of fetal heart rate monitoring for fetal surveillance. For example, we have learned that idiopathic IUGR fetuses behave in a different way than IUGR fetuses seen in preeclamptic patients or in diabetic patients.34 Therefore, we believe that the rst step of future research would be to prospectively learn about the natural history of the different IUGR fetuses. This is a study that we are conducting in our ultrasound laboratory.

G. Mari and F. Hanif

7. Wladimiroff JW, Tonge HM, Stewart PA: Doppler ultrasound assessment of the cerebral blood ow in the human fetus. Br J Obstet Gynaecol 93:471-475, 1986 8. Reed KK, Chafn DG, Anderson CF, et al: Umbilical venous velocity pulsations are related to atrial contraction pressure waveforms in fetal lambs. Obstet Gynecol 89:953-956, 1997 9. Rizzo G, Arduini D, Romanini C, et al: Doppler echocardiographic assessment of atrioventricular velocity waveforms in normal and smallfor-gestational-age fetuses. Br J Obstet Gynaecol 95:65-69, 1988 10. Hecher K, Campbell S, Snijders R, et al: Reference ranges for fetal venous and atrioventricular blood ow parameters. Ultrasound Obstet Gynecol 4:381-390, 1994 11. Mari G, Deter RL, Hanif F, et al: Sequence of cardiovascular changes occurring in severe IUGR fetusespart II. Ultrasound Obstet Gynecol 2006;28:390 abstract (OC109) 12. Kiserud T, Eik-Nes SH, Blaas HG, et al: Ultrasonographic velocimetry of the fetal ductus venosus. Lancet 338:1412-1414, 1991 13. Mari G, Abuhamad A, Cosmi E, et al: Middle cerebral artery peak systolic velocitytechnique and Variability. J Ultrasound Med 24: 425-430, 2005 14. Mari G, Deter RL, Carpenter RL, et al: Non-invasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med 342:9-14, 2000 15. Zimmerman R, Carpenter RJ Jr, Durig P, et al: Longitudinal measurement of peak systolic velocity in the fetal middle cerebral artery for monitoring pregnancies complicated by red cell alloimmunisation: A prospective multicentre trial with intention-to-treat. BJOG 109:746752, 2002 16. Cosmi E, Mari G, Delle Chiaie L, et al: Noninvasive diagnosis by Doppler ultrasonography of fetal anemia resulting from parvovirus infection. Am J Obstet Gynecol 187:1290-1293, 2002 17. Detti L, Mari G, Akiyama M, et al: Longitudinal assessment of the middle cerebral artery peak systolic velocity in healthy fetuses and in fetuses at risk for anemia. Am J Obstet Gynecol 187:937-939, 2002 18. Mari G, Penso C, Sbracia M, et al: Delta OD 450 and Doppler velocimetry of the middle cerebral artery peak velocity in the evaluation for fetal alloimmune hemolytic disease. Which is the best? Am J Obstet Gynecol 176:S18, 1997 19. Pereira JC, Jenkins TM, Berghella V: Conventional management of maternal red cell alloimmunization compared with management by Doppler assessment of middle cerebral artery peak systolic velocity. Am J Obstet Gynecol 189:1002-1006, 2003 20. Oepkes D, Seaward PG, Vandenbussche FP, et al: Doppler ultrasonography versus amniocentesis to predict fetal anemia. N Engl J Med 13: 355-364, 2006 21. ACOG Practice Bulletin. Management of alloimmunization during pregnancy. Obstet Gynecol 75:457-464, 2006 22. Mari G, Roberts A, Detti L, et al: Perinatal morbidity and mortality rates in severe twin-twin transfusion syndrome: results of the International Amnioreduction Registry. Am J Obstet Gynecol 185:708715, 2001 23. Kontopoulos EV, Quintero RA, Chmait RH, et al: Percent absent enddiastolic velocity in the umbilical artery waveform as a predictor of intrauterine fetal demise of the donor twin after selective laser photocoagulation of communication vessels in twin-twin transfusion syndrome. Ultrasound Obstet Gynecol 30:35-39, 2007 24. Senat MV, Loizeau S, Couderc S, et al: The value of middle cerebral artery peak systolic velocity in the diagnosis of fetal anemia after intrauterine death of one monochorionic twin. Am J Obstet Gynecol 189: 1320-1324, 2003 25. Mari G, Hanif F: Intrauterine growth restriction: how to manage and when to deliver. Clin Obstet Gynecol 50:497-509, 2007 26. Cosmi E, Ambrosini G, DAntona D, et al: Doppler, cardiotocography, and biopgysical prole changes in growth restricted fetuses. Obstet Gynecol 106:1240-1245, 2005 27. Hecher K, Bilardo CM, Stigter RH, et al: Monitoring of fetuses with

References
1. Stuart B, Drumm J, FitzGerald DE, et al: Fetal blood velocity waveforms in normal pregnancies. Br J Obstet Gynaecol 87:780-785, 1980 2. Trudinger BJ, Giles WB, Cook CM, et al: Fetal umbilical artery ow velocity waveforms and placental resistance: clinical signicance. Br J Obstet Gynaecol 92:23-30, 1985 3. Giles WB, Trudinger BJ, Baird PJ: Fetal umbilical artery ow velocity waveforms and placental resistance: pathological correlation. Br J Obstet Gynaecol 92:31-38, 1985 4. Westergaard HB, Langhoff-Roos J, Lingman G, et al: A critical appraisal of the use of umbilical artery Doppler ultrasound in high-risk pregnancies: use of meta-analyses in evidence-based obstetric. Ultrasound Obstet Gynecol 17:466-476, 2001 5. Mari G, Moise KJ Jr, Deter RL, et al: Doppler assessment of the pulsatility index in the cerebral circulation of the human fetus. Am J Obstet Gynecol 160:698-703, 1989 6. Mari G, Adrignolo A, Abuhamad AZ, et al: Diagnosis of fetal anemia with Doppler ultrasound in the pregnancy complicated by maternal blood group immunization. Ultrasound Obstet Gynecol 5:400-405, 1995

Fetal Doppler
intrauterine growth restriction: a longitudinal study. Ultrasound Obstet Gynecol 18:564-570, 2001 28. Gembruch U, Harman CR: The sequence of changes in Doppler and biophysical parameters as severe fetal growth restriction worsens. Ultrasound Obstet Gynecol 18:571-577, 2001 29. Ferrazzi E, Bozzo M, Rigano S, et al: Temporal sequence of abnormal Doppler changes in the peripheral and central circulatory systems of the severely growth-restricted fetus. Ultrasound Obstet Gynecol 19: 140-146, 2002 Baschat 30. Mari G, Hanif F, Cosmi E, et al: Middle cerebral artery peak systolic velocity: A new Doppler parameter in the assessment of IUGR fetuses. Ultrasound Obstet Gynecol 29(3):310-316, 2007

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31. Hanif F, Drennan K, Mari G: Variables affecting the middle cerebral artery peak systolic velocity in anemic and IUGR fetuses. Am J Perinatol 28:377-383, 2008 32. Mari G, Hanif F, Cosmi E, et al: Middle cerebral artery peak systolic velocity: A new Doppler parameter in the assessment of IUGR fetuses. Ultrasound Obstet Gynecol 29(3):310-316, 2007 33. Mari G, Hanif F, Treadwell M, et al: Gestational age at delivery and Doppler waveforms in very preterm IUGR fetuses as predictors of perinatal mortality. J Ultrasound Med 26:555-559, 2007 34. Mari G, Hanif F, Kruger M: Cardiovascular changes sequence in severe IUGR in pregnancies with and without preeclampsia. Prenat Diagn 28:377-383, 2008

Monitoring of Fetal Well-Being: Role of Uterine Artery Doppler

Alessandro Ghidini, MD,* and Anna Locatelli, MD
Doppler interrogation of the uterine arteries provides information on the physiologic transformation of the spiral arteries during pregnancy. Lack or suboptimal conversion of such arteries by the late second or third trimester of pregnancy is a strong indicator of increased risk for adverse pregnancy outcome, in particular, iatrogenic prematurity due to severe fetal growth restriction or preeclampsia. Uterine artery Doppler can thus play a role in the presence of medical conditions antedating pregnancy, which have greater risk of abnormal placentation, like chronic hypertension, to identify the subgroup with increased pregnancy complications and adverse outcome. In the presence of pregnancy complications related to inadequate placentation, such as fetal growth restriction or preeclampsia, uterine artery Doppler also plays a role, as abnormal ndings signal increased severity of the disease and thus greater likelihood of unfavorable perinatal outcome. Semin Perinatol 32:258-262 2008 Elsevier Inc. All rights reserved. KEYWORDS uterine artery, Doppler velocimetry, fetal growth restriction, preeclampsia, abnormal placental implantation

oppler ultrasonographic interrogation of the arterial velocity waveforms allows the estimation of vascular impedance to ow by comparing systolic and diastolic waveforms. In the presence of downstream resistance to ow diastolic velocity diminishes in relation to systolic ow. Under the effect of trophoblastic migration into the spiral arteries, the uterine vascular bed undergoes marked changes during pregnancy, becoming a low resistance circuit, with ow throughout diastole. Concomitantly, as the placental implantation progresses, a sharp decrease in uterine artery (UtA) impedance to ow occurs and the early diastolic notch present in the nonpregnant UtA disappears. Placentation is usually completed by 24 weeks, and indeed less prominent changes in UtA Doppler occur in the third trimester. Normative data for UtA Doppler throughout gestation are available.1,2 Abnormal development of the placental vasculature, signaled by increased impedance to ow at UtA Doppler, may lead over time to the development of obstetrical complications, such as fetal growth restriction (FGR), preeclampsia, or abruption.
*Perinatal Diagnostic Center, Inova Alexandria Hospital, Alexandria, VA. Department of Obstetrics and Gynecology, University of Milano-Bicocca, Monza, Italy. Reprints not available. Address correspondence to Alessandro Ghidini, MD, Perinatal Diagnostic Center, Inova Alexandria Hospital, 4320 Seminary Road, Alexandria, VA 22304. E-mail: Alessandro.Ghidini@Inova.org

In the presence of obstetric complications in the third trimester of pregnancy, UtA Doppler is ideally positioned to provide valuable prognostic information allowing the recognition of complications associated with abnormal placentation. Several maternal pathologies antedating pregnancy, such as chronic hypertension, inherited and acquired thrombophilias, diabetes mellitus, and autoimmune disorders including lupus erythematosus, increase the probability of abnormal development of the placental vasculature with the related risk of obstetric complications. Once again, UtA Doppler at completion of placentation has been used to identify the subset of such high-risk pregnancies, which may benet from increased surveillance, whereas in the subset with appropriate placentation, normal UtA Doppler ndings can provide reassurance to the parents and the health care providers.

Technique
The technique of UtA Doppler interrogation is fairly simple. Using color-ow mapping, each uterine artery is identied where it crosses over the external iliac artery. The range gate should be placed over the entire diameter of the artery distal to the crossover point and before division into branches. The angle of insonation should be minimized and kept at least 60. Once waveforms are obtained with a clear envelope, at least three waveforms can be averaged and impedance indi-

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0146-0005/08/$-see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2008.04.019

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259

Hypertensive Complications of Pregnancy

Placental vascular lesions due to abnormal placentation are a characteristic nding in the presence of preeclampsia and other hypertensive complications of pregnancy. UtA Doppler obtained on admission for such conditions offers precious information, identifying the majority of pregnancies at higher risk for indicated preterm delivery, and neonates with worse FGR and need for NICU admission.13-15 For example, in a cohort study of 186 cases of preterm preeclampsia diagnosed on average at 31.3 3.6 weeks and delivered at 32.8 3.3 weeks, those with abnormal UtA Doppler ndings on admission had signicantly lower gestational age delivery (32.5 versus 35.3 weeks), higher rates of very low birth weight (52% versus 5%), and of FGR (70% versus 23%).14 Of interest, UtA Doppler predictive ability was independent of laboratory indicators of severity of preeclampsia.14 The information provided by UtA Doppler operates along a continuum, so that the risk for such adverse outcomes is directly correlated with the severity of abnormal UtA Doppler ndings15 (Table 2).

Figure 1 Abnormal uterine artery Doppler waveform at 28 weeks, with increased impedance to ow. Color ow mapping is used for visualization of the artery and proper positioning of the sample volume.

ces calculated (Figs. 1 and 2) Interobserver variability of UtA Doppler has been reported as approximately 10%, with intraobserver variability of 2.5 to 10.1%.3-5

Decreased Fetal Movements

Only one study has examined the value of UtA Doppler at the time of nonstress test done for decreased fetal movements at a mean gestational age of 36 weeks. Abnormal UtA Doppler ndings were signicantly associated with delivery within 2 days of testing, with emergency cesarean delivery and operative delivery for fetal distress, but not with more objective measures of adverse neonatal outcome.16

Uterine Artery Doppler in the Presence of Obstetric Complications

Fetal Growth Restriction
In the presence of ultrasonographic evidence of FGR, abnormal UtA Doppler identies fetuses at higher risk of preterm delivery and lower birth weight.6,7 Low gestational age at delivery is the most important independent predictor of adverse neonatal outcome in FGR.8 In one study of FGR fetuses with abnormal UtA Doppler, only 20% of those delivered at 34 weeks had uncomplicated neonatal course, compared with 60% of those delivered at 34 weeks.9 In the largest study of 294 FGR fetuses delivered after 34 weeks, adverse neonatal outcome dened as admission to the neonatal intensive care unit (NICU) for reasons other than low birth weight alone occurred more frequently in cases with abnormal than normal UtA Doppler waveforms (35% versus 11%, OR 3.2; 95% CI, 1.9-5.3) (Table 1). Logistic regression analysis demonstrated that abnormal UtA Doppler ndings remained a signicant predictor of adverse neonatal outcome after controlling for occurrence of preeclampsia (OR 4.1, 95% CI, 2.2-7.5).10 Umbilical artery Doppler is a major prognosticator among FGR cases, particularly those delivered preterm. In cases with normal umbilical artery Doppler ndings, UtA Doppler prognosticates increased risk for emergency cesarean section.11 Not surprisingly, UtA Doppler has been found to be a predictor of perinatal mortality and major neonatal morbidity.9 Finally, abnormal results at UtA Doppler in the presence of FGR identies women at increased risk for subsequent development of preeclampsia.12

Obstetric Complications
In a large cohort of pregnancies with a variety of complications, including gestational hypertension with or without proteinuria, oligohydramnios, suspected FGR, vaginal bleeding, preterm labor, postterm pregnancy, decreased fetal movement, or history of adverse outcome, 54% (399/741) developed adverse perinatal outcome, dened as low Apgar score, low arterial or venous pH, preterm delivery, cesarean delivery for fetal distress, admission to NICU, birth weight 2 SD below expected, or perinatal death. UtA Doppler ob-

Figure 2 Normal uterine artery Doppler waveform at 28 weeks.

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A. Ghidini and A. Locatelli

Table 1 Perinatal Outcome in Relation to Maternal Uterine Artery Doppler Waveform in Growth-Restricted Fetuses Delivered at >34 weeks Uterine Artery Abnormal (n 109) Preeclampsia Gestational age at delivery (wk) Meconium-stained amniotic uid Cesarean delivery (CD) CD for non-reassuring fetal testing Birth weight (g) Birth weight percentile Umbilical artery pH Admission to NICU Length of stay in NICU (days)
Mean SD or (%). Reprinted with permission.10

Doppler Waveform Normal (n 185) 11% 38.8 1.6 0.6% 15% 10% 2524 379 9.3 10.2 7.29 0.07 11% 16.5 10.3

P value
0.02 <0.001 0.32 <0.001 <0.001 <0.001 <0.001 0.20 <0.001 0.14

22% 37.7 2.0 3% 38% 27% 2193 446 4.8 5.1 7.28 0.07 35% 20.7 10.2

tained at an average of 38.6 weeks (range: 25.6-43.1) predicted the occurrence of adverse outcome with odds ratios and positive likelihood ratios (LR) directly proportional to the severity of the UtA Doppler abnormality (Table 3).17 Similarly, in a study of 633 pregnancies at high risk due to hypertensive complications of pregnancy, oligohydramnios, suspected FGR, vaginal bleeding, postterm pregnancy, decreased fetal movement, previous adverse outcome (ie, stillbirth, small for gestational age (SGA) baby, or preeclampsia), UtA Doppler at an average of 35 weeks predicted risk of SGA neonates, need for cesarean delivery, and prematurity, with a predictive ability that was independent and superior to that of umbilical artery Doppler.18 These ndings were conrmed by an independent study of UtA Doppler in 282 women at high risk due to a variety of medical conditions (including chronic hypertension, renal or autoimmune disease, as well as history of adverse obstetric outcome). Compared with normal UtA Doppler ndings, abnormal UtA Doppler results at 28 weeks were associated with higher risk for preeclampsia (LR 7.6, 95% CI, 3.7, 7.6), SGA baby (LR 11.2, 95% CI, 6.6-18.7), fetal demise (LR 7.3, 95% CI, 2.4-7.3), or severe complications, dened as the development of preeclampsia, hypertensive disease with a SGA baby, intrauterine demise of a structurally normal fetus, or elective delivery before 34 weeks for maternal or fetal indications (LR 12.5, 95% CI, 8.8-13.6).19

Uterine Artery Doppler in the Presence of Preexisting Medical Complications

Chronic Hypertension
Superimposed preeclampsia and FGR are the two most common obstetric complications in women with chronic hypertension and can be predicted by Doppler interrogation of UtA at completion of placentation. In an initial study, 78 women with chronic hypertension underwent UtA Doppler at 24 weeks gestation. The screen positive rate was 32% when abnormal ndings were dened by elevated resistance indices, and 17% when dened by presence of bilateral notching. The rates of preeclampsia (12% versus 0%) and FGR (52% versus 2%) were signicantly different between those with versus without increased impedance to ow using resistance indices, as well as between those with versus without notching (preeclampsia: 23% versus 0%; FGR: 85% versus 2%, respectively).20 In another study of 182 women with chronic hypertension undergoing UtA Doppler at 29 4 weeks, 36% had increased resistance to ow. Rates of superimposed preeclampsia (28% versus 5%), SGA fetuses (46% versus 14%), and severe complications (60% versus 18%) were signicantly higher among cases with increased impedance to ow.

Table 2 Effect of Severity of Uterine Artery Doppler Results on Probability of Adverse Outcome in Preeclampsia Score 0 Total Severe preeclampsia Weeks at delivery Delivery <34 weeks Birth weight <10th centile 363 13% 38 2 2% 2% Score 1 76 26% 37 3 16% 3% Score 2 79 25% 37 4 16% 10% Score 3 35 34% 36 4 17% 17% Score 4 17 59% 32 5 53% 24%

Uterine Artery Score denition: Score 0: normal ow in both arteries; Score 1: one abnormal parameter (high Pulsatility Index >1.2 or notch present); Score 2: two abnormal parameters; Score 3: three abnormal parameters; Score 4: four abnormal parameters. Reprinted with permission.15

Monitoring of fetal well-being

261

Table 3 Predictive Ability of Uterine Artery Score for Adverse Perinatal Outcome in Pregnancies with Obstetric Complications UtA Doppler Score 0 1 2 3 4
Reprinted with permission.17

Adverse Outcome (n) 37% (142/389) 68% (128/188) 74% (76/103) 84% (42/50) 100% (11/11)

Odds Ratio (95% CI) 1.0 1.64 (1.00 to 2.70) 1.86 (1.00 to 3.54) 4.03 (1.77 to 10.32) (3.20 to )

Likelihood Ratio 1.0 2.4 3.5 7.3

Moreover, gestational age at delivery (36.6 3.1 versus 38.7 1.7 weeks) and birth weight (2409 698 versus 3146 517 g) were signicantly different between the two groups.21

Antiphospholipid Syndrome (APS)

A study with over 100 cases of APS showed that abnormal UtA Doppler at completion of placentation was present in 20 to 30% of cases and it was independently associated with subsequent occurrence of adverse outcome (dened as FGR, preeclampsia, or stillbirth).22 Similarly, a smaller study of 43 women with APS showed that abnormal UtA Doppler was associated with increased risk of preterm preeclampsia or abruption (LR 5.6, 95% CI, 2.4-5.6).23 At variance with these ndings, a large study on 170 women with APS (all with history of habitual abortion) showed that abnormal UtA Doppler at 24 weeks was not predictive of subsequent occurrence of preeclampsia or birth weight 10th centile.24 However, a subanalysis suggested that presence of bilateral notch at UtA Doppler was a powerful predictor of preeclampsia (LR 12.8, 95% CI, 2.2-75) or SGA neonates (LR 13.6, 95% CI, 1.9-96) among the 45 women with lupus anticoagulant.

Diabetes Mellitus
UtA Doppler in the third trimester independently identies among pregnancies with diabetes mellitus and vasculopathy, those at increased risk of preeclampsia and greater risk of cesarean delivery for non-reassuring fetal status.25 Once again, the information provided by UtA Doppler operates along a continuum, so that in women with diabetes mellitus antedating pregnancy the risk for adverse perinatal outcome (dened as operative delivery for fetal distress, preterm delivery, 5-minuteApgar score 5, low umbilical artery pH, and SGA infants) is directly correlated with the severity of the abnormal UtA Doppler ndings.26 Finally, among women with gestational diabetes, abnormal UtA Doppler ndings are signicantly associated with greater risk of subsequent preeclampsia (positive LR of 10.4, 95% CI, 6.6-10.4).27

Conclusions
UtA Doppler can identify women with obstetrical complications related to abnormal placentation. Such predictive ability is often independent of other demographic, obstetric, or laboratory characteristics. UtA Doppler has the potential to be incorporated in the routine evaluation of women with preexisting medical conditions associated with increased risk

of abnormal placentation, as well as in the evaluation of healthy women who experience obstetric complications related to placental vascular pathology. One of the appealing features of UtA Doppler is that the evaluation needs to be made only once in the late second or third trimester, as abnormal values are unlikely to improve after placental implantation is completed. UtA Doppler is also an ideal tool to establish or rule out placental vascular origin of pathologic processes affecting the fetus, for example, in the presence of FGR. Screening of high-risk patients has also potential benets for those with normal results, including reassurance to the patient and benet in quality of life, less need for unnecessary testing in the third trimester, and reduced time lost from employment while undergoing evaluations and rest. For example, a retrospective study on 170 women at high risk for preeclampsia due to history of preeclampsia, preterm delivery, FGR, fetal demise, abruption, chronic hypertension, diabetes mellitus, or renal disease showed that normal UtA Doppler at 24 weeks, which was found in 69% of cases, had a negative-predictive value of 99% for subsequent occurrence of preeclampsia.5 Prospective studies are needed to conrm these potential benets. The time is ripe for larger and better designed studies to evaluate the independent predictive ability of UtA Doppler using multivariate analysis and dening unfavorable pregnancy outcome with objective criteria. Conrmation of UtA Doppler as prognosticator of outcome could herald widespread implementation of this simple technique. It should be remembered that UtA Doppler is of little use for obstetric complications in which fetal risk is not due to impaired placentation, eg, postterm pregnancy or premature rupture of membranes.28,29 More studies are also needed to establish how UtA Doppler identication of patients at increased risk of adverse outcome can affect their management. It is currently unproven whether increased frequency of monitoring of fetal wellbeing, closer ultrasonographic surveillance of fetal growth, more frequent monitoring of maternal blood pressure or proteinuria, and administration of corticosteroid prophylaxis for fetal lung maturity may effect the outcome of patients with abnormal UtA Doppler ndings. Finally, the cost benet analysis of implementation of UtA Doppler still needs to be tested.

References
1. Arduini D, Rizzo G: Normal values of Pulsatility Index from fetal vessels: a cross-sectional study on 1556 healthy fetuses. Perinat Med 18: 165-172, 1990

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2. Gudmundsson S, Marsal K: Umbilical artery and uteroplacental blood ow velocity waveforms in normal pregnancya cross-sectional study. Acta Obstet Gynecol Scand 67:347-354, 1988 3. Aardema MW, Saro MC, Lander M, et al: Second trimester Doppler ultrasound screening of the uterine arteries differentiates between subsequent normal and poor outcomes of hypertensive pregnancy: two different pathophysiological entities? Clin Sci (Lond) 106:377-382, 2004 4. Parretti E, Mealli F, Magrini A, et al: Cross-sectional and longitudinal evaluation of uterine artery Doppler velocimetry for the prediction of pre-eclampsia in normotensive women with specic risk factors. Ultrasound Obstet Gynecol 22:160-165, 2003 5. Harrington K, Fayyad A, Takur V, et al: The value of uterine artery Doppler in the prediction of uteroplacental complication in multiparous women. Ultrasound Obstet Gynecol 23:50-55, 2004 6. Ferrazzi E, Bulfamante G, Mezzopane R, et al: Uterine Doppler velocimetry and placental hypoxic-ischemic lesion in pregnancies with fetal growth restriction. Placenta 20:389-394, 1999 7. Ghosh G, Breborowicz A, Brazert M, et al: Evaluation of third trimester uterine artery ow velocity indices in relationship to perinatal complications. J Matern Fetal Neonatal Med 19:551-555, 2006 8. Vergani P, Roncaglia N, Ghidini A, et al: Can we predict adverse neonatal outcome in fetal growth restriction near term? Am J Obstet Gynecol 195:S206, 2006 (abstract) 9. Lobos H, Rennie JM, Lees C: The natural history of fetal growth restriction in women with abnormal uterine artery Doppler. Prenat Diagn 25:331-332, 2005 10. Vergani P, Andreotti C, Roncaglia N, et al: Doppler predictors of adverse neonatal outcome in the growth restricted fetus at 34 weeks gestation or beyond. Am J Obstet Gynecol 189:1007-1011, 2003 11. Severi FM, Bocchi C, Visentin A, et al: Uterine and fetal cerebral Doppler predict the outcome of third-trimester small-for-gestational age fetuses with normal umbilical artery Doppler. Ultrasound Obstet Gynecol 19:225-228, 2002 12. McCowan LM, North RA, Harding JE: Abnormal uterine artery Doppler in small-for-gestational-age pregnancies is associated with later hypertension. Aust NZ J Obstet Gynaecol 41:56-60, 2001 13. van Asselt K, Gudmundsson S, Lindqvist P, et al: Uterine and umbilical artery velocimetry in pre-eclampsia. Acta Obstet Gynecol Scand 77: 614-619, 1998 14. Frusca T, Soregaroli M, Platto C, et al: Uterine artery velocimetry in patients with gestational hypertension. Obstet Gynecol 102:136-140, 2003 15. Li H, Gudnason H, Olofsson P, et al: Increased uterine artery vascular impedance is related to adverse outcome of pregnancy but is present in

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only one-third of late third-trimester pre-eclamptic women. Ultrasound Obstet Gynecol 25:459-463, 2005 Korszun P, Dubiel M, Kudla M, et al: Doppler velocimetry for predicting outcome of pregnancies with decreased fetal movements. Acta Obstet Gynecol Scand 81:926-930, 2002 Hernandez-Andrade E, Brodszki J, Lingman G, et al: Uterine artery score and perinatal outcome. Ultrasound Obstet Gynecol 19:438-442, 2002 Gudmundsson S, Korszun P, Olofsson P, et al: New score indicating placental vascular resistance. Acta Obstet Gynecol Scand 82:807-812, 2003 Soregaroli M, Valcamonico A, Scalvi L, et al: Late normalisation of uterine artery velocimetry in high risk pregnancy. Eur J Obstet Gynecol Reprod Biol 95:42-45, 2001 Frusca T, Soregaroli M: Role of uterine artery Doppler investigation in pregnant women with chronic hypertension. Eur J Obstet Gynecol 79:47-50, 1998 Roncaglia N, Crippa I, Locatelli A, et al: Prediction of superimposed preeclampsia using uterine artery Doppler velocimetry in women with chronic hypertension. Prenat Diagn 2008 (in press) Le Thi Huong D, Wechsler B, Vauthier-Brouzes D, et al: The second trimester Doppler ultrasound examination is the best predictor of late pregnancy outcome in systemic lupus erythematosus and/or the antiphospholipid syndrome. Rheumatology 45:332-338, 2006 Farrell T, Dawson T: Can uterine artery Doppler velocimetry predict adverse pregnancy outcome in women with antiphospholipid syndrome? Acta Obstet Gynecol Scand 80:609-610, 2001 Venkat-Raman N, Backos M, Teoh TG, et al: Uterine artery Doppler in predicting pregnancy outcome in women with antiphospholipid syndrome. Obstet Gynecol 98:235-242, 2001 Bracero LA, Schulman H: Doppler studies of the uteroplacental circulation in pregnancies complicated by diabetes. Ultrasound Obstet Gynecol 1:391-394, 1991 Pietryga M, Brazert J, Wender-Ozegowska E, et al: Abnormal uterine Doppler is related to vasculopathy in pregestational diabetes mellitus. Circulation 112:2496-2500, 2005 Pietryga M, Brazert J, Wender-Ozegowska E, et al: Placental Doppler velocimetry in gestational diabetes mellitus. J Perinat Med 34:108-110, 2006 Brar HS, Horenstein J, Medearis AL, et al: Cerebral, umbilical, and uterine resistance using Doppler velocimetry in postterm pregnancy. J Ultrasound Med 8:187-191, 1989 Abramowicz JS, Sherer DM, Warsof SL, et al: Fetoplacental and uteroplacental Doppler blood ow velocity analysis in premature rupture of membranes. Am J Perinatol 9:353-356, 1992

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Assessing Cardiac and Neurological Maturation During the Intrauterine Period

Curtis L. Lowery, MD, R. B. Govindan, PhD, Pamela Murphy, RN, and Hari Eswaran, PhD
The worlds rst magnetoencephalography (MEG) system specically designed for fetal and newborn assessment has been installed at the University of Arkansas for Medical Sciences. This noninvasive system called SARA (SQUID Array for Reproductive Assessment) consists of 151 primary superconducting sensors that detect biomagnetic elds from the human body. Since the installation of SARA, signicant progress has been made toward the ultimate goal of developing a clinical neurological assessment tool for the developing fetus. Using appropriate analysis techniques, cardiac and brain signals are recorded and studied to gain new understanding of fetal maturation. It is clear from our investigations that a combination of assessment protocols including both fetal heart and brain activity is necessary for the development of a comprehensive new method of fetal neurological testing. We plan to implement such a test protocol for fetuses at high risk for neurological impairment due to certain maternal risk factors and/or fetal diagnostic ndings. Semin Perinatol 32:263-268 2008 Elsevier Inc. All rights reserved. KEYWORDS fetal magnetoenecephalogram, fetal magnetocardiogram, HRV measures

lthough there has been a decrease in perinatal morbidity and mortality rates of the fetus and neonate over the past four decades, antenatal hypoxia and/or asphyxia continues to be a signicant health problem leading to major motor and cognitive disabilities such as cerebral palsy, hearing and visual impairment, and mental retardation. Although for many years both clinicians and the general population have believed that birth trauma and perinatal asphyxia were the primary cause of these handicaps, clinical studies in recent years have disputed this misconception.1-7 Most experts in this eld have estimated that the incidence of cerebral palsy associated with labor events is around 10%. One major problem arises from the fact that it is currently impossible to determine the timing, the type, the duration, or the severity of the insults that are associated with neurological decits in the newborn. Terms such as perinatal asphyxia, intrapartum asphyxia, hypoxic-ischemic encephalopathy, neonatal neurological dysfunctional syndrome, and fetal-neonatal anemia have all been used to describe the affected newborn. The nonselective use of these terms has produced great confusion

Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, AR. Address reprint requests to Curtis L. Lowery, MD, Department of Obstetrics and Gynecology, SARA Research Center, University of Arkansas for Medical Sciences, Little Rock, AR 72205. E-mail: LoweryCurtisL@ uams.edu

in the clinical literature. Because a thorough investigation attempting to identify the cause of neonatal neurological depression is often not attempted or is incomplete, the diagnoses of perinatal asphyxia is many times made by default.8 Electronic fetal heart rate monitoring is commonly used to assess fetal well-being in utero. While a reassuring fetal heart rate pattern predicts the birth of an infant with a 5-minute Apgar score of seven or greater with an accuracy 99%, nonreassuring tests have been associated with a false-positive rate of greater than 50%.9 Traditionally the neurological maturation of the fetus has been assessed using ultrasound studies.10,11 Although it has been possible to observe and evaluate fetal neurological development on a limited basis using ultrasound, direct access to the fetal electro-cortical signals is required for specic testing and analysis. Currently, evidence-based clinical decisions concerning fetal neurological damage as a result of hypoxia or asphyxia cannot be made with conventional techniques. To address these issues, SQUID Array for Reproductive Assessment (SARA) was developed through a grant provided by the National Institutes of Health/National Institute of Neurological Disorders and Stroke and is currently under operation at the University of Arkansas for Medical Sciences.12,13 The system has a 151 primary sensor array curved to t the shape of the maternal abdomen. This instrument is completely noninvasive and detects weak biomagnetic elds associated with the electrophysiological activity in the human 263

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264 body. To investigate the cardiac and neurological status of the fetus, we conduct serial fetal magnetocardiography (fMCG) and fetal magnetoencepalography (fMEG) recordings starting at 28 weeks of gestation.13-19 Newborn follow-up studies using the same fMEG protocol20 are performed within 2 weeks of delivery using a specially designed cradle that can be attached to the SARA system. All studies are performed with the aim of providing improved monitoring techniques for maternalfetal health and assisting physicians in the management of pregnancy and delivery. Some of the key results obtained through analysis of the signals obtained by SARA from the fetal cardiac and brain systems will be discussed in the next sections.

C.L. Lowery et al
determined using a portable ultrasound scanner after the patient sits down in front of the array. A fourth localization coil is then attached to the maternal abdomen at that site to provide additional positional information related to sensor coordinates. The ultrasound examination to evaluate fetal head position and distance from surface is repeated at the end of the study but before the patient moves from the array. The raw SARA recording consists of maternal heart, fetal heart, and brain signals. To perform data analysis we nullify the dominant maternal heart vectors by orthogonal projection. This method is rst applied to the raw signal to remove maternal heart artifact. At this point, the fetal heart data can be analyzed. This process is then reapplied to the residual data set (devoid of maternal heart) to remove fetal heart artifact to analyze the brain signals.

Methods
Subjects
The studies performed with SARA were approved by the University of Arkansas for Medical Sciences Human Research Advisory Committee and informed written consent was obtained from all subjects. A total of 433 fetal recordings lasting 6 minutes were performed on fetuses with gestational ages ranging from 27 to 40 weeks. Three hundred seventeen of these were acquired from 72 fetuses classied as high risk due to maternal complications such as pregnancy-induced/ chronic hypertension, hemoglobinopathies, or smoking21 that may compromise normal fetal development. The highrisk group was further subdivided into fetuses of mothers who smoked (smokers; 55 datasets from 23 mothers), fetuses who were diagnosed with intrauterine growth restriction (IUGR, 36 datasets from 10 fetuses), and all other high-risk fetuses. Of the 72 high-risk fetuses, 7 (9 datasets) had poor neonatal outcome. The demographic information of these subjects is given in Table 1. For details of the inclusion criteria for all high-risk mothers we refer to ref.21. The remaining 126 recordings were obtained from 37 healthy mothers and fetuses who were classied as low risk.

Results
Fetal Cardiac System
Beat-to-beat intervals were computed for all the fMCG signals using threshold detection technique. Standard heart rate variability (HRV) measures such as standard deviation of normal to normal intervals (SDNN), root mean square deviation of the successive differences (RMSSD), fraction (p) of the normal intervals greater than the chosen tolerance of x milliseconds from their previous values (pNNx), and the variance of the detrended time series at different time windows s containing s number of beat-to-beat intervals. To understand the differential maturation of the high-risk fetuses compared with the low-risk fetuses, we divided the data into the following three gestational age groups, 27 to 30 weeks, 31 to 35 weeks, and 36 to 40 weeks. Although we have repeated recordings from the same subjects in multiple gestation ages, we treat them all independently based on the following assumptions: dependency of the heart rate on the gestation age and the state of the fetus. Unlike SDNN, which captures the global variability in the beat-to-beat intervals, RMSSD captures the short-term variability (and hence high-frequency component of the HRV). pNNx is another measure that captures the short-term variability and quanties the uctuations in the ring of the sinus rhythm. It is computed by calculating the ratio of the number of normal to normal intervals which differ by a chosen tolerance value of x milliseconds from their previous value to the total number of intervals. We used three different tolerance values, namely, 10, 15, and 20 milliseconds, and found that the best difference between the groups was observed only with the tolerance of 10 milliseconds.21 All three measures are indicators of the alterations in the cardiac dynamics and can be used to quantify the maturation of the fetus based on the cardiac dynamics. The results obtained for SDNN, RMSSD, and pNN10 are shown in Figure 1 in different gestational ages. In SDNN there is a difference between the high-risk and low-risk groups in the 27 to 31 week and 36 to 40 week divisions and no difference in the 31 to 35 week division. In RMSSD and pNN10 there is a signicant difference between the low-risk

General Recording Methods and Analysis

The routine recording sessions range from 6 to 12 minutes in a continuous mode at a sampling rate of 312.5 Hz and a band pass of direct current (dc) to 100 Hz. The position and orientation of the mothers abdomen, relative to the sensor array, are determined using two localization coils placed at duciary points on the mothers right and left side and one on her spine at the level of the umbilicus. These coils do not interfere with the MEG recordings. The fetal head position and distance of head from maternal abdominal surface are

Table 1 Demographic Information of the High-Risk Mothers Maternal Number of Age* Subjects 18 to 20 21 to 35 36 to 48 11 44 9 Race White Black Hispanic (Others) Number of Subjects 37 31 3

*Information was not available for the remaining seven subjects.

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Figure 1 Comparison of HRV measures of low-risk and high-risk fetuses in three different gestational age groups (A, D, G) SDNN, (B, E, H) RMSSD and (C, F, I) pNN10. The difference between the groups was assessed using Students t-test is given in the inset and P 0.05 was considered to be statistically signicant. (Color version of gure is available online.)

and high-risk groups in the 31 to 35 week and 360 to 400 week division as well. In the 31 to 35 week division low-risk fetuses had lower values of pNN10 and RMSSD compared with high-risk fetuses, while in the 36 to 39 week division an exactly opposite behavior was observed.21 We performed a subgroup analysis by separating the IUGR fetuses and compared their pNN10 measures with low-risk fetuses. We found that in the 31 to 35 week division there was a signicant difference between IUGR fetuses and low-risk fetuses. Further, in this gestational week division the values of pNN10 for IUGR fetuses were less compared with the low-risk fetuses.21 There was no difference between these two groups in the 27 to 31 week division. In the 36 to 40 week division no comparison was made because of fewer number of datasets in the IUGR group. We did not nd any signicant difference between the low-risk fetuses and fetuses of the smokers and fetuses with poor neonatal outcome either. For low-risk fetuses there was a positive trend in the pNN10 ( 2 0.052; P 0.0114) and RMSSD ( 2 0.048;

P 0.012) as a function of gestational age, while no such trend was observed for SDNN ( 2 0.012; P 0.220).21 Also no trend was observed in any of the HRV measures for the high-risk fetuses. The values of pNN10 and RMSSD in the 31 to 35 week division show that high-risk fetuses demonstrate an increase in maturation rate compared with low-risk fetuses. In the later gestational age, low-risk fetuses tend to mature at normal rates while the high-risk fetuses did not show continuing maturation. This fact combined with the dependency of pNN10 and RMSSD of the low-risk fetuses with gestational age and absence of such a trend for high-risk fetuses clearly indicate that the low-risk fetuses show a progressive maturation while high-risk fetuses show an early maturation. The difference in the pNN10 values between low-risk and IUGR fetuses in 31 to 35 week division indicate that the later group lack normal maturation. To quantify the variations in the fetal cardiac beat-to-beat intervals, we performed detrended time series (DTS) analysis.

266

C.L. Lowery et al

Figure 2 Beat-to-beat intervals (in beats per minute, bpm) for (A) low-risk fetus, (D) high-risk fetuses, and (E) IUGR fetus (B, E, F), respectively, show the moving average obtained for the data shown in (A, D, E) for a window size of s containing 32 beats. (C, F, I) Detrended time series, DTS, which is the original data (shown in the top panel) minus the trend (shown in the middle panel). Note that qualitatively the uctuations in DTS are high in the low-risk fetus and low in the IUGR fetus. (Color version of gure is available online.)

This approach consists of the following three steps: (i) a running average is performed on the beat-to-beat interval time series for a chosen window s (usually in powers of 2) to obtain a trend series; (ii) The trend obtained is then subtracted from the beat-to-beat interval to get the DTS; and (iii) standard deviation (SD) is computed for the DTS. The steps (i-iii) are repeated for different s values usually ranging from 2 to one-fourth of the length of the data and SD is computed for each value of s. Here, we varied s from 2 beats to 256 beats. In Figure 2 beat-to-beat intervals, the trend obtained for a window containing 32 beats, and the DTS are shown for a low-risk fetus (Fig. 2A-C), high-risk fetus (Fig. 2D-F), and an IUGR fetus (Fig. 2G-I). In general, SD for a large value of s corresponds to the quantifying low-frequency component of the beat-to-beat variability and vice versa. The SDs are log-transformed to produce Gaussian-distributed error and

then subjected to least-squares regression to identify trends with gestation age. The residuals resulting from trend removal are compared between different groups using t-tests with multiple-comparison adjustment via step-down permutation. These results are given in Table 2. Low-risk and highrisk groups show difference only in the low-frequency component (at large time scales). Low-risk and high-risk fetuses show signicant difference from the IUGR group at highfrequency component (at short time scales). This result is in agreement with the pNN10 results obtained for low-risk and IUGR fetuses. Further, low-risk and high-risk fetuses show higher variability compared with high-risk and IUGR fetuses and, between the low-risk and high-risk fetuses, low-risk showed higher variability. These results point to the fact that in IUGR fetuses the autonomous nervous system is suppressed.22

Assessing cardiac and neurological maturation during the intrauterine period

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Table 2 Comparison of the SD(s) of the Detrended Time Series at Different Window Sizes for the Three Groups of Fetuses Are Compared for the Three Groups of Fetuses

P Value
Low-Risk vs High-Risk Variable SD(2) SD(4) SD(8) SD(16) SD(32) SD(64) SD(128) SD(256) Raw 0.429 0.959 0.822 0.373 0.164 0.066 0.030* 0.0381 Adjusted 0.532 0.959 0.8936 0.526 0.283 0.140 0.082* 0.097 Low-Risk vs IUGR Raw 0.005 0.001a 0.010 0.121 0.491 0.704 0.512 0.275 Adjusted 0.016 0.003a 0.026 0.211 0.621 0.704 0.621 0.395 High-Risk vs IUGR Raw 0.081 0.001a 0.012 0.058 0.165 0.184 0.079 0.038 Adjusted 0.628 0.006a 0.035 0.098 0.199 0.199 0.114 0.081

*Statistically signicant cases. The raw P values and also the P values adjusted for multiple comparisons using step-down permutations are given. P < 0.05 is considered to be statistically signicant.

Fetal Brain System

To analyze the fetal brain data, we performed spectral analysis on the residual data that is devoid of maternal and fetal heart signals. The data were ltered in a band width ranging from 0.5 to 25 Hz using a band-pass lter. We compared the spectral results of the low-risk fetuses with all the high-risk group fetuses. For this purpose power spectra were computed for all 151 SARA sensors with a frequency resolution of 0.1 Hz. For each sensor, the spectral power was computed in (0.5-4 Hz), (4-8 Hz), (8-13 Hz), and (13-25 Hz) bands and normalized by the total power which is sum of the powers in all four bands. The power in each band was averaged over all the sensors to get the estimate of the same. The estimated powers in the four bands were compared between different groups using Students t-test and a P value less than 0.1 was considered to be statistically signicant. The results are summarized in Table 3. There is a signicant difference

between the groups at least in one of the spectral bands except of high risk and smokers, where there is no difference between them in any of the spectral bands. A further study in this direction by identifying the continuous and discontinuous brain patterns may help to understand these differences and will be pursued in the future.

Summary
In summary, investigation of magnetic fetal brain responses with MEG is becoming an established eld of research. Using the SARA system, we have performed many fMEG and fMCG studies in both low-risk and high-risk patient populations. To improve fetal neurological testing, a combination of comprehensive assessment protocols including fetal heart and brain activity is valuable. We have developed a combination of recording parameters using auditory and visual stimuli and spontaneous brain activity for a multimodal approach to the investigation of fetal health. This protocol can be referred to as SNAP (SARA Neurological Assessment Protocol) and can be used to evaluate the neurological status of the fetus and newborn.

Table 3 Comparison of the Spectral Power of Low-Risk (LR), High-Risk (HR), Smokers (SM), and Poor Outcome (PO) and IUGR Fetuses in Four Different Spectral Band (0.5 to 4 Hz), (4 to 8 Hz), (8 to 13 Hz), and (13 to 25 Hz) Using t-Test

P Values Obtained by Testing the Null Hypothesis that the Two Groups Have the Same Mean Value at the Signicance Level of 0.1
Group HRPO SMPO HRPO LRHR LRSM LRPO IUGRLR LUGRHR IUGRPO IUGRSM 0.094* 0.048* 0.536 0.001* 0.001* 0.19 0.108 0.035* 0.97 0.013* 0.690* 0.513 0.653 0.001* 0.001* 0.001* 0.298 0.001* 0.003* 0.001* 0.098* 0.061* 0.766 0.001* 0.001* 0.23 0.122 0.04* 0.99 0.02* 0.082* 0.053* 0.536 0.08* 0.02* 0.001* 0.076* 0.63 0.002* 0.398

References
1. Low JA: Reections on the occurrence and signicance of antepartum fetal asphyxia. Best Pract Res Clin Obstet Gynaecol 18.3:375-382, 2004 2. Nelson KB: Dening hypoxic-ischemic birth events. Dev Med Child Neurol 45.1:71-72, 2003 3. Nelson KB: Neonatal encephalopathy: etiology and outcome. Dev Med Child Neurol 47(5):292, 2005 4. Nelson KB, Dambrosia JM, Ting TY, et al: Uncertain value of electronic fetal monitoring in predicting cerebral palsy. N Engl J Med 334(10): 613-618, 1996 5. Nelson KB, Grether KB: Causes of cerebral palsy. Curr Opin Pediatr 11(6):487-491, 1999 6. Grether JK, Nelson KB: Maternal infection and cerebral palsy in infants of normal birth weight. JAMA 278(3):207-211, 1997 7. Grether JK, Nelson KB, Walsh E, et al: Intrauterine exposure to infection and risk of cerebral palsy in very preterm infants. Arch Pediatr Adolesc Med 157(1):26-32, 2003 8. Freeman JM, Nelson KB: Intrapartum asphyxia and cerebral palsy. Pediatrics 82(2):240-249, 1988

*Statistically signicant difference. P < 0.1 is considered to be statistically signicant.

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9. Miller DA, Rabello YA, Paul RH: The modied biophysical prole: antepartum testing in the 1990s. Am J Obstet Gynecol 174(3):812-817, 1996 10. Awoust J, Levi S: Neurological maturation of the human fetus. Ultrasound Med Biol 2:583-587, 1983 11. Luz NP: Auditory evoked response of the human fetus: simplied methodology. J Perinat Med 19(3):177-183, 1991 12. Robinson SE, Burbank MB, Fife AA, et al: A biomagnetic instrument for human reproductive assessment. Biomag 2000, Proceedings of the 12th International Conference in Biomagnetism: Nenonen J, et al (eds): Helsinki Univ. of Tech., Espoo, Finland, 2001, pp 919-922 13. Eswaran H, Lowery CL, Robinson SE, et al: The challenges of recording human fetal auditory evoked elds using magnetoencephalography. J Matern Fetal Med 9(5):303-307, 2000 14. Preissl H, Lowery CL, Eswaran H: Fetal magnetoencephalography: current progress and trends. Exp Neurol 190:S37-S43, 2004 15. Holst M, Eswaran H, Lowery CL, et al: Development of auditory evoked elds in human fetuses and newborns: a longitudinal MEG study. Clin Neurophysiol 116(8):1949-1955, 2005

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16. Eswaran H, Wilson JD, Preissl H, et al: Short-term serial magnetoencephalographic recordings of fetal auditory evoked responses. Neurosci Lett 331(2):128-132, 2002 17. Eswaran H, Wilson JD, Preissl H, et al: Magnetoencephalographic recordings of visual evoked brain activity in the human fetus. Lancet 360(9335):779-780, 2002 18. Eswaran H, Lowery CL, Wilson JD, et al: Functional development of the visual system in human fetus using magnetoencephalography. Exp Neurol 190:S52-S58, 2004 19. Rose DF, Eswaran H: Spontaneous neuronal activity in fetuses and newborns. Exp Neurol 190:S28-S36, 2004 20. Haddad N, Shihabuddin B, Lowery CL, et al: Magnetoencephalography in healthy neonates. Clin Neurophysiol 117:289-294, 2006 21. Govindan RB, Lowery CL, Campbell JQ, et al: Early maturation of sinus rhythms in high-risk fetuses. Am J Obstet Gynecol 196:572e1-572e7, 2007 22. Kikuchi A, Shimizu T, Hayashi A, et al: Nonlinear analyses of heart rate variability in normal and growth-restricted fetuses. Early Hum Dev 82:217-226, 2006

Antenatal Testing: Diabetes Mellitus

Michael P. Nageotte, MD
Diabetes complicating pregnancy is a problem for which fetal surveillance testing is considered to be the standard of care. In response to the unacceptable frequency of stillbirth in such pregnancies, fetal testing historically was rst introduced to manage women whose pregnancies were complicated by diabetes. Essentially all forms of antepartum testing have been used to assess fetal well-being during the third trimester of pregnant diabetics. The contraction stress test became established as the gold standard, yet other testing protocols have been used successfully. It is clear that control of diabetes throughout gestation, not just in the later stages, is more important for optimal outcome than is a specic form of fetal testing. Biweekly testing has become the standard and with well-controlled diabetics, allowing the gestation to continue until the onset of spontaneous labor, even when the gestation exceeds 40 weeks, is appropriate management with normal testing. Semin Perinatol 32:269-270 2008 Elsevier Inc. All rights reserved. KEYWORDS diabetes, fetal surveillance, antepartum testing

erinatal mortality in diabetic women continues to be reported at signicantly higher rates than in women without diabetes.1 How much of this difference is due to poor control of maternal disease, increased risk of congenital anomalies, pregnancy complications such as intrauterine growth restriction (IUGR) or preeclampsia, or true uteroplacental insufciency is unclear. While sudden unexplained intrauterine fetal death has became a far less common pregnancy complication for women with diabetes, concern over the adequacy of placental function at various gestational ages in such patients has led to the routine use of fetal surveillance in diabetic pregnancies. Historically, before the implementation of fetal testing, diabetic women often had their delivery date determined by the severity of their disease. Following a protocol initiated at the Joslin Clinic in an effort to prevent stillbirth, women with diabetes complicated by vascular disease were delivered at 35 to 36 weeks or earlier. Women with less advanced disease delivered no later than 37 to 38 weeks. Many of these were Cesarean deliveries and were associated with a signicant incidence of neonatal respiratory morbidity and mortality. It was unclear if such management was necessarily improving outcome when compared with prior management protocols.
Department of Obstetrics and Gynecology, University of California, Irvine, CA. Address reprint requests to Michael P. Nageotte, MD, Associate Chief Medical Ofcer, Long Beach Memorial Medical Center, Professor, Department of Obstetrics and Gynecology, University of California, Irvine, CA 90806. E-mail: mnageotte@memorialcare.org

With three main goals of antepartum fetal surveillance being avoidance of fetal deaths, early detection of fetal compromise, and prevention of unnecessary premature birth, diabetes complicating pregnancy poses an ideal metabolic disorder to assess the potential value of various testing modalities. Unfortunately, there have been no adequately sized prospectively randomized studies that compare the efcacy of different testing protocols.

Nonstress Test (NST)

In many centers today, the NST is the preferred antepartum heart rate test for women with diabetes. While testing is initiated generally at 32 weeks gestation, it is started as early as 28 weeks gestation in diabetic women with renal disease, vascular disease, or suspected intrauterine growth restriction. Golde and Montoro reported using the NST in diabetic patients with the contraction stress (CST) as backup.2 No stillbirths were reported in 107 insulin-dependent patients using this testing protocol. In a review of 13 studies using the NST weekly for fetal surveillance, Lavery reported that among the 23 stillbirths reported within a week of a reactive NST which did not result from acute clinical events, 10 were in women with insulin-dependent diabetes.3 Based on this report and others, the recommended frequency of testing for women with diabetes increased to twice per week. In 1995, Kjos and coworkers reported on twice weekly NST and amniotic uid volume assessment in 2134 women with diabetes in pregnancy.4 There were no stillbirths within 269

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270 4 days of the last test and the overall corrected stillbirth rate for the group was 1.4/1000. Further, while use of amniotic uid assessment did not appear signicant, factors predictive of a need for Cesarean delivery for fetal labor were the presence of a deceleration, nonreactivity, or the presence of both ndings.

M.P. Nageotte
Landon and Gabbe reported on 35 insulin-dependent women followed with umbilical artery Doppler studies.10 One-half of the women with vascular disease complicating their diabetes had abnormal Doppler studies, while only 12% of uncomplicated diabetics had such ndings. Further, these authors stated that the S/D ratio was independent of glycemic control. Johnstone and coworkers reported on a large cohort of diabetic pregnancies followed with both BPP and Doppler.11 Of concern was the nding that over half of the women delivered for an abnormal BPP had a normal Doppler but the infants were severely depressed. It would appear that mild to moderate fetal acidosis may not be detected by umbilical artery Doppler.

Contraction Stress Test

The CST has a longer history of use for fetal surveillance in pregnancies complicated with diabetes than any other means of testing. Based on the evaluation of the fetal heart rate response to uterine contractions, the CST has the potential to test for a chronic condition and serve as a surrogate for placental function. Ray and Freeman reported on the use of the CST in a cohort of diabetic women.5 Thirty-eight women had a weekly CST performed with the results blinded. Of the nine patients whose last CST before delivery was a positive test, two had a fetal demise and three had low 5-minute Apgar. This led to the wide adoption on the CST in the management of diabetes in pregnancy. While performed only weekly, the predictive value of a negative test remained very impressive for various centers implementing this form of testing.6 However, there are signicant problems with the CST. While there are very rarely false-negative results, the falsepositive rates approach 50 to 60%. Further, the frequency of such positive testing led to delivery for an abnormal test in upwards of 10% of tested diabetic women. Thus, the CST is overall less efcient, more costly, and more inconvenient that the NST. Consequently, few perinatal centers continue to use the CST as their primary means of antepartum fetal surveillance.

Conclusions
Fetal surveillance remains the standard in pregnancies complicated with diabetes. What is unclear is the efcacy of such testing for whatever type in patients with well-controlled or true gestational diabetes. Fetal heart rate monitoring as primary surveillance would appear appropriate with a testing frequency of every 3 to 4 days. Abnormal tests should have a backup test performed due to the high rate of false-positive testing. This is an area that would benet from well-designed prospective studies addressing the issue of test type as well as timing and frequency of testing.

References
1. Kodama Y, Sameshima H, Ikenoue T: Regional population-based study on pregnancy outcomes in women with diabetes mellitus in Japan. J Obstet Gynecol Res 33(1):45-48, 2007 2. Golde SH, Montoro M: The role of nonstress tests, fetal biophysical prole and contraction stress tests in the outpatient management of insulin-requiring diabetic pregnancies. Am J Obstet Gynecol 148:269275, 1984 3. Lavery JP: Nonstress fetal heart rate testing. Clin Obstet Gynecol 25: 689-694, 1982 4. Kjos SL, Leung A, Henry OA, et al: Antepartum surveillance in diabetic pregnancies: predictors of fetal distress in labor. Am J Obstet Gynecol 173(5):1532-1539, 1995 5. Ray M, Freeman R: Clinical experience with the Oxytocin challenge test. Am J Obstet Gynecol 114:1-6, 1972 6. Freeman RK, Anderson G, Dorchester W: A prospective multi-institutional study of antepartum fetal heart rate monitoring. I. Risk of perinatal mortality and morbidity according to the antepartum fetal heart rate test results. Am J Obstet Gynecol 143:771-777, 1982 7. Johnson JM, Lange IR: Biophysical prole scoring in the management of the diabetic pregnancy. Obstet Gynecol 72:841-845, 1988 8. Bracero L, Schulman H: Umbilical artery velocimetry in diabetes and pregnancy. Obstet Gynecol 68:654-658, 1986 9. Oloffson P, Lingman G, Marsal K, et al: Fetal blood ow in diabetic pregnancy. J Perinat Med 15:545-553, 1987 10. Landon MB, Gabbe SG: Doppler umbilical artery velocimetry in pregnancy complicated by insulin-dependent diabetes mellitus. Obstet Gynecol 73:961-965, 1989 11. Johnstone F, Steel JM, Haddad NG, et al: Doppler umbilical artery ow velocity waveforms in diabetic pregnancy. Br J Obstet Gynaecol 99: 135-140, 1992

Biophysical Prole (BPP)

The BPP combines acute (NST, fetal breathing, movement, and tone) and chronic (amniotic uid quantity) markers. The BPP has been used for fetal surveillance in insulin-dependent patients with reportedly excellent negative-predictive value. Johnson and Lange reported on the use of twice weekly BPP in 50 insulin-dependent and 188 gestational diabetic pregnancies.7 No stillbirths were reported; abnormal BPP rate was only 3.3%, and of the eight women whose last BPP was abnormal, three had signicant neonatal morbidity. Thus, the BPP used twice weekly appears to be an adequate test with few unnecessary interventions.

Doppler Velocimetry
Bracero and Schulman and Olofsson and coworkers described the use of umbilical artery Doppler velocimetry in diabetic pregnancies.8,9 Signicant positive associations were noted between systolic/diastolic (S/D) ratio and maternal serum glucose level. Further, elevated S/D ratios were associated with subsequent fetal labor intolerance.

Antepartum Testing in Patients with Hypertensive Disorders in Pregnancy

Roger K. Freeman, MD
Antepartum fetal testing in pregnant patients with hypertensive disorders may be benecial in preventing stillbirth and hypoxic sequelae in the fetus. The highest risk patients in this category are those with intrauterine growth restriction, superimposed preeclampsia, associated medical complications such as diabetes, systemic lupus erythematosis, chronic renal disease, or history of a prior stillbirth. The current recommended method of primary testing is a twice weekly modied biophysical prole with either a full BPP or a contraction stress test for backup evaluation of those patients with lack of reactivity or decreased amniotic uid volume on a modied biophysical prole. Even uncomplicated patients with chronic hypertension or pregnancy-induced hypertension carry an increased risk of perinatal mortality and for these patients testing should begin at 33 to 34 weeks gestation. Patients with complications of intrauterine growth restriction, preeclampsia, diabetes, systemic lupus erythematosis, or chronic renal disease should have antepartum testing begin when intervention for fetal indications is judged to be appropriate, usually beginning at about 26 weeks gestation. Doppler velocimetry may be helpful in further evaluation of those patients in the early third trimester with abnormal primary testing. Semin Perinatol 32:271-273 2008 Elsevier Inc. All rights reserved. KEYWORDS hypertension, antepartum testing, IUGR, modied biophysical prole

here are various hypertensive disorders that may complicate pregnancy. The three main entities are chronic hypertension with diagnosis preceding pregnancy, pregnancyinduced hypertension where the elevated blood pressure is rst recognized during pregnancy, and preeclampsia where in addition to hypertension developing during pregnancy the patient manifests the onset of proteinuria and may also have other systemic ndings including liver function abnormalities, platelet count decrease, hemolysis, and in the extreme the patient may develop full-blown eclampsia with seizures. Further complications may affect the mother, the worst being cerebral hemorrhage. Other disorders may have hypertension as part of the disease process including such diagnoses as chronic renal disease, systemic lupus erythematosis, vascular involvement with diabetes, and the hemolytic uremic syndrome. In these later diagnoses sometimes it is difcult to determine whether the patient has preeclampsia or proteinuria due to one of these other causes.

The fetus also is impacted by hypertensive disorders in pregnancy. Because of vasoconstriction affecting the uteroplacental circulation, intervillous space blood ow may be compromised and this can result in interruption in the supply of oxygen to the fetus. When uteroplacental insufciency is present, another complication may develop, a reduction in amniotic uid volume. Oligohydramnios may result in loss of protection of the umbilical cord from mechanical compression and can further result in decreased respiratory function of the placenta. Chronic fetal compromise resulting from uteroplacental insufciency caused by these various hypertensive disorders may result in intrauterine growth restriction (IUGR) and abnormal fetal heart rate patterns during labor and may cause permanent CNS damage from fetal hypoxia and in the extreme may result in antepartum or intrapartum fetal demise.

University of California at Irvine, Long Beach Memorial Medical Center, and Miller Childrens Hospital, Long Beach, CA. Address reprint requests to Roger K. Freeman, MD, University of California at Irvine, Department of Obstetrics and Gynecology, 2801 Atlantic Ave., Long Beach, CA 90801. E-mail: docrkf@aol.com

Methods for Antepartum Fetal Evaluation in Hypertensive Patients

Until the early 1970s the only methods available to evaluate fetal well-being in such conditions were fetal movement 271

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272 counting and clinical measurement of uterine growth. Biochemical methods to evaluate uteroplacental function were the rst strategies introduced using laboratory values that showed some correlation with fetal well-being. Twenty-four hour urinary and plasma estriol determinations were the primary biochemical methods employed for evaluation of fetal well-being in hypertensive gravidas. While there was a general correlation with fetal growth, the utilization of these methods for the timing of delivery aimed at avoiding fetal death or damage was imprecise.1 In the 1970s biophysical methods including the contraction stress test (CST), nonstress test (NST), and imaging ultrasound were introduced. The biophysical prole (BPP) and umbilical artery Doppler velocimetry were introduced in the 1980s and today various combinations of these tests for both primary surveillance and secondary evaluation (backup support of abnormal primary test results) are the principle methods employed for fetal surveillance in patients with hypertensive disorders in pregnancy. IUGR is associated with hypertensive pregnancies and represents a clinical manifestation signaling signicant uteroplacental insufciency, placing the fetus at increased risk for death or damage. For this reason serial ultrasound scans to detect lagging fetal growth are a necessary piece of antenatal testing in hypertensive pregnancies. Scans should occur every 3 to 4 weeks beginning as early as 26 weeks after initial dating scans in the rst trimester and anatomical survey in the second trimester establishing baseline numbers. In patients who develop preeclampsia growth scans should occur at the time of diagnosis and be repeated every 3 to 4 weeks thereafter. Doppler velocimetry may be helpful in differentiating between growth lag due to uteroplacental insufciency, IUGR due to anomalies, genetic defects, infection, and constitutional small size. Antepartum fetal heart rate testing (AFHRT) was originally done using the CST.2 While this method has been largely abandoned for primary surveillance due to the difculty and time-consuming nature of the test, and some contraindications to the test such as premature labor, rupture of membranes, or prior classical cesarean section, there is no test that has proven to have fewer false-negative results than the CST.3-5 This test includes an acute marker, which is the evaluation for fetal heart rate accelerations, and a chronic marker, the fetal heart rate response to uterine contractions, which is a good measure of uteroplacental reserve. Today the CST serves mainly as a backup test when a NST is not reactive and or the modied BPP is either nonreactive or has reduced amniotic uid volume. Nipple stimulation has largely replaced the administration of IV oxytocin for induction of contractions. The test, when used for primary surveillance, need be done only once a week following a negative test. Reactive positive CSTs do not demand intervention before fetal maturity and if such a patient labors after this test result, about half of the patients will require intervention for nonreassuring fetal status.6 However, if the CST is nonreactive and positive, the likelihood of tolerating labor is very small and one study indicates that there may be signicant neurological damage in some cases.7

R.K. Freeman
In the 1980s the NST was introduced for primary surveillance but disappointing results showed it to be no better than no testing in four randomized controlled trials when done once weekly.8-11 A study by Boehm and coworkers showed twice weekly NSTs were less likely to be followed by stillbirth when done twice weekly but the results did not reach statistical signicance.12 While the NST is still used as a sole test for fetal well-being, it is only an acute marker of fetal condition at the time of the test and is not a good predictor of future status of the fetus. For this reason we do not use it as a stand-alone test. In the 1980s Manning and coworkers introduced the concept of the BPP, which includes the measurement of fetal breathing, tone, movement, and amniotic uid volume in addition to the NST.13 With a maximum of two points given for each function measured, a perfect score of 10 is possible. Most clinicians consider a score below 6 to be non-reassuring and depending on the gestational age a decision for delivery may be made. The BPP has a false-negative rate similar to the CST but in addition gives information on fetal malformations. It contains both acute markers (NST, movement, tone) and a chronic marker (amniotic uid index [AFI]). It is used for both primary surveillance on a once weekly basis and as a backup test for the NST or modied BPP. Eden and coworkers14 rst introduced the concept of the modied BPP, which includes an acute marker (NST) and a chronic marker (AFI), and subsequent evaluations of the test have shown sensitivity and specicity comparable to the CST and full BPP for primary surveillance.15 When the NST part is non-reactive or the AFI part of the test is low, a CST or full BPP is used for backup.16 The modied BPP should be done twice weekly. This is the most common primary surveillance method used today in hypertensive patients. Doppler umbilical arterial velocimetry appears to have its maximum use as secondary surveillance especially in pregnancies early in the third trimester where reactivity may not be present because of gestational age and intervention may be delayed based on the test result in such very premature gestations.

Which Hypertensive Patients Should Be Tested?

In a large multi-institutional study of AFHRT hypertension was the second most common indication for fetal testing and the incidence of positive CSTs as the worst test result was 3.9% compared with 1.6% for postdates and 7.4% for IUGR as the primary indication for testing. In the most recent American College of Obstetricians and Gynecologists practice bulletin on chronic hypertension in pregnancy,17 they do not recommend antepartum fetal testing in patients with mild to moderate blood pressure abnormalities and in the absence of preeclampsia and/or IUGR. Sibai and coworkers recommended testing all chronic hypertensives in 198318 but in 2007 they recommend testing only those hypertensive patients with preeclampsia and/or IUGR.19 In a 1994 study by Rey and Couturier, they found uncomplicated chronic hypertension to have almost twice the incidence of IUGR and

Antepartum testingtesting for hypertensive disorders

over twice the perinatal mortality rate compared with the general population.20,21 In hypertensive patients with a history of a prior stillbirth, we found the incidence of a positive CST to be 12% compared with only 3.7% if a prior stillbirth was the only indication for testing.22 Thus it would appear that all patients with a diagnosis of mild to moderate chronic hypertension in pregnancy are candidates for AFHRT.

273 improve outcome especially in patients with IUGR in the early third trimester. There is certainly a great need also to evaluate long-term outcomes in the progeny of patients with hypertensive disorders in pregnancy who are followed with antepartum testing for fetal well-being.

References
1. Neilson JP: Biochemical tests of placental function for assessment on pregnancy. Cochrane Database Syst Rev (2):CD000108, 2003 2. Freeman R: The use of the oxytocin challenge test for antepartum clinical evaluation or uteroplacental respiratory function. Am J Obstet Gynecol 121(4):481-489, 1975 3. Freeman R, Anderson G, Dorchester W: A prospective multi-institutional study of antepartum fetal heart rate monitoring. I. Risk of perinatal mortality and morbidity according to antepartum fetal heart rate test results. Am J Obstet Gynecol 143:771-777, 1982 4. Freeman R, Anderson G, Dorchester W: A prospective multi-institutional study of antepartum fetal heart rate monitoring. II. Contraction stress test versus nonstress test for primary surveillance. Am J Obstet Gynecol 143:778-781, 1982 5. Nageotte M, Towers C, Asrat T, et al: The value of a negative antepartum test: contraction stress test and modied biophysical prole. Obstet Gynecol 84:231-234, 1994 6. Braly P, Freeman R: The signicance of fetal heart rate reactivity with a positive oxytocin challenge test. Obstet Gynecol 50:689-694, 1977 7. Beischer N, Drew J, Ashton P, et al: Quality of survival of infants with critical fetal reserve detected by antenatal charditocography. Am J Obstet Gynecol 146:662-670, 1983 8. Kidd L, Patel N, Smith R: Non-stress antenatal cardiotocographya prospective randomized clinical trial. Br J Obstet Gynecol 92:11561159, 1985 9. Flynn A, Kelly J, Manseld H, et al: A randomized controlled trial of antepartum non-stress cardiotocography. Br J Obstet Gynecol 89:427433, 1982 10. Brown V, Sawyers S, Parsons R, et al: The value of antepartum cardiotocography in the management of high risk pregnancy: a randomized controlled trial. Br J Obstet Gynecol 89:716-722, 1982 11. Lumley J, Lester J, Anderson I, et al: A randomized trial of weekly cardiotocography in high-risk obstetric patients. Br J Obstet Gynecol 1018-1026, 1983 12. Boehm FH, Salyer S, Shah D: Improved outcome of twice weekly nonstress testing. Obstet Gynecol 67:566-568, 1986 13. Manning F, Platt L, Sipos L: Antepartum fetal evaluation: development of a biophysical prole. Am J Obstet Gynecol 136:787-795, 1980 14. Eden R, Seifert R, Kodack L, et al: A modied biophysical prole for antenatal surveillance. Obstet Gynecol 71:365-369, 1988 15. Clark S, Sabey P, Jolley K: Non-stress testing with acoustic stimulation and amniotic volume assessment: 5973 tests without unexpected fetal death. Am J Obstet Gynecol 160:694-697, 1989 16. Nageotte M, Towers C, Asrat T, et al: Perinatal outcome with the modied biophysical prole. Am J Obstet Gynecol 170:1672-1676, 1994 17. American College of Obstetricians and Gynecologists Practice Bulletin Number 29. Chronic Hypertension in Pregnancy. Washington, DC, ACOG, July, 2001 18. Sibai B, Abdella T, Anderson G: Pregnancy outcome in 211 patients with mild chronic hypertension. Obstet Gynecol 61:571-576, 1983 19. Sibai B: Chronic hypertension in pregnancy, in Queenan J (ed): Management of High Risk Pregnancy. Washington, DC, ACOG, 2007 20. Rey E, Couturier A: The prognosis of women with chronic hypertension in pregnancy. Am J Obstet Gynecol 171:410-416, 1994 21. Jain L: Effect of pregnancy induced and chronic hypertensionon pregnancy outcome. J Perinatol 17:425-427, 199 22. Freeman R, Dorchester W, Anderson G: The signicance of a previous stillbirth. Am J Obstet Gynecol 151:7-13, 1985 23. Pircon R, Lagrew D, Towers C, et al: Antepartum testing in the hypertensive patient: when to begin. Am J Obstet Gynecol 164:1563-1570, 1991

When to Start AFHRT in Hypertensive Gravidas?

Depending on when in pregnancy stillbirths are likely to occur and when AFHRT is likely to result in intervention for fetal jeopardy, one must decide when to initiate testing. Assuming that ultrasound surveillance has been initiated, the detection of IUGR should prompt testing as soon as fetal viability is determined to be sufcient to allow intervention for an abnormal test. This appears to be about 26 weeks in most institutions. In a study reported in 1991, Pircon and coworkers at our institution looked at 917 patients with chronic hypertension (n 408) or pregnancy-induced hypertension (PIH) (n 509) without preeclampsia followed with CST for primary surveillance.23 During the course of testing some of the patients developed preeclampsia and some were found to have IUGR. They also looked at all patients who presented with stillbirths whether tested or not. The results showed that there was only one fetal death in tested hypertensive patients and that patient had only NST surveillance. There were nine fetal deaths in untested patients with a diagnosis of chronic hypertension or PIH. There were no fetal deaths in the patients who were followed with CST primary surveillance and there were no neonatal deaths from prematurity in patients who had intervention for abnormal AFHRT results. If one looks at the gestational ages where intervention for abnormal AFHRT results occurred and the gestational age where fetal death occurred, all cases that occurred before 34 weeks were in patients with complicating diagnoses of superimposed preeclampsia, diabetes, chronic renal disease, or systemic lupus erythematosis. Using the results of this large trial, we begin testing uncomplicated chronic hypertensives or patients with PIH without preeclampsia at 33 to 34 weeks. In hypertensive patients with superimposed preeclampsia, IUGR, diabetes, chronic renal disease, or systemic lupus erythematosis we recommend beginning testing as soon as fetal viability is determined to be sufcient to allow intervention for an abnormal test. This is usually about 26 weeks. There are no randomized trials comparing the recommended testing protocols described here to no testing with respect to outcome. However, less rigorous studies of antepartum testing in the pregnant patient with a hypertensive disorder appear to suggest a benet in the reduction of stillbirth and may help to avert permanent hypoxia-caused CNS damage in their children. While randomized studies comparing AFHRT to no testing will not be done due to the perceived benet and medicallegal considerations, further studies comparing methods of testing, especially outlining the role of various Doppler velocimetry methodologies including umbilical, uterine, and middle cerebral artery evaluations, may

Fetal Growth Restriction

Jena Miller, MD, Sifa Turan, MD, and Ahmet A. Baschat, MD
Normal fetal growth is determined by the genetically predetermined growth potential and further modulated by maternal, fetal, placental, and external factors. Fetal growth restriction (FGR) is a failure to reach this potential and is clinically suspected if sonographic estimates of fetal weight, size, or symmetry are abnormal. Integration of fetal anatomy assessment, amniotic uid dynamics, uterine, umbilical, and fetal middle cerebral artery Doppler is the most effective approach to differentiate potentially manageable placentabased FGR from aneuploidy, nonaneuploid syndromes, and viral infection. Although placental dysfunction results in a multisystem fetal syndrome with impacts on short- and long-term outcome, only cardiovascular and behavioral responses are helpful to guide surveillance and intervention. Early-onset FGR before 34 weeks gestation is readily recognized but challenging to manage as questions about optimal delivery timing remain unanswered. In contrast, near-term FGR provides less of a management challenge but is often missed as clinical ndings are more subtle. Once placenta-based FGR is diagnosed, integrating multivessel Doppler and biophysical prole score provides information on longitudinal progression of placental dysfunction and degree of fetal acidemia, respectively. Choosing appropriate monitoring intervals based on anticipated disease acceleration and intervention when fetal risks exceed neonatal risks are the prevailing current management approaches. Semin Perinatol 32:274-280 2008 Elsevier Inc. All rights reserved. KEYWORDS fetal growth restriction, placental dysfunction, antenatal surveillance, biophysical prole scoring, Doppler ultrasound

ormal fetal growth depends on maternal, fetal, placental, and external factors combined with the genetically predetermined growth potential.1 The multisystem impacts of placental dysfunction produce an increase in the already elevated background mortality and morbidity.2,3 In preterm fetal growth restriction (FGR) uncertainty about delivery timing increases perinatal mortality and morbidity due to iatrogenic prematurity.4,5 Near-term questions about delivery timing are less critical. However, difculty in identifying term FGR contributes to over 50% of unexplained stillbirths.6,7 Accurate diagnosis, appropriate surveillance, and certainty about timing interventions are considered important prerequisites to improve these statistics. A systematic approach to the diagnosis and management of placenta-based FGR requires recognition of the clinical spectrum of this condition.

Pathophysiology of Placental Dysfunction

Effective rst-trimester trophoblastic adherence initiates placental development, ultimately resulting in the formation of a low impedance and high capacitance circulatory interface between the fetal and maternal circulations as well as a carrier system for principal nutrients.8 Despite this efciency of the placental unit in normal pregnancies, the fetus is vulnerable to nutrient deprivation when placental dysfunction supervenes. As the placenta extracts a xed proportion of the nutrient stream (70% of glucose and 40% of oxygen supplied to the uterus), fetal nutrition is restricted to the surplus that remains after placental demands have been met.8 Even mild placental dysfunction may restrict nutrient transfer and blood ow to the fetus while placental nutrition is maintained.9 When growth delay becomes clinically apparent, a number of fetal responses including adjustments in metabolism, endocrine axes, and hematologic parameters as well as cardiovascular and behavioral responses may already have taken place. Of these, cardiovascular and behavioral manifestations can be used in FGR management. While not amenable to management, adjustments in other organ systems still have

Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland, Baltimore, MD. Address reprint requests to Ahmet A. Baschat, MD, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland, Baltimore, 405 Redwood Street, Baltimore, MD 21201. E-mail: aabaschat@hotmail.com

274

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Fetal growth restriction

a profound impact on short- and long-term outcome and ultimately dene the consequences of placental dysfunction.

275 of the villous vascular tree has been damaged.14 However, placental vascular dysfunction with fetal hypoxemia may exist in the absence of any of these Doppler ndings.15,16 The detection of such subtle placental dysfunction requires the examination of fetal responses (Figs. 1-3).

Maturational Impacts of Placental Dysfunction

A reduction of uterine perfusion below 0.6 mL/Kg/min measurably decreases fetal glucose and amino acid delivery. This reduction in substrate availability leads to downregulation of both the insulin and the insulin-like growth factor-1 endocrine axis and hepatic glucose metabolism.10 The result is glycogenolysis with a decrease in liver size, redirection of gluconeogenic amino acids from endogenous protein breakdown, and eventually, delayed longitudinal growth.8 A reduction in fatty acid transfer decreases the availability of precursor molecules for a wide range of bioactive substances. These changes are important antecedents for the manifestation of FGR.8 With increased accumulation of lactate and ketone bodies the fetal brain, heart, and erythrocytes become scavengers for these metabolites, thereby maintaining acid base balance. Endocrine responses correlate with the degree and level of hypoxemia and include central and peripheral hypothyroidism, upregulation of the adrenocortical axis, and bone demineralization.8 Hematologic responses of the fetus initially consist of a compensatory increase in red cell mass but eventually may exacerbate placental vascular dysfunction. Hypoxemiastimulated extramedullary hematopoiesis may no longer be observed as placental dysfunction escalates.8 Under these circumstances the risk for thrombocytopenia may increase 10fold11 and increased blood viscosity, decreased erythrocyte pliability, as well as platelet aggregation worsen intraplacental blood ow dynamics further.12 Cellular and humoral immune dysfunction also correlates to the degree of fetal acidemia and explains the higher susceptibility to postpartum infection.8 While these consequences of placental dysfunction have no immediate value in the diagnosis and surveillance in FGR, they illustrate the multisystem effects of placental dysfunction. Accordingly, compromise at many levels is undetectable by antenatal surveillance and not amenable to therapy. When FGR manifests early in pregnancy, marked abnormalities of placental function are typically evident. In near-term FGR these abnormalities are far more subtle and may escape clinical evaluation.

Circulatory and Behavioral Responses to Placental Dysfunction

Fetal circulatory responses to placental insufciency may be passively mediated by high placental blood ow resistance or by active organ autoregulation. Redistribution of cardiac output toward the left ventricle occurs with relative increases in right ventricular afterload as documented by a decrease in the ratio of Doppler indices in cerebral and umbilical arteries

Doppler Evidence of Placental Dysfunction

An elevated uterine artery Doppler index and/or persistent waveform notching beyond 24 weeks indicate increased spiral artery blood ow resistance in the maternal compartment of the placenta. In the fetal compartment the earliest sign of abnormal villous perfusion is a decrease in umbilical venous ow.9 Umbilical artery end-diastolic velocity (UA EDV) decreases and resistance indices become elevated when 30% of villous vasculature is abnormal.13 Progression to absent- or even reversed end-diastolic velocity occurs when 60 to 70%
Figure 1 Flow velocity waveforms obtained from the uterine artery beyond 24 weeks gestation. In the rst patient (A) high-volume diastolic ow is established, indicating successful trophoblast invasion. Elevated placental vascular resistance is associated with a decline in diastolic velocities and a subsequent rise in the Doppler index (B). Persistence of an early diastolic notch in the uterine artery ow velocity waveform is evidence of increased spiral artery blood ow resistance. Frequently notching is more subtle beyond 32 weeks (C) than in the late second or early third trimesters (D). (Reprinted with permission.36)

276

J. Miller, S. Turan, and A.A. Baschat

Figure 2 The normal umbilical artery ow velocity waveform has marked positive end-diastolic velocity that increases in proportion to systole toward term (A). Moderate abnormalities in the villous vascular structure raise the blood ow resistance and are associated with a decline in end-diastolic velocities (B). When a signicant proportion of the villous vascular tree is abnormal (50-70%), end-diastolic velocities may be absent (C) or even reversed (D). Depending on the magnitude of placental blood ow resistance and the fetal cardiac function, reversal of end-diastolic velocities may be minimal (D), moderate (E), or severe (F). In the latter case precordial venous ows were universally abnormal. (Reprinted with permission.36)

(cerebroplacental Doppler ratio CPR).16 This is virtually always present in fetuses with absent end diastolic velocity (AEDV). Diversion of umbilical venous blood from the liver to the heart and decrease in cerebral blood ow impedance are active vascular phenomena. Together these compensatory responses result in preferential channeling of oxygen and nutrient-rich umbilical venous blood to the myocardium and brain (venous redistribution and brain sparing).17 Reversal of umbilical artery end-diastolic velocity and evidence of abnormal forward cardiac function indicate the progression to late cardiovascular manifestations. Increasing Doppler indices in the precordial veins are the hallmark of circulatory deterioration. This is most apparent through a decrease in atrial systolic forward velocities in the triphasic venous ow velocity waveform. In extreme cases, increased atrial pressure waves are transmitted all the way back into the free umbilical vein, resulting in pulsatile ow (Figs. 4 and 5). Fetal behavioral responses to placental insufciency can also be subdivided into early and late. Unlike in the cardiovascular system, early behavioral abnormalities are not clinically apparent as they predominantly consist of maturational delay. Clinically most relevant is delayed establishment of fetal heart rate reactivity, which may be absent in up to 60% of FGR pregnancies before 32 weeks. Individual fetal behaviors are lost in a relatively preserved sequence that is related to gestational age and the degree of hypoxemia. If fetal heart rate reactivity was present, it is lost rst. Fetal breathing disappears next followed by decreased gross body movements and tone. This sequence is often accompanied by a gradual decline in amniotic uid volume. Spontaneous late decelerations may also be observed as a late nding. In preterm FGR before 30 to 32 weeks, late Doppler abnormalities precede the deterioration of the biophysical pro-

le score (BPS). While the progression from brain sparing to spontaneous late decelerations has been reported within 2 weeks, the interval is variable and probably inuenced by gestational age, maternal factors, and severity of placental disease.18-22 For the clinician, escalating ductus venosus Doppler indices indicate accelerating fetal disease, while the BPS may still be normal. In term FGR where Doppler abnormalities are subtle, isolated brain sparing may provide such evidence. However, deterioration of the BPS is more likely associated with oligohydramnios or may have no antecedents.23

Relationship Between Fetal Testing Parameters and AcidBase Balance

Both Doppler and biophysical parameters predict acid base balance in FGR. A decreased CPR, brain sparing, and UA AEDV indicate an increased risk for hypoxemia with a normal pH as long as venous Doppler parameters are normal. Elevation of venous Doppler indices, either alone or in combination with umbilical venous pulsations, increase the risk for acidemia. Dependent on the cutoff (2 versus 3 SD) and the combinations of veins examined, sensitivity for prediction of acidemia in preterm FGR ranges from 70 to 90% and specicity from 70 to 80%.24,25 The ve-component BPS shows a reliable and reproducible relationship with the fetal pH irrespective of the underlying pathology and gestational age.26 Loss of fetal tone and movement are typically observed at a median pH of 7.10 and therefore provide the most consistent prediction of prelabor academia.27 In contrast to Doppler parameters which are under the inuence of several factors,

Fetal growth restriction

277 Doppler abnormalities of the umbilical arteries are common. In term FGR attention should focus on the middle cerebral artery Doppler and amniotic uid volume. The differential diagnosis always needs to consider aneuploidy, nonaneuploid syndromes, viral infection, other toxins (smoking, cocaine), and the constitutionally small fetus. A clinical history, review of dates, sonographic exclusion of anomalies, consideration of invasive tests, and serial observations are often necessary to conrm the diagnosis. Once the diagnosis of placenta-based FGR has been made, perinatal management is warranted. This requires the consideration of fetal status and gestational age. A reduction of potentially preventable perinatal damage therefore relies on an accurate assessment of these variables.

Surveillance of the Growth-Restricted Fetus

As there is no intrauterine therapy for FGR, accurate determination of fetal status by antenatal surveillance is a key component to direct intervention and monitoring intervals. Both of these requirements must be met to decrease perinatal damage. In this context performance of fetal surveillance tests is greatly inuenced by the manifestation of fetal compromise across gestational age. Biophysical parameters are closely related to acid base balance and therefore reect current fetal status. Doppler parameters and amniotic uid volume reect disease progression and therefore guide in the choice of monitoring intervals. The American College of Obstetricians and Gynecologists recommends twice weekly modied BPS (nonstress test and amniotic uid index) and umbilical artery Doppler velocimetry for the surveillance of FGR.28 Application of this recommendation requires some modication based on the clinical presentation. If fetal heart rate reactivity is not established, as can be expected in early-onset FGR, a full ve-component BPS is required. If there are signs of advancing disease as indicated by loss of umbilical artery end-diastolic velocity or oligohydramnios, frequency of testing may be increased up to daily testing to avoid unexpected stillbirth.29 In FGR presenting before 32 weeks where safe prolongation of pregnancy may be a key component of improving outcome, a more complex integrated approach has been proposed. Integrated fetal testing requires the concurrent evaluation of arterial and venous Doppler with the BPS. In addition to UA AEDV and oligohydramnios, onset of brain sparing or elevated venous Doppler indices are also considered as markers of accelerating disease requiring appropriate adjustment of monitoring intervals (Tables 2 and 3).8

Figure 3 The normal middle cerebral artery ow pattern has relatively little diastolic ow (A). With elevation of placental blood ow resistance the changes in the middle cerebral artery waveform may be subtle, although the cerebroplacental ratio may become abnormal as in fetus B. With progressive placental dysfunction there may be an increase in the diastolic velocity, resulting in a decrease in the Doppler index (Brain sparing, C). With marked brain sparing, the systolic down slope of the waveform becomes smoother so that the waveform almost resembles that of the umbilical artery (D). The associated rise in the mean velocity results in a marked decline in the Doppler index. (Reprinted with permission.36)

regulation of fetal behaviors is more closely linked to oxygenation of their regulatory centers. Therefore, a closer correlation between behaviors and acid base status has been observed at steady state.

Diagnosis of Growth Restriction due to Placental Disease

The diagnosis of FGR due to placental disease is essential to identify the fetus in need of management. This excludes constitutionally small fetuses and those with other underlying etiologies where outcomes are unlikely improved by intervention. The physical manifestations of FGR and the cardiovascular signs of placental disease are listed in Table 1. Any combination of these abnormalities should raise the suspicion of placenta-based FGR. In preterm FGR diagnostic

Management of Placenta-Based Growth Restriction

In the perinatal management of FGR the timing of interventions depends on the balance of fetal and neonatal risks. In term FGR where the primary problem lies in identifying the

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J. Miller, S. Turan, and A.A. Baschat

Figure 4 In the ductus venosus blood ow is always antegrade throughout the cardiac cycle under normal circumstances. Pulsatility is less pronounced in waveform patterns obtained at the inlet (A) versus the outlet (B). With impaired cardiac forward function there is a decline in forward ow during atrial systole (C). If progressive atrial forward ow may be lost (D) or reversed (E, F). (Reprinted with permission.36)

fetus at risk the neonatal risks are low. There are no randomized trials of elective delivery once the diagnosis of FGR has been made near term. However, prospective stillbirth risk data from a large US cohort suggest that in the presence of risk factors such as FGR delivery as early as 37 weeks may be required to decrease stillbirth rate.30 From this it may be

Table 1 Manifestations of Diagnostic Value Physical manifestations of fetal growth delay Sonographically estimated fetal weight below the 10th percentile Abdominal circumference <5th percentile HC/AC ratio <10th percentile Individualized growth potential <10th percentile Femur length/abdominal circumference ratio >23.5 Abdominal circumference growth velocity <11 mm in 14 days Cardiovascular manifestations of placental dysfunction Increased uterine artery Doppler index and/or notching Increased umbilical artery Doppler index Decreased middle cerebral artery Doppler index Decreased cerebroplacental Doppler ratio Maximum amniotic uid pocket <2 cm Amniotic uid index <5 cm Table 2 Signs of Accelerating Placental Dysfunction Umbilical artery absent or reversed end-diastolic velocity Decreased cerebroplacental ratio Onset of brain sparing Elevated venous Doppler indices Umbilical vein pulsations Oligohydramnios Abnormal biophysical prole score Spontaneous late decelerations

Figure 5 In the umbilical vein the normally constant waveform pattern may show subtle pulsations with elevated placental blood ow resistance (A). With progressive increase in precordial venous indices monophasic, biphasic, and even triphasic pulsations may be observed (B, C, D). (Reprinted with permission.36)

Fetal growth restriction

Table 3 Integrated Fetal Testing in Fetal Growth Restriction Finding Abnormal UA and/or CPR; normal MCA and veins BPS >8/10, AFV normal Blood ow redistribution Low MCA, normal veins BPS >8/10, AFV normal Signicant blood ow redistribution UA A/REDV normal veins BPS > 6/ 10, Oligohydramnios Fetal compromise Increased DV pulsatility BPS >6/10, Oligohydramnios Interpretation Asphyxia extremely rare Increased risk for intrapartum distress Hypoxemia possible, asphyxia rare Increased risk for intrapartum distress Hypoxemia common, acidemia or asphyxia possible, onset of fetal compromise Hypoxemia common, acidemia or asphyxia likely Action

279

Deliver for obstetric, or maternal factors only, fortnightly Doppler Weekly BPS Deliver for obstetric, or maternal factors only, weekly Doppler BPS 2 times/wk >34 weeks: deliver; <32 weeks: antenatal steroids repeat all testing daily >32 weeks: deliver <32 weeks: admit, steroids, individualize testing daily vs. three times per day Deliver at tertiary care center with the highest level of NICU care

Fetal decompensation Compromise by above criteria, absent or reversed DV a-wave, pulsatile UV BPS <6/10, Oligohydramnios

Cardiovascular instability, metabolic compromise, stillbirth imminent, high perinatal mortality irrespective of intervention

concluded that a low threshold for delivery should be used in these fetuses. Delivery criteria may include documented lung maturity, complete arrest of fetal growth, oligohydramnios, abnormal BPS, and UA AEDV. Matters are more complicated in preterm FGR presenting before 34 weeks where deterioration may occur rapidly and where prematurity-related morbidity is signicantly increased compared with appropriately grown counterparts.31 With early-onset growth restriction viability (50% neonatal survival) is reached at 26 weeks and over half of these neonates do have major morbidity until 29 weeks. The neonatal survival benet for each additional day in utero is estimated at 2% until 29 weeks gestation.32 Moreover, long-term follow-up from the Growth Restriction Intervention Trial shows an increased risk of prematurity provoked neurodevelopmental delay if these fetuses are delivered too early.33 Unfortunately there are no concluded randomized intervention trials that identify optimal intervention in this critical subset of growth-restricted fetuses. The Growth Restriction Intervention Trial was a prospective randomized multicenter study of over 500 women with pregnancies complicated by FGR. Patients were randomly assigned to immediate versus delayed delivery based on physician discomfort. No difference in short-term outcome was observed but immediate delivery was associated with higher neonatal mortality while delayed delivery carried the price of a higher stillbirth rate. The long-term impacts on neurodevelopment were not anticipated by these short-term outcomes. Based on these studies it has been concluded that safe prolongation of pregnancy offers the best combination of decreased perinatal mortality, morbidity, and improved neurodevelopment.34 In this context, the trial of umbilical and fetal ow in Europe compares the performance of computerized fetal heart rate analysis with ductus venosus Doppler. In

the integrated fetal management approach multivessel Doppler and BPS are combined as indicated in Table 3. This protocol is based on the observation that integration of testing variables provides improved prediction of outcome even when the computerized fetal heart rate analysis is used.35 Integrated fetal testing is initiated at 24 weeks. If umbilical artery pulsatility is increased but end-diastolic ow is preserved, weekly BPS and biweekly Dopplers are performed. With the onset of brain-sparing, BPS and Doppler are repeated weekly. Testing frequency escalates with the degree of cardiovascular compromise. Delivery is based on a combination of late Doppler and biophysical abnormalities. The variety of management approaches to these highest risk pregnancies is not based on strong evidence and underlines the urgent need for development of randomized management trials.

References
1. Gardosi J, Chang A, Kalyan B, et al: Customised antenatal growth charts. Lancet 339:283-287, 1992 2. Baschat AA, Gembruch U, Reiss I, et al: Relationship between arterial and venous Doppler and perinatal outcome in fetal growth restriction. Ultrasound Obstet Gynecol 16:407-413, 2000 3. Bernstein IM, Horbar JD, Badger GJ, et al: Morbidity and mortality among very-low-birth-weight neonates with intrauterine growth restriction. The Vermont Oxford Network. Am J Obstet Gynecol 182: 198-206, 2000 4. Zeitlin J, Ancel PY, Saurel-Cubizolles MJ, et al: The relationship between intrauterine growth restriction and preterm delivery: an empirical approach using data from a European case-control study. BJOG 107:750-758, 2000 5. GRIT Study Group: A randomized trial of timed delivery for the compromised preterm fetus: short term outcomes and Bayesian interpretation. BJOG 110:27-32, 2003 6. Clausson B, Cnattignius S, Axelsson O: Outcomes of post-term births; the role of fetal growth restriction and malsformations. Obstet Gynecol 94:758-762, 1999

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7. Froen JF, Gardosi JO, Thurmann A, et al: Restricted fetal growth in sudden intrauterine unexplained death. Acta Obstet Gynecol Scand 83:801-807, 2004 8. Baschat A: fetal responses to placental insufciency: an update. BJOG 111:1031-1041, 2004 9. Rigano S, Bozzo M, Ferrazzi E, et al: Early and persistent reduction in umbilical vein blood ow in the growth-restricted fetus: a longitudinal study. Am J Obstet Gynecol 185:834-838, 2001 10. Reece EA, Wiznitzer A, Le E, et al: The relation between human fetal growth and fetal blood levels of insulin-like growth factors I and II, their binding proteins, and receptors. Obstet Gynecol 84:88-95, 1994 11. Baschat AA, Gembruch U, Reiss I, et al: Absent umbilical artery enddiastolic velocity in growth-restricted fetuses: a risk factor for neonatal thrombocytopenia. Obstet Gynecol 96:162-166, 2000 12. Trudinger B, Song JZ, Wu ZH, et al: Placental insufciency is characterized by platelet activation in the fetus. Obstet Gynecol 93:180, 1999 13. Giles WB, Trudinger BJ, Baird PJ: Fetal umbilical artery ow velocity waveforms and placental resistance: pathological correlation. Br J Obstet Gynaecol 92:31-38, 1985 14. Morrow RJ, Adamson SL, Bull SB, et al: Effect of placental embolization on the umbilical arterial velocity waveform in fetal sheep. Am J Obstet Gynecol 161:1055-1060, 1989 15. Hecher K, Spernol R, Stettner H, et al: Potential for diagnosing imminent risk to appropriate- and small-for-gestational-age fetuses by Doppler sonographic examination of umbilical and cerebral arterial blood ow. Ultrasound Obstet Gynecol 2:266-271, 1992 16. Bahado-Singh RO, Kovanci E, Jeffers A, et al: The Doppler cerebroplacental ratio and perinatal outcome in intrauterine growth restriction. Am J Obstet Gynecol 180:750-756, 1999 17. Baschat A: The fetal circulation and essential organsa new twist to an old tale. Ultrasound Obstet Gynecol 27:349-354, 2006 18. Hecher K, Bilardo CM, Stigter RH, et al: Monitoring of fetuses with intrauterine growth restriction: a longitudinal study. Ultrasound Obstet Gynecol 18:564-570, 2001 19. Ferrazzi E, Bozzo M, Rigano S, et al: Temporal sequence of abnormal Doppler changes in the peripheral and central circulatory systems of the severely growth-restricted fetus. Ultrasound Obstet Gynecol 19: 140-146, 2002 20. Baschat AA, Gembruch U, Harman CR: The sequence of changes in Doppler and biophysical parameters as severe fetal growth restriction worsens. Ultrasound Obstet Gynecol 18:571-577, 2001 21. Cosmi E, Ambrosini G, DAntona D, et al: Doppler, cardiotocography, and biophysical prole changes in growth-restricted fetuses. Obstet Gynecol 106:1240-1245, 2005

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22. Baschat AA, Galan HL, Bhide A, et al: Doppler and biophysical assessment in growth restricted fetuses: distribution of test results. Ultrasound Obstet Gynecol 27:41-47, 2006 23. Manning FA, Hill LM, Platt LD: Qualitative amniotic uid volume determination by ultrasound: antepartum detection of intrauterine growth retardation. Am J Obstet Gynecol 139:254-258, 1981 24. Rizzo G, Capponi A, Talone PE, et al: Doppler indices from inferior vena cava and ductus venosus in predicting pH and oxygen tension in umbilical blood at cordocentesis in growth-retarded fetuses. Ultrasound Obstet Gynecol 7:401-410, 1996 25. Baschat AA, Gcl S, Kush ML, et al: Venous Doppler in the prediction of acid-base status of growth-restricted fetuses with elevated placental blood ow resistance. Am J Obstet Gynecol 191:277-284, 2004 26. Manning FA, Snijders R, Harman CR, et al: Fetal biophysical prole score. VI. Correlation with antepartum umbilical venous fetal pH. Am J Obstet Gynecol 169:755-763, 1993 27. Vintzileos AM, Fleming AD, Scorza WE, et al: Relationship between fetal biophysical activities and umbilical cord blood gas values. Am J Obstet Gynecol 165:707-713, 1991 28. American College of Obstetricians and Gynecologists (ACOG): Intrauterine Growth Restriction. ACOG Pract Bull 12:1-12, 2000 29. Divon MY, Girz BA, Lieblich R, et al: Clinical management of the fetus with markedly diminished umbilical artery end-diastolic ow. Am J Obstet Gynecol 161:1523-1527, 1989 30. Kahn B, Lumey LH, Zybert PA, et al: Prospective risk of fetal death in singleton, twin, and triplet gestations: implications for practice. Obstet Gynecol 102:685-692, 2003 31. Garite TJ, Clark R, Thorp JA: Intrauterine growth restriction increases morbidity and mortality among premature neonates. Am J Obstet Gynecol 191:481-487, 2004 32. Baschat AA, Cosmi E, Bilardo CM, et al: Predictors of neonatal outcome in early-onset placental dysfunction. Obstet Gynecol 109:253-261, 2007 33. Thornton JG, Hornbuckle J, Vail A, et al: GRIT study group. Infant wellbeing at 2 years of age in the Growth Restriction Intervention Trial (GRIT): multicentred randomised controlled trial. Lancet 364:513520, 2004 34. Lees C, Baumgartner H: The TRUFFLE studya collaborative publicly funded project from concept to reality: how to negotiate an ethical, administrative and funding obstacle course in the European Union. Ultrasound Obstet Gynecol 25:1005-1007, 2005 35. Turan S, Turan OM, Berg C, et al: Computerized fetal heart rate analysis. Doppler ultrasound and biophysical prole score in the prediction of acid-base status of growth-restricted fetuses. Ultrasound Obstet Gynecol 30:750-756, 2007 36. Baschat AA, Hecher K: Fetal growth restriction due to placental disease. Semin Perinatol 28:67-80, 2004

Antenatal Fetal Assessment: Multifetal GestationAn Overview

Lawrence D. Devoe, MD
As prevalence of multifetal gestation has increased in the United States, antenatal surveillance of these pregnancies has gained importance. This article focuses on the assessment of twin pregnancy, since critical data are lacking for the surveillance of higher order multiple gestations. Twin pregnancies encounter risks that differ in nature, frequency, and intensity from those seen in singleton pregnancies. Most of these risks stem from subnormal or discordant fetal growth or abnormalities of placentation. Sonographic modalities play key roles in antepartum surveillance. These include fetal biometry, serial growth studies, amniotic uid volume assessment, Doppler velocimetry of fetal-placental circulation, and biophysical prole testing. Fetal heart rate testing, specically nonstress testing, has also been used extensively in twin surveillance. This article examines the specic application of these modalities to twin gestation and reviews the best evidence available for their support. Assessment of unique risk conditions of twintwin transfusion, monoamniotic twinning, and intrauterine death of one twin is addressed. Based on current data, a strategic outline for assessment of twin pregnancy is presented. Semin Perinatol 32:281-287 2008 Elsevier Inc. All rights reserved. KEYWORDS multifetal gestation, antenatal testing, ultrasound, Doppler velocimetry, fetal heart rate, biophysical prole

his article describes the approaches for antenatal surveillance of multifetal gestations. It examines the evidence that supports these surveillance tools and strategies and their relative merits and shortcomings. The focus is on twin gestation as few data exist on the antenatal testing of higher order multiple gestations. With the increasing use of assisted reproductive technology, multifetal gestation and, specically twin pregnancy, has become more prevalent in the United States. Greater use of obstetric ultrasound has also increased the likelihood that multifetal gestation will be diagnosed before the third trimester of pregnancy, providing increased opportunity for antenatal surveillance of these pregnancies. Assessment of multiple fetuses provides unique challenges since it must consider factors that increase the risk of adverse perinatal outcomes. These risk factors stem from maternal sources (advanced age, anemia, gestational diabetes and hypertension, preterm labor) and fetal sources (increased rates of congenital malfor-

Section of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta, GA. Address reprint requests to Lawrence D. Devoe, MD, Department of Obstetrics and Gynecology, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912. E-mail: ldevoe@mail.mcg.edu

mations, abnormal placentation and placental vasculature, disorders of amniotic uid, subnormal and discordant growth, and prematurity). While perinatal death rates for multifetal pregnancies have declined,1-3 they remain higher than those for singletons of comparable gestational ages. Twin gestation presents hazards for perinatal survival at all gestational ages. In the rst half of pregnancy, there is increased fetal wastage (the vanishing twin). In the third trimester, there is increased risk of fetal growth restriction compared with single pregnancies, raising the risk of fetal death and early delivery.4,5 Added risks for perinatal mortality are imposed on twins that are monozygous and/or share a monochorionic placenta.6-8 It has been estimated that after 37 to 38 weeks gestation, the risk of intrauterine death is equivalent to that of a postterm single gestation.7 Although growth restriction and twintwin transfusion contribute to this excess mortality, Barigye and colleagues8 note that being a monochorionic twin alone may be hazardous. Fetal deaths unrelated to the above conditions occurred at a rate of nearly 50/1000.8 Robinson and coworkers reported that the lowest risk for perinatal death occurs at 37 weeks gestation.9 Therefore, when considering strategies of fetal assessment, it will be important to account for chorionicity and zygosity as well as assessment of fetal growth. 281

0146-0005/08/$-see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2008.04.011

282 The methods applied to twin gestations were initially developed and evaluated in single pregnancies. As will be noted later, tracking fetal growth is also a different proposition for twin pregnancy. Different standards are needed and considerable debate exists on the best standards for biometry and growth nomograms.10 Twin gestations present challenges for antenatal surveillance not encountered in single pregnancies: (1) twintwin transfusion syndrome; (2) monoamniotic twinning; (3) intrauterine death of a single twin fetus. Surveillance of these twin-specic complications will be discussed later in this article.

L.D. Devoe
mur length).15 During ultrasound examinations performed at monthly intervals during the second half of pregnancy, this group found that BPD and abdominal circumference growth curves declined signicantly from singleton curves after 31 and 32 weeks, while femur length growth remained similar to that of singletons. Grennert and coworkers, using a Swedish database, indicated impact of zygosity on the evaluation of fetal growth parameters for twin pregnancies. Although this study was limited to BPD measurements of 46 dizygous and 45 monozygous twin pairs, monozygous twin BPDs were smaller than those of dizygous twins at all gestational ages beyond 28 weeks.16 This was correlated with lower mean birth weights for monozygous twins. Ananth and coworkers applied six singleton and two twin sonographic nomograms for fetal weight to 1302 twin pairs to predict birth weight below the 10th percentile for gestational age.10 Singleton nomograms appeared to be applicable to twin gestations in a narrow gestational age range (32 to 34 weeks). Singleton nomograms underestimated fetal weight in twins 32 weeks and overestimated fetal weight in twins 34 weeks gestation. They also conrmed that monochorionic twins had lower birth weights than those of dichorionic twins.

Antepartum Assessment in Twin Gestation: Initiation

Only three decades ago nearly half of twin pregnancies were not diagnosed before parturition. The benets of early identication of twin pregnancy were noted during an early Swedish population study11 in which obstetric ultrasonography was used routinely. Nearly 90% of all twin gestations were identied. Antenatal detection of twin pregnancy was associated with lower infant mortality and low birth weight rates and greater gestational age at delivery. Routine ultrasound examination of all pregnancies is not endorsed at present; two-thirds of all pregnancies in the United States receive at least one antenatal ultrasound study.12 This increases the likelihood that most twin pregnancies receiving prenatal care will be detected early enough in gestation for reliable dating, anatomic survey, and antenatal assessment.

Summary
Nomograms for biometry and fetal weight estimation for twin gestations are quite limited. Observational studies (Level II-3) support the need for twin-specic nomograms for individual biometric parameters and fetal weight estimation. Singleton nomograms are problematic and may produce errors in weight estimation and detection of abnormal fetal growth.

Antepartum Assessment: Selection of Test and Follow-Up

Should twins receive the same antenatal tests and testing protocols as do singletons? While many studies of antenatal testing have been conducted in single gestations, it does not follow necessarily that their outcomes can be applied directly to the management of twin gestations. These singleton studies have been criticized for their predictive shortcomings13 in assessing growth-restricted fetuses, the greatest source of perinatal mortality in the third trimester.1

Methods for Detection of Subnormal Growth and Fetal Weight Discordance

Subnormal fetal growth and discordant fetal growth between twins contribute signicantly to perinatal morbidity and mortality. Crane and coworkers were among the rst to demonstrate that fetal weight differences of more than 20% were associated with an increased risk for stillbirth.17 Table 1 summarizes several studies, evaluating different criteria for the detection of twin discordancy. Most of these studies were initiated at 26 weeks gestational age or greater and repeated their evaluations at 2- to 4-week intervals. Four reports18-21 identied estimated fetal weight differences alone or in combination with other biometry in their efforts to identify discordant growth. Doppler velocimetry of the umbilical arteries was incorporated as a separate tool for detecting fetal growth restriction and discordance.22-25 The results of these small studies varied and most failed to support Doppler velocimetry as an effective independent tool for this purpose. However, abnormal systolic:diastolic ratios were shown by Degani and coworkers to appear several weeks ahead of abnormal sonographic fetal growth.25 Divon and colleagues26 compared a variety of sonographic parameters in 58 twin pairs of which 30% were subsequently found to have discordant fetal weights (twin weight differences exceeding 15%). In this study, a combina-

Ultrasonography: Fetal Growth

The cornerstone of fetal assessment in twin pregnancy is the identication of abnormal fetal growth or discordancy. This is essential to investigate causation (anatomic ultrasonography) or to assess intrauterine adaptation (fetal testing). As with singleton pregnancies, the identication of fetal growth restriction requires accurate fetal biometry and reliable standards for fetal growth patterns at all gestational ages. The accuracy of such a diagnosis requires the existence of standards for determining normal twin baseline growth. Although numerous standards have been reported for singletons, the data for twin gestations are quite limited.14 Grumbach and colleagues performed one of the most comprehensive early studies for twin sonographic biometry (biparietal diameter (BPD), abdominal circumference, and fe-

Antenatal fetal assessment: multifetal gestation

Table 1 Detection of Twin Discordancy: Summary of Selected Studies Study OBrien, et Chitkara, et al18 al19 No. 329 42 Criteria EFW >15% BPD >20% AC EFW FL EFW >20% UA S:D <10%ile BPD >6 mm AC >20 mm FL >5 mm EFW >20% Sens 70 78 100 90 86 86 82 71 80 60 80 Spec 80 90 85 92 85 80 98 77 85 93 93 PPV 34 87 89 92 85 80 90 63 62 75 80

283

NPV 95 NA NA NA NA 86 96 83 93 87 93

Rodis, et al20 Gerson, et al22 Storlazzi, et al21

85 52 43

Reprinted with permission from Devoe LD, Ware DJ: Antenatal assessment of twin gestation. Semin Perinatol 19:413-425, 1995 (Saunders).

tion of differences in Doppler velocimetry and estimated fetal weight greater than 15% had the highest sensitivity (78%) and specicity (87%) for twin discordance.

(2.3%) in the control group had perinatal deaths, while there were no deaths in the routine NST group.

Summary
For twin gestation, there is no consensus on the best screening approach for the detection of growth restriction or discordance. Most reports have used nomograms derived from singleton rather than twin gestations, although such nomograms have limitations in their prediction of growth restriction. Discrepancies in estimated fetal weight greater than 20% appear to provide the greatest yield for this outcome but the studies supporting this criterion have examined small groups with varying prevalences of growth-restricted fetuses. Doppler velocimetry may provide added value in screening for growth disturbances in twin pregnancies; however, supportive evidence is limited (Level II-2; Level II-3).

Summary
There is limited evidence (Level II-2 and Level II-3) to support the use of NSTs in twin gestations. The few exclusive studies on twin gestation suggest that the NST has screening performance similar to that seen in singleton populations. Nonreactivity, when not attributable to fetal immaturity, has potential value in identifying growth-restricted fetuses that are at increased risk for perinatal death. The ability to perform simultaneous monitoring on a single unit is available in most contemporary fetal monitoring systems.

Biophysical Prole Testing (BPP)

Since the early 1980s, the BPP has become a leading fetal well-being test.30 Only one study has focused exclusively on BPP testing in twin gestations.31 Lodeiro and coworkers tested 49 twin pairs, 80% of which had additional indications for fetal assessment. Testing began at 26 weeks gestation. BPP scores 8 led repeat testing at weekly intervals until delivery. BPP scores 6 led to repeat testing within 4 hours. A nonreactive NST and absent breathing in one twin was used as an indication for delivery. They found that a reactive NST was always associated with a BPP score 8; more than 80% of fetuses with nonreactive NSTs had BPP scores of 8. Although this study had a sensitivity of 83% for adverse outcomes, the only deaths that occurred were due to complications of prematurity, not intrauterine compromise.

Nonstress Tests (NSTs)

Twin gestation presents a specic challenge for fetal heart rate testing. Contraction stress tests have been considered relatively contraindicated due to the concern that contraction stress tests might incite excessive uterine activity in preterm pregnancies. There is insufcient evidence to support this concern. However, as the NST became the primary method for fetal heart rate testing in twins, there was obvious need to acquire simultaneous tracings to ensure that each fetus was actually being monitored. Few studies have reported on the NST exclusively in twin pregnancies. The initial reports used independent electronic fetal monitoring systems27-29 for each fetus and reported failure rates of 2 to 15% in successfully capturing both fetuses. These studies found that reactive NSTs conferred a good prognosis (no perinatal deaths and rates of growth restriction ranging from 8 to 28%). Conversely, nonreactive NSTs were associated with rates of fetal growth restriction of 55 to 100% and perinatal mortality rates of 50% or higher. Knuppel and coworkers5 assessed the impact of initiating routine NSTs on all twins after 31 weeks gestation. This study compared a historical group of 129 twin pairs not receiving routine NSTs to a subsequent group of 90 twin pairs receiving routine weekly NSTs. Six of 258 fetuses

Summary
Biophysical testing is commonly performed on most highrisk pregnancies in contemporary practice. There are insufcient data to determine its value for twin gestations.

Doppler Velocimetry of Umbilical Arteries

Doppler velocimetry of the fetal umbilical arteries has become a standard modality in screening singleton pregnancies for the risk of adverse perinatal outcomes.32 Nimrod and coworkers showed that a discordance in systolic:diastolic

284
Table 2 Prediction of All Adverse Outcomes in Twin Gestation by Test Outcome Test Doppler NST UCG AFV All tests Sensitivity 49 44 46 39 53 Specicity 90 90 90 88 88 PPV 63 59 54 52 55 NPV 84 84 84 81 88 OR (95% CI) 8.6 (3.5 to 21.1) 7.5 (3.1 to 18.0) 6.5 (2.8 to 15.1) 4.5 (2.1 to 10.5) 9.2 (3.7 to 22.6)

L.D. Devoe

Accuracy 80 79 78 75 82

Reprinted with permission from Devoe LD, Ware DJ: Antenatal assessment of twin gestation. Semin Perinatol 19:413-425, 1995 (Saunders).

(S/D) ratios of more than 50% was associated with a higher probability of poor outcome in the twin with the higher S/D ratio.33 Subsequent larger trials by Gaziano and coworkers34 and Jensen35 supported these results. Giles and coworkers reported a study of 272 twin sets in which umbilical artery S/D ratios were concealed (rst 100 sets) and revealed to clinicians (remaining 172 sets).36 The availability of Doppler results were associated with a reduction in corrected perinatal mortality from 42/1000 to 9/1000. Rates of neonatal intensive care admissions decreased from 38% in the Doppler-concealed group to 21% in the Dopplerrevealed group. Subsequently, Giles and colleagues conducted a randomized trial of Doppler assessment in 526 twin gestations.37 Their study assigned twin gestations at 25 weeks to receive either ultrasound biometry or ultrasound biometry and umbilical artery Doppler velocimetry at 30 and 35 weeks gestation. There were no signicant differences in perinatal death rates between the two groups. The perinatal mortality rates of 12/1000 and 8/1000 in the control and Doppler groups, respectively, were attributed to the potential confounding benets of close surveillance of all enrolled subjects.

immaturity). Follow-up of an abnormal BPP was individualized and based on the degree of fetal immaturity. Table 2 shows the prediction of adverse perintatal outcome (perinatal death, intrapartum distress, neonatal metabolic acidosis, growth restriction) according to individual testing method. The addition of Doppler velocimetry to the NST improved posttest probability for an adverse outcome to 95% if both were abnormal and decreased posttest probability for an adverse outcome to 37% if both tests were normal. The posttest probability of growth restriction and twin discordancy was nearly 100% when both Doppler velocimetry and growth curves were abnormal and only 23% when both tests were normal. Nearly all growth-restricted fetuses (86%) had abnormal Doppler studies for 1 to 8 weeks before abnormal ultrasound growth proles appeared.

Summary
Most twin pregnancies have indications for antenatal testing that are similar to those used in singleton gestations. As is the case for singleton surveillance, the sensitivities of individual assessment methods are at or below 50% while their specicities typically exceed 90%. Since the data are limited, falsenegative or positive rates for the tests used in twin surveillance are not well established. The major role of AFV assessment occurs when there is disparity between the sizes of the fetal sacs. Doppler velocimetry may improve the utility of the other tests, especially when combined with NST or ultrasound growth curves (Level II-2).

Summary
Doppler velocimetry has been a valuable addition to the fetal assessment strategies for singleton pregnancy. The data to support similar value in twin gestation are quite limited and somewhat conictual (Level I; Level II-1, Level II-2, Level II-3).

Combinations of Current Antenatal Testing Modalities

Comparisons of the screening performance of different antepartum tests for twin gestations have been limited. How does each of these approaches contribute individually or in combination to the prediction of outcome in twin gestations? Kim and coworkers studied 100 twin pairs receiving weekly modied BPPs (NST and AFV by maximal vertical pocket) and umbilical artery Doppler velocimetry.38 NSTs were performed semiweekly (if amniotic uid volume [AFV] and Doppler studies were normal) and ultrasound tracking of fetal growth was performed every 3 weeks. Seventy-one percent of twin pregnancies had other medical or obstetric indications for fetal assessment. Abnormal Doppler velocimetry led to increased frequency of testing. Abnormal growth curves or AFVs, or persistently nonreactive NSTs, were followed either by delivery (fetal maturity) or by full BPP (fetal

Unique Fetal Conditions in Twin Assessment

The Role of Doppler Velocimetry in the Assessment of Twin Transfusion Syndrome
Twin-to-twin transfusion syndrome (TTS) is a serious complication in about 10% to 20% of monozygous twin gestations. Its impact on fetal growth and survival generally depends on when the vascular communications become functional. Intact survivorship is strongly related to the nature and timing of therapeutic interventions (amnioreduction, fetoscopic photocoagulation). Discordant fetal weight and AFV often heralds this condition; however, there is controversy about the best method for assessing affected fetuses in such pregnancies. The stakes for fetal assessment in TTS are very high as the death of either twin augurs poorly for its surviving cotwin. Van Heteren and colleagues report a nearly

Antenatal fetal assessment: multifetal gestation

50% rate of perinatal death or signicant morbidity for the surviving twin after in utero death of its cotwin in a TTS pregnancy.39 It was anticipated that Doppler velocimetry would assist perinatal surveillance in TTS. However, there is lack of consensus on this point. Erskine and coworkers reported that death of the donor twin did not alter the pulsatility index of its surviving cotwin.40 Pretorius and coworkers noted that in eight twin pairs with three surviving infants, all pairs had S/D ratio differences that exceeded 0.4; in six of eight sets the donor twin had higher S/D ratios than the recipient twin.41 Giles and coworkers reported on 11 twin sets and did not nd that the S/D ratio difference was useful for prediction of TTS in discordant twin pairs.42 Rizzo and coworkers compared the S/D ratio differences in 15 sets of discordant twins without TTS and those in 10 sets of discordant twins with TTS.43 In the former group, there were major differences in S/D ratios at the initial recordings; in the latter group, these differences were not apparent until other testing modalities, such as NST, became abnormal.

285 the survivor.48,49 The risk of cerebral damage with multicystic encephalomalacia is much more likely in monochorionic twins with vascular communications than in dichorionic twins. Fetal imaging with ultrasound or magnetic resonance imaging may aid in this diagnosis. Antenatal testing of the surviving twin has been recommended. The interval to delivery is usually short and not always the result of intervention based on antenatal testing.49

Summary
In utero death of a single twin in the third trimester should signal the initiation of antenatal surveillance. Data to demonstrate optimal testing schemes or benets are lacking.

Conclusions: Clinical Decision-Making and Antenatal Testing in Twin Gestation

Figure 1 outlines a model antenatal assessment algorithm for twin gestation. Antenatal assessment of twin gestation should begin with ultrasound diagnosis, accurate gestational dating, and anatomic surveys. Conditions that may not be aided by antepartum surveillance include preterm labor and fetal anomalies. Conditions that may possibly benet from serial antenatal assessment include twins with subnormal or discordant growth, single surviving twin, monoamniotic twins, and TTS. While early identication of rare complications such as TTS and monoamniotic twins is important for enabling possible management options, it is not clear that specic fetal well-being tests will improve perinatal outcome once these conditions are known. Selection of individual or grouped fetal surveillance tests,

Summary
Current data on antenatal assessment of TTS gestations are derived from limited or uncontrolled series. Differences in umbilical artery S/D ratios may not differentiate either affected twin. This is not surprising as the timing and extensiveness of the vascular anastomoses involved in TTS may vary considerably. There are few data on the value and results of specic posttreatment surveillance in this condition.

Antenatal Assessment of Monoamniotic Twins

Monoamniotic twinning is a rare complication, occurring in 1% of monozygous twins. It has the potential for considerable perinatal morbidity and mortality. Antenatal diagnosis is made by the failure to detect a dividing amniotic membrane and close proximity of the insertions of both umbilical cords. Etiologies of perinatal death may stem from intravascular anastomoses as in TTS or umbilical cord entanglement.44 A large retrospective survey of 133 sets of monoamniotic twins45 suggested that perinatal loss rates doubled approximately every 2 weeks from 30 to 38 weeks (6, 11, and 22%, respectively). Two recent small studies suggest that close antenatal surveillance accompanied by delivery at 32 weeks gestation may yield the best outcomes.46,47 Dickinsons review indicates that there is a scarcity of large well-controlled studies to resolve this clinical problem.44

Summary
While the number of reports on monoamniotic twin gestations have increased, there are insufcient data to support a best testing strategy or timing of delivery.

Antenatal Assessment of Surviving Cotwin After Single Fetal Death in the Third Trimester
In utero death of one member of a twin pair has been implicated in both cerebral impairment and growth restriction of
Figure 1 Decision-tree for antenatal assessment and management of twin gestation.

286 the timing of their initiation, and the frequency of their repetition remains an unresolved issue. Although Doppler velocimetry has been well studied in single pregnancies, the only randomized controlled trial in twin gestation37 was disappointing. Doppler velocimetry may be an early marker for fetal growth restriction and may improve prediction of outcome when added to other biophysical testing methods (Level II-2 and Level II-3). The routine use of NST as a primary surveillance test in twins is supported by Level II-2 and Level II-3 evidence. Data on the use of BPP in twin pregnancies are very limited (Level II-3 evidence). AFV assessment plays a principal role in the detection and follow-up of discordant twins at risk for TTS. A major concern with antepartum surveillance in twin pregnancy is the consequence of intervention based on testing methods with known high false-positive rates in single gestations. This creates a major dilemma when tests are normal in one twin and abnormal in the other. This is compounded by the frequent testing of pregnancies 32 weeks gestation, a subgroup for which there are limited data on singleton testing. Iatrogenic prematurity resulting from interventions in preterm twin pregnancies may cause signicant morbidity, possibly harming both twins. While approaches using more than one antenatal test may reduce positive- and negative-predictive errors and enhance sensitivity, further investigation with larger twin populations will be needed. In summary, all of the commonly used antenatal surveillance methods that have been reported for singleton pregnancies have received some level of investigation in twin gestations. With the exception of Doppler velocimetry, none of these methods has been subjected to randomized controlled evaluation. Of the observational trials performed on the other testing methods, most have involved fewer than 100 twin pairs. It is uncertain that the screening performances of these antenatal tests are equivalent to those observed in single pregnancies, particularly at the earlier gestational ages when they are likely to be used. Not only are more data obtained from larger well-designed trials needed for twin gestation but the paucity of data on surveillance of higher order multifetal gestations suggests yet another area needing future study.

L.D. Devoe
7. Sairam S, Costeloe K, Thilaganathan B: Prospective risk of stillbirth in multiple gestation pregnancies: a population-based analysis. Obstet Gynecol 100:638-641, 2002 8. Barigye O, Pasquini L, Galea P, et al: High risk of unexpected late fetal death in monochorionic twins despite intensive ultrasound surveillance: a cohort study. PLoS Med 2:e172, 2005 9. Robinson J, Healy, Beatty T, et al: The optimal age for twin delivery. Am J Obstet Gynecol 193:S183, 2005 10. Ananth CV, Vintzileos AM, Shen-Schwartz S, et al: Standards of birth weight in twin gestations stratied by placental chorionicity. Obstet Gynecol 91:917-924, 1998 11. Persson P, Grennert L, Gennser G, et al: On improved outcome of twin pregnancies. Acta Obstet Gynecol Scand 58:3-7, 1979 12. ACOG Committee on Practice Bulletins: ACOG Practice Bulletin No. 58. Ultrasonography in Pregnancy. Obstet Gynecol 104:1449-58, 2004 13. Devoe LD: Antenatal fetal assessment: contraction stress test, nonstress test, vibroacoustic stimulation, amniotic uid volume, biophysical prole, modied biophysical prole. An Overview. Semin Perinatol 32: 247-252, 2008 14. Jones JM, Sbarra AJ, Cetrulo CL, et al: Antepartum management of twin gestation. Clin Obstet Gynecol 33:32-41, 1990 15. Grumbach K, Coleman BG, Arger PH, et al: Twin and singleton growth patterns compared using ultrasound. Radiology 158:237-241, 1986 16. Grennert L, Persson PH, Gennser G, et al: Zygosity and intrauterine growth of twins. Obstet Gynecol 55:684-687, 1980 17. Crane JP, Tomich PG, Kopta M: Ultrasonic growth pattern in normal and discordant twins. Obstet Gynecol 55:678-683, 1980 18. Chitkara U, Berkowitz GS, Levine R, et al: Twin pregnancy: routine use of ultrasound examinations in the prenatal diagnosis of intrauterine growth retardation and discordant growth. Am J Perinatol 2:49-53, 1985 19. OBrien WF, Knuppel RA, ScerboJ C, et al: Birth weight in twins: an analysis of discordancy and growth retardation. Obstet Gynecol 67: 483-486, 1986 20. Rodis JF, Vintzileos AM, Campbell WA, et al: Intrauterine fetal growth in discordant gestation. J Ultrasound Med 9:443-448, 1990 21. Storlazzi E, Vintzileos AM, Campbell WA, et al: Ultrasonic diagnosis of discordant fetal growth in twin gestations. Obstet Gynecol 69:363-367, 1987 22. Gerson A, Johnson A, Wallace D, et al: Umbilical arterial systolic/ diastolic values in normal twin gestation. Obstet Gynecol 72:205, 1988 23. Farmakides G, Schulman H, Saldana LR, et al: Surveillance of twin pregnancy with umbilical arterial velocimetry. Am J Obstet Gynecol 153:789-792, 1985 24. Hastie SJ, Danskin F, Neilson JP, et al: Prediction of small for gestational age twin fetus by Doppler umbilical artery waveform analysis. Obstet Gynecol 74:730-733, 1989 25. Degani S, Gonen R, Shapiro I, et al: Doppler ow velocity waveforms in fetal surveillance of twins. J Ultrasound Med 11:537-541, 1992 26. Divon MY, Girz BA, Sklar A, et al: Discordant twinsa prospective study of the diagnostic value of real-time ultrasonography combined with umbilical artery velocimetry. AmJ Ohstet Gynecol 161:757-760, 1989 27. Bailey D, Flynn AM, Kelly J: Antepartum fetal heart rate monitoring in multiple pregnancy. Br J Obstet Gynecol 87:561-564, 1980 28. Devoe LD, Azor H: Simultaneous nonstress fetal heart rate testing in twin pregnancy. Obstet Gynecol 58:450-455, 1981 29. Blake GD, Knuppel RA, Ingardia CJ, et al: Evaluation of nonstress fetal heart rate testing in multiple gestations. Obstet Gynecol 63:528-532, 1984 30. Manning FA, Platt LD, Sipos L: Antepartum fetal evaluation: development of a biophysical prole. AmJ Obstet Gynecol 136:787-791, 1980 31. Lodeiro JG, Vintzileos AM, Feinstein SJ, et al: Fetal biophysical prole in twin gestation. Obstet Gynecol 67:824, 1986 32. Fleischer A: Doppler blood ow studies. Clin Obstet Gynecol 32:627647, 1989 33. Nimrod C, Davis D, Harder J, et al: Doppler ultrasound prediction of fetal outcome in twin pregnancies. Am J Obstet Gynecol 156:402-406, 1987

References
1. Farooqui MO, Grossman JH, Shannon RA: A review of twin pregnancy and perinatal mortality. Obstet Gynecol Surv 28:144-153, 1973 (suppl) 2. Keith L, Ellis R, Berger GS, et al: The Northwestern University multihospital twin study. I. A description of 588 twin pregnancies and associated pregnancy loss, 1971 to 1975. Am J Obstet Gynecol 138:781789, 1980 3. Chervenak FA, Youcha S, Johnson RE, et al: Twin gestation: antenatal diagnosis and perinatal outcome in 385 consecutive pregnancies. J Reprod Med 29:727-730, 1984 4. Hawrylyshyn PA, Barkin M, Bernstein A, et al: Twin pregnanciesa continuing perinatal challenge. Obstet Gynecol 59:463-466, 1982 5. Knuppel RA, Rattan PK, Scerbo JC, et al: Intrauterine fetal death in twins after 32 weeks. Obstet Gynecol 65:172-175, 1985 6. Kahn B, Lumey lH, Zybert PA, et al: Prospective risk of fetal death in singleton, twin, and triplet gestations: implications for practice. Obstet Gynecol 102:685-692, 2003

Antenatal fetal assessment: multifetal gestation

34. Gaziano EP, Knox E, Bebdel RP, et al: Is pulsed Doppler velocimetry useful in management of multiple-gestation pregnancies? Am J Obstet Gynecol 164:1426-1433, 1991 35. Jensen OH: Doppler velocimetry in twin pregnancy. Eur J Ohstet Gynecol Reprod Biol 45:9-12, 1992 36. Giles WB, Trudinger BJ, Cook CM, et al: Umbilical artery ow velocimetry waveforms and twin pregnancy outcome. Obstet Gynecol 72:894-898, 1988 37. Giles W, Gisits A, OCallaghan S, et al: Doppler assessment in multiple pregnancy: randomised controlled trial of ultrasound biometry versus umbilical artery Doppler ultrasound and biometry in twin pregnancy. BJOG 10:593-597, 2003 38. Kim ES, Croom CS, Devoe LD: Determination of fetal wellbeing in twin gestation by Doppler velocimetry, nonstress testing, amniotic uid volume estimation, and ultrasound assessment of growth. Am J Obstet Gynecol 170:320, 1994 39. Van Heteren CF, Nijhuis JG, Semmekrot BA, et al: Risk for surviving twin after fetal death of co-twin in twin-twin transfusion syndrome. Obstet Gynecol 92(2):215-219, 1998 40. Erskine RLA, Ritchie JWK, Murnaghan GA: Antenatal diagnosis of placental anastomosis in pregnancy using Doppler ultrasound. Br J Obstet Gynaecol 93:955-959, 1986 41. Pretorius DH, Manchester D, Barkin S, et al: Doppler ultrasound of twin transfusion syndrome. J Ultrasound Med 7:117-124, 1988

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42. Giles WB, Trudinger BJ, Cook CM, et al: Doppler umbilical artery studies in twin transfusion syndrome. Obstet Gynecol 76:1097-1099, 1990 43. Rizzo G, Arduini D, Romanini C: Cardiac and extracardiac ows in discordant twins. Am J Obstet Gynecol 170:1321-1327, 1994 44. Dickinson JE: Monoamniotic twin pregnancy: a review of contemporary practice. Aust NZ J Obstet Gynaecol 45:474-478, 2005 45. Roque H, Gillen-Goldstein J, Funai E, et al: Perinatal outcomes in monoamniotic twin gestations. Matern Fetal Neonatal Med 13:414421, 2003 46. Pasquini L, Wimalasundera RC, Fichera A, et al: High perinatal survival in monoamniotic twins managed by prophylactic sulindac, intensive ultrasound surveillance, and Cesarean delivery at 32 weeks gestation. Ultrasound Obstet Gynecol 28:681-687, 2006 47. Shveiky D, Ezra Y, Schenker JG, et al: Monoamniotic twins: an update on antenatal diagnosis and treatment. J Matern Fetal Neonatal Med 16:180-186, 2004 48. Pharoah PO, Adi Y: Consequences of in-utero death in a twin pregnancy. Lancet;355:1597-1602, 2000 49. Kilby MD, Govind A, OBrien PM: Outcome of twin pregnancies complicated by a single intrauterine death: a comparison with viable twin pregnancies. Obstet Gynecol 84;107-109, 1994

Amniotic Fluid Abnormalities

Christopher R. Harman, MD
The complex nature of amniotic uid reects contributions from many fetal systems, many functional roles, and multiple interactions with fetal maturation, obstetric, and maternal factors. Simple ultrasound measurement, probably done best with the maximum vertical pocket method, has a clinical role in fetal surveillance, substantiated by extensive level II and some level I evidence. Interventions (amnioinfusion for oligohydramnios, amnioreduction for polyhydramnios) have not been studied effectively in controlled fashion, with the exception of intrapartum applications, where effective reduction of cesarean delivery for fetal distress and perinatal impacts of meconium aspiration may follow amnioinfusion. A wealth of research opportunities exists into regulation of amniotic uid constituents and their relation to preterm delivery. Semin Perinatol 32:288-294 2008 Elsevier Inc. All rights reserved. KEYWORDS amniotic uid, maximum vertical pocket, perinatal outcome, amnioinfusion, amnioreduction

mniotic uid regulation represents a complex interaction of many systemsfetal respiratory, cardiovascular, uid balance, urinary tract, gastrointestinal, skin, neurologic, placenta and membranes, and maternal factors, to name a few. Several aspects of simple amniotic uid volume (AFV) measurement have been studied in randomized, controlled fashion, but this likely represents a tiny proportion of the information available.

Normal Amniotic Fluid

Amniotic uid functions (Table 1) can be categorized as physical (preventing fetal injury, increasing placental surface, regulating temperature), functional (mobility for practice breathing preventing pulmonary hypoplasia; swallowing exercises the digestive tract; skeletal muscle movement of every kind), and homeostasis (maintaining amnion integrity, ghting infection, discouraging contractions, maintaining cervical length and consistency). In this context, it is not surprising that deciencies in amniotic uid have multiple impacts. Such impacts are prominent in midwifery folklore for millennia: dry birth suggests stillbirth and lethal anomalies; broken water suggests sepsis and onset of labor; uid staining accompanies fetal demise; and polyhydramnios is

related to maternal death, abruption, intrapartum complications, and neonatal death (Rh-alloimmune hydrops and congenital syphilis). Modern understanding of fetal urinary tract and neurologic and placental impacts on AFV are supplemented by current research. Proteomics reveals multiple related amniotic uid compounds that predict preterm labor, premature cervical effacement, and fetal infection.1 The inammatory cascade leading to cervical incompetence, preterm rupture of membranes, and preterm labor and delivery, all may begin in the rst trimester, according to amniocentesis results. Sludge on ultrasound suggests inammatory amniocytes accumulating as inappropriate cervical effacement begins (Fig. 1).2 Several of the amniotic uid defensive properties shown are signicantly elevated in preterm labor (asterisks in Table 2). When women fail tocolysis for preterm labor, many of these protective chemicals are low or absent.3 These qualitative changes are not detected just by measuring AFV on ultrasoundmore research will determine the role of amniocentesis in managing preterm labor.

Amniotic Fluid Volume

AFV is directly correlated with perinatal mortality (Fig. 2) and many serious morbidities: fetal abnormalities (renal agenesis with oligohydramnios; duodenal atresia; gross neurologic anomalies with polyhydramnios); birth weight (intrauterine growth restriction [IUGR] with oligohydramnios; diabetic macrosomia with polyhydramnios); and so on.4,5 These correlations determine monitoring decisions and sug-

Division of Maternal and Fetal Medicine, School of Medicine, University of Maryland Baltimore, Baltimore, MD. Address reprint requests to Christopher R. Harman, MD, University of Maryland Baltimore, Division of Maternal and Fetal Medicine, 22 S. Greene Street, Room N6E10, Baltimore, MD 21201. E-mail: charman@umm.edu

288

0146-0005/08/$-see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2008.04.012

Amniotic uid abnormalities

Table 1 What Is Amniotic Fluid For? * * * * * * Amnion metabolism Uterine shape Surface area: contractions, vessels Umbilical cord mobility Spacecranium, bones, lungs Recirculation, urine, spit, regurgitation * * * * * *

289

Hydraulic protection Thermoregulation Transportamnion, placenta Bacteriostatic Anti-inammatory Practicebreathing, swallowing, crying, movement of every kind.

gest specic tests depending on history, ultrasound examination, and progressive changes.

monitoring in an obstetric population. It might be fairer to observe that obstetric decisions should not be made based an AFV alone.

Amniotic Fluid Volume and Perinatal Outcome

Relationships between AFV and perinatal outcome are established in obstetric lore and AFV measurement is crucial to most ultrasound-based systems of fetal assessment, including the Biophysical Prole Score and modied Biophysical Prole (BPP).6 Recently, however, Ott7 suggested There is no relationship between amniotic uid volume and gestational age and AFI is not signicantly correlated with perinatal outcome. Reconciling this with dozens of studies to the contrary requires a few steps. Fewer than 6000 patients were reviewed retrospectively and had normal outcome, so the range of AFV was narrow, the nadir of Figure 2. Clinically, AFV is used longitudinallythis cross-sectional study was weakly predictive for individual cases. When anomalies, postdates pregnancy, severe IUGR, uncontrolled diabetes, and other maternal complications are excluded to attain normal outcome, many cases of abnormal amniotic uid are also articially excluded. The nadir of the AFV curve is then a at line, between single pocket depths of 3 to 8 cm, with no relationship to perinatal mortality or gestational age. Of course, this does not eliminate the value of amniotic uid

Amniotic Fluid Dynamics

Early transudation across skin and placental surfaces becomes negligible by completion of skin maturation at about 22 weeks. Amniotic uid is formed primarily from lung uid (about 100 mL per day) and fetal urine (7-10 mL/kg per hour) and is eliminated primarily by fetal swallowing, up to 1 L per day.8 Maturation is important for bothnear term, urine concentration increases and volume of production falls. Rest between swallowing becomes longer, from about 30 minutes at 24 weeks, up to 80 minutes between feedings at term. Other normal fetal functions also contributeregurgitation, diuresis (eg, caffeine or hyperglycemia from maternal diabetes), and individual efciency of fetal swallowing (some fetuses make repeated swallowing motions, without increasing stomach diameter; others dilate their stomachs with a few gulps).

Impact of Anomalies
These dynamics are markedly altered by fetal abnormalities (Table 3). Abnormal swallowing (obstruction or neurologic) means many fetuses with anomalies, including aneuploidy,

Figure 1 (A) (upper panel) Cervical funneling at 20 weeks gestation. Intraamniotic sludge (arrow) associated with cervical dilation (lower panel) within 6 days. (B) Similar cervical funneling without inammatory sludge at 20 weeks (upper panel) is unchanged after several weeks (lower panel). (Color version of gure is available online.)

290
Table 2 Amniotic Fluid Defensive Properties Specic inhibition, cell wall destruction of tissue corroding bacteria such as GBS* Opsonins,* macrophages, chemotactic factors, IL-1 RA,* IL-10,* a-defensins,* lysozyme, lactoferrin,* Ca psoriasin, PAF inhibitors, MMP3 antagonists At least 100 unique proteins in amniotic uid proteome
*Elevated in PTL, low in PTL-failed tocolysis.

C.R. Harman

chelaters,

have polyhydramnios. Urinary tract anomalies are often related to oligohydramnios. Interaction of multiple effects (for example, the fetus who has both a T-E stula and a renal dysplasiareduced elimination and reduced production) may yield normal AFV in anomalous fetuses.

Oligohydramnios
Reduced amniotic uid triggers a series of questions. Ultrasound examination determines if kidneys are present, do they currently work, and will normal renal function be maintained? Does ancillary information suggest inadequate prerenal volume (eg, severe IUGR with markedly abnormal placental Dopplers, donor status in twin-to-twin transfusion syndrome, or early midtrimester pregnancy with markedly elevated alpha fetoprotein (AFP) where perinatal mortality may reach 800/1000)? If all of these observations appear to be normal, there may be a uterine or maternal explanation for decreased uid provision. There may not be any problem with production occult preterm rupture of membranes (PROM) is often the explanation in that case. Oligohydramnios presents several other challenges. Ultrasound visualization is more difcult due to lack of contrast and lack of fetal mobility. If anomalies due to aneuploidy are suspected, amniocentesis may be very difcult. Severe oligohydramnios with fetal distress at early gestation means intervention (often classical cesarean delivery) is considered with no certainty about a normal outcome. In such dilemmas, amnioinfusion may be helpful. We reviewed 155 cases (unpublished data) of ultrasound-guided diagnostic amnioinfusion with warmed normal saline (200 mL before 28 weeks, 300 mL after 28 weeks) with the following results. In 102 cases, postinfusion high-resolution ultrasound found new anomalies. In 32, preterm premature rupture of membranes was diagnosed. In six, a suspected anomaly was disproved, while in 10%, no value could be dened, even in retrospect. A further 6% progressed in preterm labor to deliver with fatal outcome, an unexpected resolution of the problem. There were no direct maternal complications. Amnioinfusion has an important diagnostic role in oligohydramnios of unknown origin. Chronic oligohydramnios itself may produce additional adverse fetal effects. Even when the fetus is initially normal, chronic oligohydramnios from PROM (iatrogenic from chorion villus sampling (CVS) or amniocentesis, or spontaneous) may cause pulmonary hypoplasia, abnormal chest wall compliance, contractures, and lethal infection. Onset, duration, and severity of amniotic uid loss are important cofactors, but the gestational age at delivery remains the overriding issue. The severity of this problem has generated attempts to patch iatrogenic holes in the membrane, glue the cervix shut, or chronically replace the uid. In one randomized trial of 34 patients and several well-documented nonrandomized, noncontrolled series totaling more

Amniotic Fluid Volume Measurement

In invasive studies, using amniocentesis to instill dye, then remeasuring after mixing, neither single maximum vertical pocket (MVP) nor the four-quadrant amniotic uid index (AFI; Fig. 3) produce very accurate evaluation. Five dye-dilution trials examined 185 patients: the correlation coefcient for AFI (0.52) is modestly superior to MVP (r2 0.48). In 11 studies of sensitivity, most found no signicant difference, while specicity for oligohydramnios was superior for MVP set at 2 cm (a low level reached in 5% of pregnancies) to the clinically common AFI threshold of 5 cm.9,10 Categorization of polyhydramnios by MVP is more closely associated with clinical outcome, but neither method is very accurate. In management comparisons (especially for oligohydramnios), MVP gives better performancethe same predictive accuracy, fewer false alarms, and better correlation with biophysical and Doppler variables. It is true that either method is only an estimate. Clinical correlations, however, are established between these ultrasound estimates and clinical outcome, so direct inference of absolute volume is not a primary issue.

Figure 2 Perinatal mortality varies according to amniotic uid volume, as determined by maximum vertical pocket (MVP) in centimeters. In the normal range (MVP, 3 to 8 cm), the curve becomes at (nonsignicant) when all cases with abnormality (IUGR, diabetic macrosomia, and postdates) are removed. (Color version of gure is available online.)

Amniotic uid abnormalities

Table 3 Amniotic Fluid Dynamics Normal Daily Production Transudation skin, placenta Normal Daily Elimination

291

Swallowing up to 1 L/d, about every 30 minutes at 24 weeks, every 40 minutes at 32 weeks, only every 80 minutes at term Inhalation (minor) Renal maturity (decreased urine production)

Lung uid 100 mL (20% is exhaled, the rest is swallowed) Fetal urine 7-10 mL/kg/hr 24 weeks 150 mL 30 weeks 350 mL 34 weeks 600 mL 39 weeks 600 mL Regurgitation Fetal diuresis Gestational age effect Decreased Elimination Polyhydramnios

Decreased Production

Oligohydramnios

Anomalies Choanal Atresia Facial cleft T-E stula Esophageal atresia Imperforate anus Reduced swallowing: Neurological Behavior Drug induced Polyuriaabnormal kidneys, brain injury, diabetes

Urinary Tract Obstruction Renal failure (bad kidneys) Oliguria Placental failure (hypovolemia and hypoxia) Renal agenesis Absent lung uid (eg, tracheal atresia)

than 250 patients, amnioinfusion for PROM was studied.11,12 High variability in case selection means it is difcult to translate these results into clinical action. Study entry ranged from 16 to 34 weeks. In 50 to 75% of cases, the procedure was unsuccessful. In cases where late gestation or borderline reduced uid

(AFI of 6-8) suggests retrospectively the procedure was not required, outcomes were good. In 16 to 30%, where amnioinfusion did restore MVP 2 cm, outcomes were as good. Thus, it is reasonable to attempt amnioinfusion for early oligohydramnios. When AFV is restored, outcomes are likely better, but in the vast

Figure 3 (A) Maximum vertical pocket (MVP) method of amniotic uid measurement. (B) Four-quadrant amniotic uid index (AFI) method. (Color version of gure is available online.)

292 majority, the procedure is not required in the rst place or will be unsuccessful. Amnioinfusion for oligohydramnios of unknown origin is even less well-documented. Four historic series relate amnioinfusion to similar cases managed without intervention.13 In general, pregnancies were prolonged up to 30 days, deliveries were somewhat later, and babies signicantly larger, but there were no differences in perinatal mortality, short-term morbidity, or long-term morbidity (limited reporting). These collective data cannot be termed a meta-analysis, because they are so disparate in structure. Further, mounting a formal randomized control trial would be extremely difcult, considering variable IUGR severity (which might require delivery on a fetoplacental basis despite normalizing amniotic uid), differing maternal characteristics (eg, severe maternal preeclampsia, again requiring delivery), and differing onset of subject cases. Overall, amnioinfusion for the restoration of AFV in the midtrimester and early third trimester has been incompletely studied. There is probably no maternal danger and fetal outcomes have not been proven to be worse, so it may be considered in individual cases. Three trials and three clinical series examined maternal hydration (increased water intake, oral or intravenous with oral follow-up) for borderline oligohydramnios (AFI 8 cm in four, 6 cm in two). When oligohydramnios was judged by AFI, improvement was apparent, but there was no increase in borderline uid or oligohydramnios dened by MVP (two studies), no increase in normal AFI (two studies), and increased AFI was not sustained 48 hours (three studies).14 Clinical benets were not studied. In practices where AFI 5 cm mandates delivery, these data might improve management, but if MVP of 2 cm were applied, most would not require delivery in the rst place. Low risk of hydration and potential reduction in intervention might substantiate a randomized control trial. An important design issue is uterine tone. On ultrasound, uterine activity draws in the anks of the uterus, which has the effect of decreasing available vertical pockets for the AFI method. Maternal hyperhydration, with its known effect of reducing uterine contractility, might simply produce the illusion of more uid. Oligohydramnios later in the third trimester presents a different set of challenges. Since the strictest denitions (MVP 1 cm or MVP 2 cm) relate consistently to adverse outcome, delivery may be appropriate. Such outcomes include stillbirth and neonatal death, fetal distress in labor, delivery pH, Apgar score, and many neonatal complications. Criteria for subjectively reduced AFV describe preoligo situations but correlate weakly with poor outcome. Maternal relationships also correlate with MVP 2 cm, including severe pre-eclampsia, poor performance on external cephalic version, reduced success with induction of labor or vaginal birth after cesarean delivery, poor pain control in labor, and postpartum sepsis. As long-term studies relate to composite fetal condition (for example, the Biophysical Prole Score), or to neonatal condition requiring intensive resuscitation, it is difcult to assign longer term implications directly to oliTable 4 Amnioinfusion for Oligohydramnios Odds Ratio For cord compression FHR abnormal C/S fetal distress All C/S Acidemia Umb Art pH < 7.20 Maternal endometritis For meconium aspiration MAS-standard peripartum care Cesarean section Apgar5 < 7 MAS-Limited peripartum care 0.24 0.23 0.52 0.40 0.60 0.59 0.89 0.90 0.25

C.R. Harman

C.I. 0.17 to 0.34 0.15 to 0.35 0.40 to 0.68 0.30 to 0.55 0.36 to 1.01 0.28 to 1.25 0.73 to 1.10 0.58 to 1.41 0.13 to 0.47

Abbreviation: MAS, meconium aspiration syndrome

gohydramnios alone. Especially when oligohydramnios accompanies abnormal Doppler ultrasound indicating placental insufciency, or abnormal biophysical or fetal heart rate testing indicating increased risk of asphyxia, delivery is the principal treatment. For isolated oligohydramnios when other fetal testing is reassuring, amnioinfusion may allow safe vaginal delivery. Before considering these intrapartum amnioinfusion studies, one must carefully consider the decision to deliver. AFI 5 cm as a trigger for delivery is associated with increased fetal distress, more Cesarean sections, and signicant maternal morbidity. Many of those women would labor on their own before the MVP trigger of only 2 cm is reached, with signicant improvement in obstetric parametersa trial comparing doing nothing versus inducing labor with amnioinfusion has not been done. Table 4 displays trials of prophylactic transabdominal or transcervical amnioinfusion immediately before or in early labor at term, randomly compared with similar women without infusion. Amnioinfusion done to eliminate fetal heart rate decelerations from cord compression (upper section of Table 4) benets conduct of labor and babys condition.15 Subsequent trials investigated intermittent versus continuous infusion, the role of electronic fetal monitoring, and application to specic causes of oligohydramnios, but the studies either are too small or reached equivocal conclusions. This intervention focuses on reducing Cesarean sectionssocial and other reasons increasing the cesarean delivery rate may mean this information has reduced impact. Also, of uncertain impact in urban settings is amnioinfusion to reduce meconium aspiration syndrome. At least 12 randomized control trials have evaluated this, summarized in a recent meta-analysis. Results show two distinct patterns. When standard peripartum care applies, undiagnosed IUGR, postdates pregnancy, severe oligohydramnios, fetal infection, and undiagnosed twins are rare, and expert neonatal care is immediate. In this situation, amnioinfusion does not improve outcome. In contrast, where antenatal and neonatal care are limited, such as underserved African communities, 75% of meconium aspiration syndrome is prevented.16

Amniotic uid abnormalities

Table 5 Polyhydramnios Degree Mild Moderate Severe SDP >8 >11 >15 AFI >24 >32 >44 Frequency 68% 19% 13% PNM 50 190 540

293

Anomalies 6% or less Up to 45% Up to 65%

Oligohydramnios Summary

AFV is an established component of perinatal monitoring. Outcome analysis includes both causes and effects of chronic oligohydramnios. MVP 2 cm has signicant adverse correlates, while AFI of 5 cm may be too conservative, introducing unnecessary intervention, reduced specicity, and confusion about the relationship. Before term oligohydramnios is probably not reliable as a sole factor indicating delivery. Amnioinfusion lacks benet antenatally but has specic intrapartum application.

Polyhydramnios
Table 5 displays the denitions, frequency of different degrees of excess amniotic uid, and associated rates of perinatal mortality and congenital abnormality.17 The majority fall into the mild group and are idiopathic (55%). No long-term sequelae are attributed to this and there are many documented cases of women with serial pregnancies affected by polyhydramnios, so maternal factors may be inuential. Fetuses with incompletely controlled diabetes account for about 25%. It is thought that fetal hyperglycemia produces fetal polyuria due to its osmotic effect. Macrosomic diabetic infants also have increased cardiac output and increased blood volume, which increase fetal GFR and urine production. Most polyhydramnios in this group are also in the mild category. Twins account for about 7% of polyhydramnios, twothirds due to recipient status of twin-to-twin transfusion syndrome, which may reach severe proportions. In this case, pure hypervolemia and corresponding maladaptive responses cause virtually continuous fetal diuresis. Abnormalities causing gastrointestinal obstruction, including tracheoesophageal (TE) stula and esophageal atresia, may generate polyhydramnios of severe proportion for which antenatal imaging is often inconclusive. Others have underlying neurologic disorders and polyhydramnios due to absent or reduced swallowing. This is often associated with reduced activity, symmetric IUGR, and nongastrointestinal anomalies (eg, cardiac anomalies, spina bida, akinesia). Fetuses with borderline cardiac failure or diuresis due to elevated atrial natriuretic peptide (ANP) or brain natriuretic peptide (BNP) are associated with mild to moderate polyhydramnios. In most, the fetal condition precedes polyhydramnios, but in some (for example intermittent severe supraventricular tachycardia), elevated AFV may exist for several weeks before the underlying cause is determined. Investigation of polyhydramnios should include high-level

ultrasound, supplemented by appropriate fetal magnetic resonance imaging, invasive testing for karyotype and metabolic disorders, and multidisciplinary consultation. Severity correlates well with the complexity of the fetal source, so cases with severe polyhydramnios may be transferred to a tertiary center care. In poorly controlled diabetics, birth weight shows a linear correlation with amniotic uid volume, suggesting an increased risk for shoulder dystocia or neonatal complications, but the variation in presentation is wide, so the predictive accuracy is limited. As well as these correlations with fetal condition, polyhydramnios severity also generates complications. Preterm labor and delivery, malpresentation due to excess fetal mobility, abruption from sudden uterine decompression, and a fourfold increase in cesarean sections in most studies and a sixfold increase in postpartum hemorrhage, all apply. Severe polyhydramnios mandates close monitoring of contractions, cervical status, and potential interventions to prolong the pregnancy. Discussion of possible long-term neurologic sequelae is important in predelivery counseling. Therapeutic approaches to polyhydramnios include amnioreduction and the use of indomethacin, neither of which have been studied in randomized controlled trials. Comparisons of rapid versus slow drainage, large volume versus repeated small volumes, and the use of tocolysis during amnioreduction have not shown signicant differences. Complications of amnioreduction relate to initial severity, gestational age at presentation, and preterm labor. As amniotic uid is removed, expansion of the placenta drains blood from the fetus, which can cause long-term central nervous system and cardiac injury. Serial amniodrainage has been successfully conducted in a number of cases, reducing the impact of prematurity. This benet must be weighed against the potential risk to mother and fetus should aggressive preterm labor or placental abruption follow the procedure. Six series have reported the use of indomethacin to treat polyhydramnios.18 Indomethacins renovascular effect reduces fetal urine productionamniotic uid volume falls, especially in those with normal amniotic uid (eg, cases of cervical incompetence), nonobstructive causes (maternal anemia or maternal renal failure), and after 26 weeks gestation (fetal renovascular responsiveness earlier is limited). The lack of randomized control data suggests cautious application. The tocolytic effect of indomethacin in prolonging such pregnancies should not be overlookedreduced amniotic uid may simply be a side effect.

Amniotic Fluid Research

Amniotic uid is a highly complex mixture, used with good effect to inhibit bacterial growth in burn victims, to promote

294 healing of burns and other skin injury, and the important pulmonary and renal effects of swallowed amniotic uid have yet to be completely dened. As a source for pluripotential cells and novel anti-inammatory compounds, amniotic uid is a focal point of research. A number of drugs, including thyroid stimulating hormone (TSH), thyroxin, antibiotics, Digoxin, and radio-opaque dye are effectively ingested by the nonasphyxiated human fetus, pointing to other experimental potentials. More systematic research approaches are necessary to decide whether deliberate manipulation of amniotic uid volumes or specic contents of amniotic uid are therapeutically worthwhile.

C.R. Harman
7. Ott WJ: Re-evaluation of the relationship between amniotic uid volume and perinatal outcome. Am J Obstet Gynecol 192(6):1803-1809, 2005 8. El-Haddad MA, Desai M, Gayle D, et al: In utero development of fetal thirst and appetite: potential for programming. J Soc Gynecol Investig 11(3):123-130, 2004 9. Magann EG, Morton ML, Nolan TE, et al: Comparative efcacy of two sonographic measurements for the detection of aberrations in the amniotic uid volume on pregnancy outcome. Obstet Gynecol 83(6):959962, 1994 10. Magann FG, Chauhan SP, Doherty DA, et al: The evidence for abandoning the amniotic uid index in favor of the single deepest pocket. Am J Perinatol 24(9):549-555, 2007 11. Tan LK, Kumar S, Jolly M, et al: Test amnioinfusion to determine suitability for serial therapeutic amnioinfusion in midtrimester premature rupture of membranes. Fetal Diagn Ther 18(3):183-189, 2003 12. Locatelli A, Vergani P, Di Pirro G, et al: Role of amnioinfusion in the management of premature rupture of membranes at 26 weeks gestation. Am J Obstet Gynecol 183(4):878-882, 2000 13. Gramellini D, Fien S, Kaihura C, et al: Antepartum amniofusion: a review. J Matern Fetal Neonatal Med 14(5):291-296, 2003 14. Hofmeyr GJ, Glmezoglu AM: Maternal hydration for increasing amniotic uid volume in oligohydramnios and normal amniotic uid volume. Cochrane Database Syst Rev (1):CD000134, 2002 15. Hofmeyr GJ: Amnioinfusion for umbilical cord compression in labour. Cochrane Database Syst Rev (2):CD000013, 2000 16. Xu H, Hofmeyr J, Roy C, et al: Intrapartum amnioinfusion for meconium-stained amniotic uid: a systematic review of randomized control trials. BJOG 114 (4):383-390, 2007 17. Dashe JS, McIntire DD, Ramus RM, et al: Hydramnios: anomaly prevalence and sonographic detection. Obstet Gynecol 100(1):134-139, 2002 18. Rodriguez MH: Polyhydramnios: does reducing the amniotic uid volume decrease the incidence of prematurity? Clin Perinatol 19(2):359366, 1992

References
1. Buhimschi CS, Weiner CP, Buhimschi IA: Proteomics part II: the emerging role of proteomics over genomics in spontaneous preterm labor/birth. Obstet Gynecol Surg 61(8):543-553, 2006 2. Bujold E, Pasquier JC, Simoneau J, et al: Intra-amniotic sludge, short cervix and risk of preterm delivery. J Obstet Gynecol Can 28(3):198202, 2006 3. Vogel I, Thorsen P, Curry A, et al: Biomarkers for the prediction of preterm delivery. Acta Obstet Gynecol Scand 84(6):516-525, 2005 4. Chamberlain PF, Manning FA, Morrison I, et al: Ultrasound evaluation of amniotic uid volume I. The relationship of marginal and decreased amniotic uid to perinatal outcome. Am J Obstet Gynecol 150(3):245249, 1984 5. Chamberlain PF, Manning FA, Morrison I, et al: Ultrasound evaluation of amniotic uid volume II. The relationship of increased amniotic uid volume to perinatal outcome. Am J Obstet Gynecol 150(3):250-254, 1984 6. Harman CR: Assessment of fetal health. In: Creasy R, Iams J, Resnik, R (eds): MaternalFetal Medicine, (ed 6). Toronto, WB Saunders, 2007

Postdates and Antenatal Testing

Michael Y. Divon, MD, and Noa Feldman-Leidner, MD
The standard denition of a prolonged pregnancy is 42 completed weeks of gestation. The incidence of prolonged pregnancy varies depending on the criteria used to dene gestational age at birth. It is estimated that 4 to 19% of pregnancies reach or exceed 42 weeks gestation. Several studies that have used very large computerized databases of well-dated pregnancies provided insights into the incidence and nature of adverse perinatal outcome such as an increased fetal and neonatal mortality as well as increased fetal and maternal morbidity in prolonged pregnancy. Fetal surveillance may be used in an attempt to observe the prolonged pregnancy while awaiting the onset of spontaneous labor. This article reviews the different methodologies and protocols for fetal surveillance in prolonged pregnancies. On the one hand, false-positive tests commonly lead to unnecessary interventions that are potentially hazardous to the gravida. On the other hand, to date, no program of fetal testing has been shown to completely eliminate the risk of stillbirth. Semin Perinatol 32:295-300 2008 Elsevier Inc. All rights reserved. KEYWORDS prolonged pregnancy, fetal testing, perinatal morbidity, prenatal mortality, nonstress test, biophysical prole, Doppler

Prolonged Pregnancy

he standard denition of a prolonged pregnancy is 42 completed weeks of gestation. This denition is endorsed by the American College of Obstetricians and Gynecologists, The World Health Organization, and the International Federation of Gynecology and Obstetrics.1-3 In view of more recent perinatal mortality data that were derived from accurately dated pregnancies, it would be reasonable to conclude that prolonged pregnancy should be dened as gestational age at birth greater than or equal to 41 weeks of gestation. The incidence of prolonged pregnancy varies depending on the criteria used to dene gestational age at birth. It is estimated that 4 to 19% of pregnancies reach or exceed 42 weeks gestation and 2 to 7% complete 43 weeks of gestation.

Prolonged Pregnancy as an Indication for Fetal Testing

Several studies that have used very large computerized databases of well-dated pregnancies provide insights into the incidence and nature of adverse perinatal outcome in proDepartment of Obstetrics and Gynecology, Lenox Hill Hospital, New York, NY. Address reprint requests to Michael Y. Divon, MD, Department of Obstetrics and Gynecology, Lenox Hill Hospital, 130 E. 77th St., New York, NY 10075. E-mail: mdivon@lenoxhill.net

longed pregnancy. Divon and coworkers evaluated fetal and neonatal mortality rates in 181,524 accurately dated term and prolonged pregnancies.4 Their study documented a small but signicant increase in fetal mortality in accurately dated pregnancies that extend beyond 41 weeks gestation and demonstrated that fetal growth restriction is independently associated with a large increase in perinatal mortality in these pregnancies. These results were conrmed by other investigators.5,6 Clausson and coworkers documented that perinatal mortality rates in small for gestational age fetuses had higher odds ratio for stillbirth and neonatal death.6 The stillbirth rate did not change signicantly when fetuses with congenital malformations were excluded. However, an 80% drop in neonatal deaths occurred when malformed neonates were excluded from the analysis. In addition, prolonged pregnancies were associated with an increased frequency of neonatal convulsions, meconium aspiration syndrome, and Apgar score of 4 at 5 minutes. Again, morbidity in postterm small for gestational age (SGA) infants was higher than in postterm AGA infants. Further support for the concept that the small and old fetus suffers from increased perinatal mortality was provided by Campbell and coworkers, who performed a multivariate analysis of factors associated with perinatal death among 65,796 singleton postterm ( 294 days) births.7 Three variables were identied as independent predictors of perinatal mortality. SGA and maternal age equal or greater than 35 years were associated with a signicant increase in perinatal mortality. Interestingly, large for gesta295

0146-0005/08/$-see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2008.04.013

296 tional age status (ie, birth weight 90th percentile for gestational age) was associated with a modest protective effect for perinatal death. However, macrosomia was associated with a higher incidence of labor dysfunction, obstetrical trauma, shoulder dystocia, and maternal hemorrhage. Several studies have shown that the incidence of macrosomia increases with advancing gestational between 37 and 43 weeks. In addition, this increase also results in doubling the cesarean rate for protraction or descent disorders.8-10 There is good evidence to suggest that fetal and maternal morbidity are also increased as gestational age advances beyond term. Tunon and coworkers compared neonate intensive care unit (NICU) admission rates among 10,048 term pregnancies and 246 prolonged pregnancies ( 296 days by both scan and last menstrual period (LMP) dates).11 Prolonged pregnancy was associated with a signicant increase in NICU admissions (odds ratio, 2.05; 95% CI, 1.35 and 3.12). Several maternal and fetal complications were evaluated in a large (n 45,673) retrospective, cohort study by Caughey and Musci.12 The authors concluded that risks to both mother and infant increase as pregnancy progresses beyond 40 weeks gestation, and that antenatal fetal testing should begin sooner than current recommendation of 42 weeks of gestation. Olesen and coworkers evaluated a large computerized Danish database of singleton, live-born term and postterm ( 42 weeks) deliveries to quantify maternal and fetal risks associated with postterm delivery.13 Both perinatal and maternal complications were increased signicantly in postterm deliveries.

M.Y. Divon and N. Feldman-Leidner

spontaneous labor resulted in healthy neonates and a much lower cesarean section rate. No stillbirths were observed in this small series.16 Several investigators have examined the efcacy of using a nonstress test (NST) as a primary testing modality with the addition of sonographic assessment of amniotic uid. Clark and coworkers tested 279 prolonged pregnancies with this testing scheme. No stillbirths were recorded.17 Miller and coworkers reported on the use of a similar protocol in 6390 prolonged pregnancies.18 The false-negative rate of this test was 0.8 per 1000 women testeda rate that favorably compares with those reported for the contraction stress test or the complete biophysical prole.15,19 An analysis of all false-positive tests showed that the routine use of nonstress testing combined with the amniotic uid index (AFI) resulted in a 60% false-positive rate in the prediction of intrapartum fetal compromise compared with a 40% false-positive rate using the complete biophysical prole. This increase in false-positive tests was felt to be partly due to the poor specicity of the AFI in predicting fetal compromise. Alrevic and Walkinshaw compared the impact on perinatal outcome of two different protocols for antenatal fetal monitoring after 42 weeks.20. One hundred forty-ve women with singleton, uncomplicated pregnancies after 42 weeks of gestation were randomly allocated to fetal monitoring by either a biophysical prole combined with computerized cardiotocography or a standard cardiotocography supplemented by measurement of the largest vertical pocket of amniotic uid. Their results documented signicantly more abnormal antenatal monitoring tests in the biophysical prole combined with the computerized cardiotocography group. There were no differences in cord blood gases, neonatal outcome, or outcomes related to labor and delivery between the two groups, but there was a trend toward more obstetric interventions in the biophysical prole combined with the computerized cardiotocography group. Amniotic uid volume after 42 weeks was more likely to be labeled as abnormal with amniotic uid index than with largest vertical pocket. Sylvestre and coworkers evaluated the incidence of abnormal testing (NST and AFI) as a function of birth weight in 792 uncomplicated prolonged pregnancies ( 41 weeks).21 They showed an inverse relationship between abnormal testing and birth weight. In addition, small fetuses were more likely to require a cesarean delivery for non-reassuring fetal status during labor than were all other fetuses. Thus, it is reasonable to conclude that the small, postterm fetus is not only more likely to die in utero but is also more likely to fail antepartum fetal testing and to be delivered by nonelective cesarean section for an intrapartum diagnosis of non-reassuring fetal status. The implicit assumption in the expectant management strategy is that the presence of an abnormal fetal test (such as oligohydramnios, low biophysical prole score, or spontaneous fetal heart rate decelarations) represents a change in fetal status that requires intervention in the from of prompt delivery. A novel view of the regulation of fetal homeostasis during late gestation was offered by Onyeije and Divon.22 These

Fetal Surveillance
Fetal surveillance may be used in an attempt to observe the prolonged pregnancy safely while awaiting the onset of spontaneous labor. On the one hand, false-positive tests commonly lead to unnecessary interventions that are potentially hazardous to the gravida. On the other hand, to date, no program of fetal testing has been shown to completely eliminate the risk of stillbirth. Data presented earlier in this review indicate that perinatal mortality is signicantly increased as early as 41 weeks gestation and possibly even earlier. The optimal gestational age for the initiation of fetal testing has not been established. Jazayeri and coworkers provided physiologic evidence of altered fetal oxygenation in patients at 41 weeks by demonstrating elevated plasma erythropoietin levels in these patients.14 Thus, it would seem prudent to initiate fetal testing at 41 weeks of gestation. Extensive experience with biophysical prole testing in high-risk populations indicates a perinatal mortality rate of 0.73 per 1000 tested pregnancies within 1 week of a normal test provided that the amniotic uid volume is normal.15 Twice-weekly testing with the biophysical prole was reported in a series of 307 patients followed beyond 42 weeks of gestation. When the prole score was normal, waiting for

Postdates and antenatal testing

authors studied the incidence of maternal ketonuria (as a reection of maternal starvation and dehydration) and its association with abnormal fetal surveillance tests. One thousand eight hundred ninety-ve patients were managed expectantly with semiweekly fetal testing. Beginning at 41 weeks gestation, clinically detectable ketonuria occurred in 10.9% of patients studied. Patients with ketonuria were at increased risk for abnormal test results, including the presence of oligohydramnios (24 versus 9.3%, P 0.0001), nonreactive NST (6.2 versus 2.15%, P 0.0001), and the presence of fetal heart rate decelerations (14 versus 9.2%, P 0.0039). The authors suggested that reversible maternal ketonuria contributes to the false-positive test results often encountered in fetal testing, and that such patients might benet from treatment of ketonuria rather than be delivered in response to the abnormal test results. The formation of amniotic uid is a complex and poorly understood process. Multiple authors have demonstrated that amniotic uid volume decreases as gestational age advances beyond 32 or 34 weeks gestation. Marks and Divon evaluated the AFI in 511 well-dated prolonged pregnancies.23 Gestational age at the time of the study ranged from 41 weeks to 43 weeks and 6 days. AFI measurements ranged from 1.7 to 24.6 cm, with a mean and standard deviation of 12.4 4.2 cm at 41 weeks. Oligohydramnios (AFI 5.0 cm) was detected in 11.5% of the study population. Longitudinal data were available from 121 patients. These patients demonstrated a mean decrease in AFI of 25% per week. Thus, the authors concluded that the majority of pregnancies at 41 weeks gestation have a normal volume of amniotic uid. In the absence of ruptured membranes or fetal urinary tract abnormalities, diminishing levels of amniotic uid volume may be related to poor placental function.24 Trimmer and coworkers detected diminished urine production in pregnancies of 42 weeks or more with oligohydramnios and suggested that decreased fetal urine production was the result of preexisting oligohydramnios, which limited fetal swallowing of amniotic uid rather than a decrease in renal perfusion.25 Bar-Hava and coworkers used pulsed-wave Doppler to evaluate resistance index values in the fetal middle cerebral artery, renal, and umbilical arteries in 57 pregnancies at 41 weeks gestation.26 It was expected that, with hypoxia, impedance in the cerebral circulation might decrease as impedance increased in the renal circulation. Oligohydramnios (AFI 5 cm) was detected in 15 patients. The various resistance index values and the ratios among them were not signicantly different in patients with or without oligohydramnios. Interestingly, the mean birth weight in patients with oligohydramnios was signicantly lower than the mean birth weight in patients with a normal AFI. The authors concluded that oligohydramnios in these patients is not associated with a noticeable redistribution of blood ow and suggested that the cause of oligohydramnios is probably unrelated to renal perfusion. The fact that oligohydramnios was found more often in the smaller fetuses is intriguing. It suggests that the appearance of oligohydramnios is a pathologic rather than a physiologic

297 process. It may indicate that the pathophysiology of oligohydramnios in prolonged pregnancy is similar to that involved with the formation of oligohydramnios in the growth-restricted fetus, and overall it is consistent with the concept that it is the small and older fetus that is more prone to complications arising from asphyxia. Leveno and coworkers used the presence of oligohydramnios to explain the increased incidence of abnormal antepartum and intrapartum fetal heart rate (FHR) abnormalities seen in prolonged pregnancies.27 These authors suggested that prolonged FHR decelerations representing cord compression preceded 75% of cesarean deliveries for fetal jeopardy. The association between reduced amniotic uid index and variable decelerations is well documented, as suggested by Gabbe and coworkers, and variable FHR decelerations detected in patients with oligohydramnios are probably related to increased umbilical cord compression.28 Both Phelan and coworkers and Divon and coworkers found that the frequency of nonstress tests demonstrating FHR decelerations or bradycardia increased as the ultrasonographic estimates of the amniotic uid declined.29-31 The use of an amniotic uid index 5.0 cm to dene oligohydramnios was rst suggested by Phelan and coworkers in 1987, as an arbitrary cutoff value based on retrospective studies. Nevertheless, it has since gained popular appeal.29,30 A meta-analysis evaluated the risk of cesarean delivery for fetal distress, 5-minute Apgar score of 7, and umbilical artery pH 7.00 in patients with antepartum or intrapartum AFI 5.0 cm.32 Eighteen reports describing 10,551 patients at various gestational ages were included in the analysis. The overall incidence of oligohydramnios was 15.2%. The authors concluded that an AFI 5.0 cm is associated with an increased risk of cesarean delivery for fetal distress (relative risk of 2.2; 95% CI, 1.5-3.4) and an Apgar score of 7 at 5 minutes (relative risk of 5.2; 95% CI, 24113). However, no association was demonstrated between oligohydramnios and severe fetal acidosis. A prospective, blinded observational study of the usefulness of ultrasound assessment of amniotic uid in the prediction of adverse outcome in the prolonged pregnancy was reported by Morris and coworkers.33 The authors demonstrated that AFI 5 cm was signicantly associated with adverse perinatal outcome. Despite these associations, the sensitivity of an AFI 5 cm was very low, ranging from 11.5 to 28.6 for major adverse outcome, fetal distress in labor, or admission to the NICU. The authors concluded that routine use is likely to lead to increased obstetric intervention without improvement in perinatal outcome and that large clinical trials are necessary to assess the effectiveness of delivery based on sonographically diagnosed oligohydramnios. In a recent study Lam and coworkers evaluated the usefulness of AFI in the fetal surveillance of postdate pregnancies.34 The authors concluded that although AFI may be used to predict the occurrence of thick meconium stained liquor and the need for intervention for fetal distress in postdate pregnancies, its role on its own is limited. The presence of sonographically diagnosed oligohydramnios is often used as an indication for delivery of pregnancies

298 that reach term gestation or extend beyond term. One should however realize that up to 50% of patients, who are diagnosed by ultrasound as having oligohydramnios, will have a normal volume of amniotic uid on articial rupture of the membranes.35 In addition, there are no large-scale prospective randomized studies documenting the benets of delivery once oligohydramnios has been diagnosed. In the absence of such studies, it would seem prudent to deliver patients at or beyond 41 weeks gestation who demonstrate oligohydramnios primarily because of the large body of data which documents an association between diminished amniotic uid volume and adverse perinatal outcome. Doppler velocimetry is often used to identify fetal compromise due to altered fetal circulation. Its role in establishing fetal well-being in prolonged pregnancies is unclear. Several studies have concluded that the use of umbilical artery Doppler velocimetry is not associated with an improvement of the positive-predictive value of fetal testing in prolonged pregnancy.36-39 Zimmermann and coworkers performed a fetal Doppler cross-sectional, prospective study in 153 pregnancies beyond 287 days of gestation (36% were followed beyond 42 weeks of gestation).39 The resistance indices of the umbilical artery and the middle cerebral artery waveforms were studied every 2 days until delivery. All velocities fell within the known 95% condence intervals for normal term fetuses. Doppler measurements were unable to predict adverse fetal outcomes, such as abnormal fetal heart rate tracings, thick meconium, the need for urgent operative delivery, acidemia at delivery, or neonatal encephalopathy. In contrast, Oz and coworkers studied 147 well-dated, singleton, postterm pregnancies, of which 21 (14.3%) had oligohydramnios.40 The authors assessed the correlation between renal and umbilical artery Doppler velocimetry, and oligohydramnios. They demonstrated that the renal artery resistance index was signicantly higher in cases with oligohydramnios. A renal artery Doppler end-diastolic velocity below the mean for gestational age signicantly increased the risk of oligohydramnios (relative risk of 1.5 with 95% CI of 1.1-2.0). Their ndings support the hypothesis that increased arterial impedance is an important factor in the development of oligohydramnios in prolonged pregnancies. Two other studies support these ndings.41,42 Recently, Lam and coworkers in a prospective observational study of 118 uncomplicated postdated pregnancies at 41 weeks evaluated the distribution of fetal cerebro-placental Doppler indices and amniotic uid volume.41 The correlation with the incidence of passage of thick meconium in labor was analyzed. The middle cerebral artery pulsatility index was found to be signicantly better than amniotic uid volume or umbilical artery pulsatility index in predicting the risk of thick meconium-stained liquor in labor. Figueras and coworkers in a prospective study of prolonged pregnancies evaluated the value of middle cerebral artery Doppler indices obtained from different sampling sites in predicting umbilical cord gases at delivery.42 Fifty-six patients were included in the nal analysis. The proximal middle cerebral artery pulsatility index was found to signicantly predict umbilical artery pO2 at delivery but did not predict pH.

M.Y. Divon and N. Feldman-Leidner

In conclusion, given the information available at the present time, it is difcult to dene the extent to which the use of Doppler velocimetry can improve the positive-predictive value of fetal testing in prolonged pregnancy. Sonographic fetal weight estimates are often obtained as part of fetal testing in prolonged pregnancies. The accurate and timely prediction of macrosomia may well inuence delivery management decisions. However, one should note that the accurate estimation of fetal weight must be viewed in its broad clinical context of feto-pelvic disproportion. Thus, the crucial factor is the relationship of the fetal size to the maternal pelvis rather than the common clinical preoccupation with macrosomia alone. Focusing on either one of these factors in isolation represents a conceptual error.43 Traditionally, obstetricians have predicted fetal weight by abdominal palpation or symphysialfundal height measurement. Ultrasound failed to fulll the expectation for a more accurate method to estimate fetal weight. Both Chervenak and coworkers and Pollack and coworkers documented that a sonographic estimate of fetal weight of 4000 g had low sensitivity and low positivepredictive value and, therefore, the authors concluded that routine sonographic screening for macrosomia in prolonged pregnancies is associated with relatively low accuracy.43-45 In an attempt to improve the accuracy of sonographic estimates of fetal weight, OReilly-Green and Divon used receiver operating characteristic curve analysis to identify optimal cutoff values of estimate of fetal weight in the prediction of macrosomia in prolonged pregnancies.46 The authors concluded that cutoff values derived from their analysis resulted in reasonable sensitivities but disappointingly low positive-predictive values. The practical implications of the low predictive value of ultrasonography have been highlighted by Rouse and coworkers. These authors have shown that in nondiabetic pregnancies the level of intervention and the economic costs of prophylactic cesarean delivery for fetal macrosomia diagnosed by mean of ultrasonography would be excessive.47,48 It would seem reasonable that as fetal weight continues to increase with advancing gestational age, delivery of those pregnancies with a potential for macrosomia might prevent some cases of shoulder dystocia and a subsequent brachial plexus injury. However, this intervention could be achieved only by increasing the rate of inductions of labor or by an increased use of cesarean deliveries, both of which would subject the patient to added morbidity or even unnecessary mortality.

Summary
Management of the prolonged pregnancy is primarily determined by the interplay of three factors: certainty of gestational dating, the risks associated with expectant management, and the likelihood of spontaneous vaginal delivery following an induction of labor. A Cochrane Database of Systematic Review from 2007 assessed the effects of interventions aimed at either reducing the incidence or

Postdates and antenatal testing

improving the outcome of postterm pregnancy. Twentysix trials of variable quality were included.49 The author concluded that routine early pregnancy ultrasound examination and subsequent adjustment of delivery date appear to reduce the incidence of postterm pregnancy. Furthermore, routine induction of labor after 41 weeks gestation appears to reduce perinatal mortality. However, there was not enough evidence to evaluate the effects of antenatal testing on fetal wellbeing.

299
19. Freeman RK, Anderson G, Dorchester W: A prospective multicenter multi institutional study of antepartum fetal heart rate monitoring. II. Contraction stress test versus non-stress test for primary surveillance. Am J Obstet Gynecol 143:778-781, 1982 20. Alrevic Z, Walkinshaw SA: A randomized controlled trial of simple compared with complex antenatal fetal monitoring after 42 weeks of gestation. Br J Obstet Gynaecol 102:638-643, 1995 21. Sylvestre G, Fisher M, Westgren M, et al: Non-reassuring fetal status in the prolonged pregnancy: the impact of fetal weight. Ultrasound Obstet Gynecol 18:244-247, 2001 22. Onyeije CI, Divon MY: The impact of maternal ketonuria on fetal test results in the setting of postterm pregnancy. Am J Obstet Gynecol 184:713-718, 2001 23. Marks AD, Divon MY: Longitudinal study of the amniotic uid index in postdates pregnancy. Obstet Gynecol 79:229-233, 1992 24. Gresham El, Rankin JH, Makowski EL, et al: An evaluation of fetal renal function in chronic sheep preparation. J Clin Invest 51:149156, 1972 25. Trimmer KJ, Leveno KJ, Peters MT, et al: Observation on the cause of oligohydramnios in prolonged pregnancy. Am J Obstet Gynecol 163: 1900-1903, 1990 26. Bar-Hava I, Divon MY, Sardo M, et al: Is oligohydramnios in post-term pregnancy associated with redistribution of fetal blood ow? Am J Obstet Gynecol 173:519-522, 1995 27. Leveno KJ, Quirk JG Jr, Cunningham FG, et al: Prolonged pregnancy observations concerning the causes of fetal distress. Am J Obstet Gynecol 150:465-473, 1984 28. Gabbe SG, Ettinger BB, Freeman RK, et al: Umbilical cord compression associated with amniotomy: laboratory observations. Am J Obstet Gynecol 126:353-355, 1976 29. Phelan JP, Smith CV, Broussard P, et al: Amniotic uid volume assessment with the four-quadrant technique at 36-42 weeks gestation. J Reprod Med 32:540-542, 1987 30. Phelan JP, Ahn MO, Smith CV, et al: Amniotic uid index measurements during pregnancy. J Reprod Med 32:601-604, 1987 31. Divon MY, Marks AD, Henderson CE: Longitudinal measurement of amniotic uid index in postterm pregnancies and its association with fetal outcome. Am J Obstet Gynecol 172:142, 1995 32. Chauhan SP, Sanderson M, Hendrix N, et al: Perinatal outcome and amniotic uid index in the antepartum and intrapartum periods: a meta-analysis. Am J Obstet Gynecol 181:1473-1478, 1999 33. Morris JM, Thompson K, Smithey J, et al: The usefulness of ultrasound assessment of amniotic uid in predicting adverse outcome in prolonged pregnancy: a prospective blinded observational study. BJOG 110:989-994, 2003 34. Lam H, Leung WC, Lee CP, et al: Amniotic uid volume at 41 weeks and infant outcome. J Reprod Med 2006 6:484-488, 2006 35. OReilly-Green CP, Divon MY: Predictive value of amniotic uid index for oligohydramnios in patients with prolonged pregnancies. J Matern Fetal Med 5:218-226, 1996 36. Strokes HJ, Roberts RV, Newnham JP: Doppler ow velocity waveform analysis in postdate pregnancies. Aust NZ J Obstet Gynecol 31:27-30, 1991 37. Guidetti DA, Divon MY, Cavalieri RL, et al: Fetal umbilical artery ow velocimetry in postdate pregnancies. Am J Obstet Gynecol 157:15211523, 1987 38. Farmakides G, Schulman H, Ducey J, et al: Uterine and umbilical Doppler velocimetry in post term pregnancy. J Reprod Med 33:259261, 1988 39. Zimmermann P, Albck T, Koskinen J, et al: Doppler ow velocimetry of the umbilical artery, uteroplacental arteries and fetal middle cerebral artery in prolonged pregnancy. Ultrasound Obstet Gynecol 5:189-197, 1995 40. Oz AU, Holub B, Mendilcioglu I, et al: Renal artery Doppler investigation of the etiology of oligohydramnios in postterm pregnancy. Obstet Gynecol 100:715-718, 2002 41. Lam H, Leung WC, Lee CP, et al: The use of fetal Doppler cerebroplacental blood ow and amniotic uid volume measurement in the surveillance of postdated pregnancies. Acta Obstet Gynecol Scand 84:844-848, 2005

References
1. American College of Obstetricians and Gynecologists (ACOG): American College of Obstetricians and Gynecologists Practice Bulletin. Management of Postterm Pregnancy, September 2004 2. World Health Organization (WHO): Recommended denition terminology and format for statistical tables related to perinatal period and rise of new certication for the cause of perinatal deaths. Modications recommended by FIGO as amended, October 14, 1976. Acta Obstet Gynecol Scan 56:247-253, 1977 3. Federation of Gynecology and Obstetrics (FIGO): Report of the FIGO subcommittee on Perinatal Epidemiology and health statistics following a workshop in Cairo, November 11-18, 1984. London, International Federation of Gynecology and Obstetrics 1986, p 54 4. Divon MY, Haglund B, Nisell H, et al: Fetal and neonatal mortality in the post-term pregnancy: the impact of gestational age and fetal growth restriction. Am J Obstet Gynecol 178:726-731, 1998 5. Ingemarsson I, Kallen K: Stillbirths and rate of neonatal deaths in 76,761 postterm pregnancies in Sweden, 1982-1991: a register study. Acta Obstet Gynecol Scand 76:658-662, 1997 6. Clausson B, Cnattingius S, Axelsson O: Outcomes of post-term births: the role of fetal growth restriction and malformations. Obstet Gynecol 94:758-762, 1999 7. Campbell MK, Ostbye T, Irgens LM: Post-term birth: risk factors and outcomes in a 10-year cohort of Norwegian births. Obstet Gynecol 89:543-548, 1997 8. Boyd ME, Usher RH, McLean FH: Fetal macrosomia: prediction, risks, proposed management. Obstet Gynecol 61:715-722, 1983 9. McLean FH, Boyd ME, Usher RH, et al: Post-term infants: too big or too small? Am J Obstet Gynecol 164:619-624, 1991 10. Nahum GG, Stanislaw H, Huffaker BJ: Fetal weight gain at term: linear with minimal dependence on maternal obesity. Am J Obstet Gynecol 172:1387-1394, 1995 11. Tunon K, Eik-Nes SH, Grottum P: Fetal outcome in pregnancies dened as post-term according to the last menstrual period estimate, but not according to the ultrasound estimate. Ultrasound Obstet Gynecol 14:12-16, 1999 12. Caughey AB, Musci TJ: Complications of term pregnancies beyond 37 weeks of gestation. Obstet Gynecol 103:57-62, 2004 13. Olesen AW, Wesergaad JG, Olsen J: Perinatal and maternal complications related to postterm delivery: a national register-based study, 1978-1993. Am J Obstet Gynecol 189:222-227, 2003 14. Jazayeri A, Tsibris JC, Spellacy WN: Elevated umbilical cord plasma erythropoietin levels in prolonged pregnancies. Obstet Gynecol 92:6163, 1998 15. Manning FA, Morrison I, Harman CR, et al: Fetal assessment based on fetal biophysical prole scoring: experience in 19,221 referred highrisk pregnancies. II. An analysis of false-negative fetal deaths. Am J Obstet Gynecol 157:880-884, 1987 16. Johnson JM, Harman CR, Lange IR, et al: Biophysical prole scoring in the management of the post term pregnancy: an analysis of 307 patients. Am J Obstet Gynecol 154:269-273, 1986 17. Clark SL, Sabey P, Jolley K: Nonstress testing with acoustic stimulation and amniotic uid volume assessment: 5973 tests without unexpected fetal death. Am J Obstet Gynecol 160:694-697, 1989 18. Miller DA, Rabello YA, Paul RH: The modied biophysical prole: antepartum testing in the 1990s. Am J Obstet Gynecol 174:812-817, 1996

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42. Figueras F, Lanna M, Palacio M, et al: Middle cerebral artery Doppler indices at different sites: prediction of umbilical cord gases in prolonged pregnancies. Ultrasound Obstet Gynecol 24:529-533, 2004 43. Pollack RN, Hauer-Pollack G, Divon MY: Macrosomia in postdates pregnancies: the accuracy of routine ultrasonographic screening. Am J Obstet Gynecol 167:7-11, 1992 44. Chervenak JL, Divon MY, Hirsch J, et al: Macrosomia in the post-date pregnancy: is routine sonography screening indicated. Am J Obstet Gynecol 161:753-756, 1989 45. Pollack RN, Divon MY: Problems in detecting fetal macrosomia. Contemporary Ob/Gyn, October 1991 46. OReilly-Green CP, Divon MY: Receiver operating characteristic

M.Y. Divon and N. Feldman-Leidner

curves of sonographic estimated fetal weight for prediction macrosomia in prolonged pregnancies. Ultrasound Obstet Gynecol 9:403-408, 1997 47. Rouse DJ, Owen J: Prophylactic cesarean delivery for fetal macrosomia diagnosed by means of ultrasonographya Faustian bargain? Am J Obstet Gynecol 181:332-338, 1999 48. Rouse DJ, Owen J, Goldenberg RL, et al: The effectiveness and costs of elective cesarean delivery for fetal macrosomia diagnosed by ultrasound. JAMA 276:1480-1486, 1996 49. Crowley P: Interventions for preventing or improving the outcome of delivery at or beyond term. Cochrane Database of Systematic Reviews 2, 2007

Antepartum Testing for Women with Previous Stillbirth

Jonathan W. Weeks, MD
Women with past histories of stillbirth have been referred for antepartum surveillance since the inception of electronic fetal monitoring. However, this approach was originally based on mid-twentieth century perinatal studies that noted an increase in adverse outcomes in pregnancies subsequent to stillbirth. When these landmark studies were done, Rh immune globulin, ultrasonography, and other important medical advances had not yet occurred. This article discusses whether women who have suffered a past stillbirth remain at increased risk for perinatal mortality and morbidity in future pregnancies and whether antepartum fetal surveillance can reduce the risk of recurrent stillbirth. Semin Perinatol 32:301-306 2008 Elsevier Inc. All rights reserved. KEYWORDS stillbirth, fetal testing, antepartum surveillance, fetal death, intrauterine fetal demise

history of stillbirth is an accepted indication for antepartum surveillance.1,2 The purpose of this article was to review the data supporting stillbirth as an indication for fetal testing and to evaluate the reported experience with antepartum surveillance in women who have suffered a previous stillbirth. We also address the question of whether antepartum surveillance is effective at preventing recurrent stillbirth.

Evidence for Stillbirth as a Risk Factor for Poor Future Pregnancy Outcome
Women who have suffered one stillbirth are at increased risk for perinatal mortality in subsequent pregnancies. This was proven in large British and U.S. population studies conducted in the mid-twentieth century. The U.S. study, conducted by the National Institute of Neurological Diseases and Stroke, determined that patients with previous stillbirths had a perinatal mortality rate of 73 per 1000 in subsequent pregnancies and nearly 2% of their surviving children were neurologically abnormal at 1 year of age.3 The British study reUniversity of Louisville School of Medicine, Louisville, KY. From Antenatal Testing: A Reevaluation, a workshop cosponsored by the Pregnancy and Perinatology Branch (PPB) at the National Institute of Child Health and Human Development, the Ofce of Rare Diseases, National Institutes of Health, the American College of Obstetricians and Gynecologists, and the American Academy of Pediatrics. Address reprint requests to Jonathan W. Weeks, MD, P.O. Box 43578, Louisville, KY 40253-0578. E-mail: jwmfm@40weeks.org

ported that the risk of poor outcomes in subsequent pregnancies was more than doubled among women with previous stillbirths.4 These historic studies predated the era of electronic fetal monitoring, but the reported experiences served as justication for inclusion of stillbirth as an indication for fetal surveillance once the technology became available. Based on the aforementioned U.S. and British perinatal studies, utilization of antepartum surveillance in women with a past history of stillbirth seems prudent. However, those studies were conducted before the development and wide implementation of several valuable medical breakthroughs such as Rh immune globulin, ultrasonography, serum screening for aneuploidy, and use of home glucose monitoring devices. Several population-based studies on future pregnancy outcomes in women who have experienced a previous stillbirth have recently been published.5-7 These newer studies have also revealed excess perinatal mortality among women with previous stillbirths. In 1993, Samueloff and coworkers published a study of recurrent stillbirths at an academic center in San Antonio. The overall stillbirth rate in the 13-year cohort was 8.3 per 1000 births. Of the 403 women who had pregnancies subsequent to stillbirths, 34 experienced recurrent stillbirths for a rate of 84.3 per 1000 births. Thus, risk was 10-fold higher than that of multiparous women who had no previous history of stillbirth. When compared with women with past histories of stillbirth and a live-born infant in subsequent pregnancies, the women who had recurrent stillbirths were more likely to 301

0146-0005/08/$-see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2008.04.014

302
Table 1 Stillbirth Rates by Race and Past History of Stillbirth History of SB Black White Overall 35.9 19.1 22.7 No History of SB 7.6 4.2 4.7

J.W. Weeks
seven stillbirths occurred in the second pregnancies; 20 were in women with past stillbirths (stillbirth rate, 19.0 per 1000 births), and 927 were in the control group (stillbirth rate, 3.6 per 1000 births; P 0.001). Although the population studies mentioned above are limited by their reliance on birth certicate data and the lack of quantitative assessment of the frequency and severity of maternal conditions, the evidence for stillbirth as a predictor of poor future pregnancy outcome and recurrent stillbirth is compelling. Even in a relatively low-risk population, the adjusted risk of stillbirth is nearly sixfold higher among those with a past history of stillbirth.5

SB rate SB per 1000 births (live births plus stillbirths). Modied from Sharma and coworkers.6

have diabetes or hypertension. However, half of women with recurrent stillbirth had no chronic medical conditions.7 Sharma and coworkers studied a large cohort of Missouri women who gave birth between 1978 and 1997.5 Future pregnancy outcomes in women who experienced a stillbirth in their rst pregnancy were compared with those of women who delivered a live birth in their rst pregnancy. The study included 404,201 women: 99.5% had a live birth in the rst pregnancy and 0.5% (1979) had a stillbirth, which was dened as an intrauterine death at 20 weeks gestation or more. Compared with women without a history of stillbirth, women with a history of stillbirth in their rst pregnancy had a 57% increase in complications in the second pregnancy, including diabetes, chronic hypertension, preeclampsia, eclampsia, and abruptio placenta. There were 1929 stillbirth cases in the second pregnancy: 45 (2.3% of all cases) occurred in women with a history of stillbirth and 1884 (97.7% of all cases) among those without a stillbirth history. Hence, the stillbirth rate in women with a previous history of fetal death at 20 weeks or more was 22.7 per 1000 as compared with 4.7 per 1000 for those who did not have a stillbirth with their rst pregnancies. Table 1 shows the stillbirth rates stratied by race and history of stillbirth in the rst pregnancy. Sharmas data revealed a nearly twofold increase in stillbirth rates among black women overall. In pregnancies subsequent to a stillbirth, black women had a stillbirth risk that was sevenfold greater than the national average. Sharma and coworkers also calculated adjusted estimates for the relationship between prior stillbirth and subsequent stillbirth recurrence. Several models for relative risk were presented in which the reference group comprised women with a live birth in the rst pregnancy, live births excluding small for gestational age (SGA), live births excluding preterm births, or live births excluding preterm or SGA. In all models the relative risk of stillbirth among the total population of women with a previous stillbirth was increased over fourfold. Most studies on stillbirth recurrence comprised patients from the general population, which include women with medical complications and risk factors. This could cause an overestimation of risk in low-risk patients. Sharma and coworkers have also conducted a population study on stillbirth recurrence in a group of relatively low-risk women.5 The data were again derived from a Missouri database. The relatively low-risk population was dened as nonsmoking women, less than 35 years of age, who were carrying singleton, nonanomalous fetuses. The study group (n 1050) had experienced a stillbirth in the previous pregnancy, while the control group had live births (n 261,384). Nine hundred forty-

Experience with Antepartum Testing for Prevention of Recurrent Stillbirth

Having proven stillbirth as a harbinger of future perinatal mortality and morbidity in studies, conducted before and after the development of important laboratory, imaging, and medical interventions, the next logical step is to consider methods to mitigate future risk. In the hopes of improving pregnancy outcomes in women with a history of stillbirth, clinicians have used antenatal testing since its inception. Prospective randomized trials to test whether fetal monitoring actually reduces recurrent stillbirth have never been done. Early in the history of electronic fetal monitoring, there was a great deal of enthusiasm for the technology and high expectations of efcacy. The apparent lack of risk associated with the use of antepartum fetal surveillance also contributed to its wide adoption for patients with histories of stillbirth. However, the real deterrent to randomized trials was, and still is, the low numbers of affected women (stillbirths occur in 1% of pregnancies) and the need to control for a large number of confounding variables. In fact, these challenges have led to a dearth of retrospective study on the performance of fetal testing to prevent recurrent stillbirth. Freeman and coworkers reported on 337 women with histories of stillbirth who were followed with antenatal testing.8 These pregnancies were a subset of a total of 7052 high-risk pregnancies undergoing antenatal testing. Although it was a multi-institutional retrospective study of women seen between 1976 and 1982, the data on antenatal testing indications and results were collected prospectively.

Table 2 Indications for Fetal Testing Among Stillbirth Patients Indication for Testing Total stillbirth patients Previous stillbirth only Previous stillbirth and hypertension Previous stillbirth and diabetes Previous stillbirth and IUGR Previous stillbirth and postdates
Note. Multiple diagnoses in some patients. Reprinted with permission.8

No. of Patients 337 163 83 71 29 21

Percent 48.3 24.6 21 8.6 6.2

Antepartum testing for stillbirth

Table 3 Antenatal Fetal Testing Indications and Incidence of Positive Contraction Stress Test Results No. Tested All tested patients No previous hx SB All previous SB SB HTN SB diabetes SB IUGR SB postdates SB only indication 7052 6744 337 83 71 29 21 163 No. CST 208 194 19 10 4 5 0 6 % 3.0 2.9 5.6* 12.0* 5.6 17.2* 3.7

303 likelihood of positive CST was not signicantly higher than those who had indications for testing, but without a previous stillbirth history (3.7% versus 2.9%). In this study, there was no evaluation of outcomes according to the presence or absence of positive tests results. Therefore, while the study clearly shows that mothers who have experienced a previous stillbirth and who have medical or obstetrical complications in future pregnancies are at greater risk for positive contraction stress test results, there is no way to determine if the outcomes in the patients with positive CST results were poorer. Freeman and coworkers did make perinatal outcome comparisons in patients with and without histories of stillbirth (Table 4). Patients with a history of stillbirth did not have higher incidences of intrauterine growth restriction, low 5-minutes Apgar scores, late decelerations in labor, or perinatal deaths than the population of patients whose indications for testing did not include stillbirth. However, a significantly higher incidence of respiratory distress syndrome did occur in patients with a history of stillbirth than in all other tested patients (3.9% versus 1.7%; P 0.05). The authors reported that the increase in respiratory distress syndrome was probably due to a greater number of induced labors and primary cesareans (without labor) in women who had histories of stillbirth plus hypertensive disorders, diabetes, or intrauterine growth restriction as their indications for testing. When induction of labor or cesarean section was undertaken in women with a stillbirth history and hypertension, diabetes, or intrauterine growth restriction, approximately half of the interventions were for abnormal fetal heart rate testing results and half were for maternal indications. While respiratory distress syndrome was increased in neonates delivered by mothers with a history of stillbirth, the neonatal death (0.3%) rate was not signicantly different than the group of tested pregnancies without a past history of stillbirth (Table 4). The important ndings of Freeman and coworkers can be summarized as follows: 1. A history of previous stillbirth is associated with a greater number of tests per patient than is seen in other patients with high-risk conditions. However, 44% of patients without stillbirth had postdates as an indication for testing, which would signicantly limit the

*P < 0.05 when compared to patients without previous stillbirth. Reprinted with permission.8

Approximately half of the 337 patients with a previous history of stillbirth had no other reason for testing (Table 2). Acknowledging that perinatal death was too rare an outcome for meaningful statistical comparisons, the authors focused on antenatal test results, morbidity, and need for intervention in the various subgroups. During the study interval, there were 396 women who were excluded from the study cohort due to noncompliance or inadequate testing. Three of these women had recurrent stillbirths. All were diabetics who were noncompliant with follow-up testing; two had only one test at 35 to 36 weeks followed by a gap in testing of more than 2 weeks. One had a stillborn infant with multiple anomalies delivered 7 days after an unsatisfactory test, owing to massive obesity. No recurrent stillbirths occurred in the group of patients who were properly tested. Nineteen of the 337 patients with a previous stillbirth had positive contraction stress test (CST) results (5.6%), which was nearly double the rate seen in patients without previous stillbirth (Table 3). However, the average number of fetal heart rate tests per patient with a history of stillbirth was 5.0 compared with 2.5 tests per patient for the total population tested. The increased risk of positive CST results among women with stillbirth histories was attributable to pregnancies with past stillbirth and hypertension and past stillbirth plus intrauterine growth restriction as the indications for testing (incidence of positive tests 12 and 17%, respectively). Among the patients with past stillbirth as the only indication for testing (ie, no maternal medical problems, or intrauterine growth restriction), the

Table 4 Perinatal Outcome for Patients with and Without a Previous Stillbirth Hx SB (n Outcome BW <10th centile 5 min Apgar <7 Late decels in labor Fetal death Neonatal death Neonatal RDS
Hx history; SB stillbirth; BW Reprinted with permission.8

No Hx SB (n % 5.0 3.9 8.6 0.3 3.9 No. 368 178 664 25 52 112 6744) % 5.5 2.6 9.8 0.4 0.8 1.7

337)

No. 17 13 29 0 1 13
birth weight.

P
NS NS NS NS NS < 0.05

304 number of CSTs that would have been done in that group. Patients who have a history of previous stillbirth and a chronic maternal condition or intrauterine growth restriction are at greater risk for having positive contraction stress test results than patients whose indications for testing did not include stillbirth. When a past history of stillbirth was the only indication for testing, there was no increased risk of positive contraction stress test results even though the stillbirth only group probably had more tests per patient than the general antepartum surveillance population. However, patients were high risk (eg, hypertension, diabetes, postdates). Without a group of low-risk controls, we cannot conclude that patients with a prior stillbirth as their only risk factor do not deserve monitoring. Antenatal testing has the potential to increase the risk of premature delivery. Mothers with medical or obstetrical problems and past stillbirths were more likely to have labor inductions and cesarean sections and their neonates were more likely to have respiratory distress syndrome. Presumably, some of these interventions were the result of false-positive contraction stress test results. Antenatal testing is likely to reduce recurrent stillbirth. Extrapolating from the perinatal collaborative data of the mid-twentieth century, in which perinatal mortality in pregnancies following at stillbirth was 7.3%, there should have been 25 perinatal deaths among the 337 women with prior stillbirths. Considering that there was only one neonatal death and no stillbirths in the 337 women who were compliant, antenatal fetal testing probably confers some protection against recurrent stillbirth. The degree to which the low perinatal mortality can be directly attributable to fetal testing as opposed to advances in medical care in the 25 years after the perinatal collaborative studies cannot be quantied.

J.W. Weeks
future pregnancies is important and whether the gestational age of the previous stillbirth inuenced future pregnancy outcomes. As with the Freeman study, the rarity of recurrent stillbirth meant that outcome data were limited to measures of morbidity. The study group comprised patients seen at two institutions in southern California between 1979 and 1991. For all but the nal 2 years, weekly contraction stress testing was used. In the nal 2 years, semiweekly modied biophysical proles (nonstress test plus amniotic uid index) were used. CST or biophysical proles were performed as needed to follow-up abnormal modied biophysical prole results. The study goal was to determine when to initiate testing in such women since a variety of approaches were being employed by the referring obstetricians (eg, begin testing 2 to 4 weeks before the gestational age of the previous stillbirth, at 32 weeks for all patients, at 36 weeks for all patients). To assess the relationship between the gestational age of the previous stillbirth and subsequent pregnancy outcome, Weeks and coworkers compared groups who had early ( 32 weeks) versus late ( 36 weeks) stillbirths in the past. Predictably, the early stillbirth group had signicantly more fetal tests per patient. They also had signicantly more abnormal test results; however, interventions for abnormal tests and evidence of fetal compromise did not differ between the groups (Table 5). There was one recurrent stillbirth and no neonatal deaths reported. The one stillbirth occurred in a women who had no live births and two previous stillbirths at 37 to 38 weeks gestation. The autopsy results for these stillbirths was normal. The mothers screening for hypertension, diabetes, thyroid disease, sexually transmitted disease, and collagen vascular disease was negative. Parental karyotypes were also normal. Three days after having a normal CST, that patient presented with a complaint of decreased fetal movement. She was released after having a reactive nonstress test; no decelerations were noted. Despite this, she returned 16 hours later stating that she was totally devoid of fetal movements for 5 hours. Intrauterine death was conrmed and the 35-week stillborn proved to be appropriately grown and structurally normal. Fifty-three of the 300 study patients delivered at less than 38 weeks (18%). In half of those instances the deliveries

2.

3.

4.

5.

In 1991, Weeks and coworkers reported on a cohort of 300 women whose sole indication for antepartum testing was a past history of stillbirth.9 Whereas Freeman and coworkers sought to determine if a past history of stillbirth remained an important risk factor in the modern obstetrics era, Weeks and coworkers sought to determine if the timing of fetal testing in

Table 5 Pregnancy Outcome by Gestational Age of Previous Stillbirth SB < 32 Weeks (n EGA delivery Birth weight EGA rst test Total tests Abnormal tests Delivery for abnormal test C/S for fetal indications IUGR 38.9 (2.0) 3270 (560) 32.1 (4.0) 13.9 (10.7) 61.70% 20% 3.50% 5.20%
cesarean section; EGA

115)

SB > 36 Weeks (n 39.1 (2.0) 3421 (567) 34.2 (3.0) 8.7 (5.2) 41.90% 20.90% 6.80% 2.70%

148)

P
NS 0.03 <0.01 <0.01 <0.01 NS NS NS
stillbirth.

SD parenthesis; IUGR intrauterine growth restriction; C/S Reprinted with permission.9

estimated gestational age; SB

Antepartum testing for stillbirth

Table 6 Delivery Indications by Gestational Age Gestational Age at Delivery Reason for Delivery Positive CST Equivocal fetal test Spontaneous labor Elective induction Abruption PIH Other* <38 Weeks (n 53) 4 (7.5%) 8 (15.1%) 27 (50.9%) 0 3 (5.7%) 4 (7.5%) 7 (13.2%) >38 Weeks (n 247) 10 (4.05%) 19 (7.69%) 156 (63.2%) 58 (23.5%) 1 (0.40%) 3 (0.12%) 0

305 and in the likelihood of having a positive result (at least when CST is the predominant testing method). 3. In most instances, otherwise healthy women with a history of stillbirth should have fetal testing initiated beyond 32 weeks gestation. This study provides unequivocal evidence of an averted stillbirth in one of six patients with positive CST results at 36 weeks. However, there is also the potential for positive tests results which could result in increased risk of neonatal morbidity owing to prematurity. In this particular study, careful follow-up testing and sound clinical judgment appears to have minimized this risk. However, it is not clear that this can be widely reproduced. 4. Given that the recurrent stillbirth occurred within 3 days of normal CST results in a patient who was compliant, it is apparent that antepartum fetal surveillance cannot prevent all stillbirth recurrences, even in otherwise healthy mothers.

*Placenta previa, anxiety, classical scar. Reprinted with permission.8

followed spontaneous labor. Approximately one-quarter of deliveries at less than 38 weeks were due to abnormal or equivocal fetal testing results (Table 6). Figure 1 shows the cumulative percentage of patients with positive fetal test results and the cumulative percentage of all women delivered for positive test results (dened as positive CST or biophysical prole (BPP) score of 4/10 or less). Of the 300 patients tested, 19 had one or more positive antenatal test results (6.4%). There were six patients with positive test results at 36 weeks, three with positive tests at 32 weeks, and three with positive tests at 32 to 35 weeks. All three of the patients with positive results at 32 weeks ultimately delivered at term; none of those pregnancies had abnormal fetal heart rate tracings, intrauterine growth restriction, cesarean for fetal distress, or low 5-minute Apgar scores. Of the three patients who were delivered for positive tests at 32 to 35 weeks, only one had unequivocal evidence of fetal compromise (decreased fetal movement, BPP 2/10, cesarean section for abnormal fetal heart rate tracing). The two remaining patients were induced for abnormal tests at 32 and 35 weeks gestation. They were appropriately grown, premature neonates without apparent intrapartum or neonatal compromise. Thirteen of the 19 patients with positive fetal test results had their positive results at 36 weeks. The authors did not report the proportion of that group with unequivocal evidence of uteroplacental or fetal compromise. The important ndings from the study of Weeks and coworkers can be summarized as follows: 1. When otherwise healthy women with histories of previous stillbirth are followed with antepartum fetal testing, the stillbirth recurrence risk is low (1 in 300). This stillbirth rate of 3.3 per 1000 is well below the national rate of 7 to 9 per 1000, suggesting that fetal testing can avert recurrent stillbirths. 2. It is not clear that an earlier gestational age at the time of the previous stillbirth correlates with increased risk in future pregnancies when the mothers do not have chronic medical conditions or concomitant obstetrical problems. However, clinicians test earlier in patients whose previous stillbirths occurred early in gestation. This practice is associated with an increase in total tests

Clinician, Where Do We Go from Here?

As discussed elsewhere in this issue of the journal, a circumspect approach to the evaluation of stillbirth is paramount if we are to identify and understand a patients particular pathophysiology and reduce the incidence of stillbirth in the United States. The American College of Obstetricians and Gynecologists has recently published a document that outlines the essential components of the maternal, fetal, and placental evaluation and the approach to counseling the family.10 Especially important is the clinicians understanding of the value of perinatal autopsy and her ability to communicate this to the bereaved family. It is often helpful to delay discussions of autopsy until the day after delivery and to emphasize that the evaluation can be done in ways that will allow mourners to view the baby at memorial ceremonies. There is compelling evidence that even in the modern obstetrical era, a history of previous stillbirth portends an increased risk in future pregnancies. Although the data on antepartum testing of patients with stillbirth as their only risk factor are limited, we can be reasonably condent that fetal testing confers some protection. CST is no longer used as a

Figure 1 Cumulative percentage of abnormal fetal test results and delivery for abnormal fetal testing with advancing gestational age.

306 primary surveillance technique. As long as the fetal testing scheme includes weekly evaluation of acute and chronic markers of fetal well-being, as with a modied BPP or biophysical proles, outcomes should be similar to those reported by Freeman and Weeks. In the absence of chronic medical conditions or concomitant obstetrical complications, healthy mothers with past stillbirths should start their antepartum testing at 32 to 36 weeks gestation.

J.W. Weeks
than 28 weeks gestation.14,15 Whether these early stillbirths can be averted with fetal movement assessment or modied antepartum surveillance programs is yet to be determined.

References
1. Eller A, Brancy D, Byrne L: Stillbirth at term. Obstetr Gynecol 108(2): 442-447, 2006 2. Antepartum Fetal Surveillance. ACOG Practice Bulletin #9. American College of Obstetricians and Gynecologists, 1999 3. Niswander K, Gordon M: Collaborative Perinatal Study of the National Institute of Neurologic Disease and Stroke: the women and their pregnancies. DHEW publication no. (NIH) 73-379, 1972 4. Butler N, Bonham D. Perinatal mortality: the rst report of the British Perinatal Mortality Survey. Edinburgh, E&S Livingston Ltd., 1963 5. Sharma P, Salihu H, Kirby R: Stillbirth recurrence in a population of relatively low-risk mothers. Pediatr Perinat Epidemiol 21(Suppl 1):2430, 2007 6. Sharma P, Salihu H, Oyelese Y, et al: Is race a determinant of stillbirth recurrence? Obstetr Gynecol 107(2):391-397, 2006 7. Samueloff A, Xenakis E, Berkus M, et al: Recurrent stillbirth: Signicance and characteristics. J Reprod Med 38(11):883-886, 1993 8. Freeman R, Dorchester W, Anderson G, et al: The signicance of previous stillbirth. Am J Obstetr Gynecol 151:7-13, 1985 9. Weeks J, Asrat T, Morsan MA, et al: Antepartum surveillance for a history of stillbirth: when to begin? Am J Obstetr Gynecol 172(2):486492, 1995 10. American College of Obstetricians and Gynecologists (ACOG): Evaluation of Stillbirth and Neonatal Deaths. ACOG Committee Opinion No. 383. Obstetr Gynecol 110:963-966, 2007 11. Moore T, Piacquadio K: A prospective evaluation of fetal movement screening to reduce the incidence of antepartum fetal death. Am J Obstetr Gynecol 160(5):1075-1080, 1989 12. Caroline C: Federal Update: Research Gaps Identied by Antenatal Testing Workshop. Obstetr Gynecol 110(6):1420-1421, 13. Froen J: A kick from withinfetal movement counting and the cancelled progress in antenatal care. J Perinat Med 32(1):13-24, 2004 14. Froen J, Arnestad M, Frey K, et al: Risk factors for sudden intrauterine unexplained death: epidemiologic characteristics of singleton cases in Oslo, Norway, 1986-1995. Am J Obstetr Gynecol 184(4):694-702, 2001 15. MacDorman M, Hoyert D, Martin J, et al: Fetal and perinatal mortality, United States, 2003. Natl Vital Statist Rep 55(6):1-17, 2007

Investigator, Where Do We Go from Here?

Antepartum surveillance for patients with a previous stillbirth is a longstanding standard of care. Hence, a prospective randomized trial of testing versus no testing is very unlikely to be done. Modied BPP and BPP have completely supplanted CST. Perhaps retrospective studies similar to those of Freeman and Weeks should be repeated. However, against a background stillbirth rate of 1%, over 3000 study patients would be needed to evaluate the risk of recurrent stillbirth. Without a very large multicenter study which includes databases to track confounding variables, fetal test results, and pregnancy outcomes, such a large retrospective study of healthy women with a history of stillbirth is not feasible. Perhaps the most interesting and feasible area for study is the utility of fetal movement for assessment of fetal wellbeing. The study by Weeks and coworkers suggests that, in some cases, a mothers perception of decreased fetal movement may be more sensitive than fetal testing. After implementing universal fetal movement assessment in a group of women in San Diego, Moore and Piacquadio11 noted a reduced stillbirth rate when compared with historical controls. More recently, J. Frederick Froen has championed the concept of assessing changes in maternal perception of fetal movement as opposed to relying on a specied alarm limit.12,13 Approximately half of all stillbirths occur at less

Management of Decreased Fetal Movements

J. Frederik Fren, MD, PhD,*, Julie Victoria Holm Tveit, MD, Eli Saastad, RN, RM, MSc,*, Per E. Brdahl, MD, PhD, Babill Stray-Pedersen, MD, PhD, Alexander E.P. Heazell, MBChB(hons), Vicki Flenady, RN, RM, MMedSc,# and Ruth C. Fretts, MD, MPH
Maternal perception of decreased fetal activity is a common complaint, and one of the most frequent causes of unplanned visits in pregnancy. No proposed denitions of decreased fetal movements have ever been proven to be superior to a subjective maternal perception in terms of identifying a population at risk. Women presenting with decreased fetal movements do have higher risk of stillbirth, fetal growth restriction, fetal distress, preterm birth, and other associated outcomes. Yet, little research has been conducted to identify optimal management, and no randomized controlled trials have been performed. The strong associations with adverse outcome suggest that adequate management should include the exclusion of both acute and chronic conditions associated with decreased fetal movements. We propose guidelines for management of decreased fetal movements that include both a nonstress test and an ultrasound scan and report ndings in 3014 cases of decreased fetal movements. Semin Perinatol 32:307-311 2008 Elsevier Inc. All rights reserved. KEYWORDS decreased fetal movements, guidelines, management, stillbirth, fetal growth restriction, fetal distress

Adverse Outcomes in Decreased Fetal Movements

lmost all pregnant women perceive fetal movements and intuitively view their experience of normal fetal activity as a sign of fetal well-being, engaging in self-screening by reporting their concerns for decreased fetal movements

*Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway. Brigham and Womens Hospital, Div. of Maternal-Fetal Medicine, Harvard Medical School, Boston, MA. Dept. of Obstetrics and Gynecology, and Center for Perinatal Research, Rikshospitalet, University of Oslo, Oslo, Norway. Akershus University College, Lillestrm, Norway. Dept. of Clinical Medicine, Section for Obstetrics and Gynecology, University of Bergen, Bergen, Norway. Maternal and Fetal Health Research Group, University of Manchester, Manchester, UK. #Centre for Clinical Studies, Mater Mothers Hospital, School of Medicine, University of Queensland, Brisbane, Australia. This work was supported in part by The Norwegian Research Council, The Norwegian Womens Public Health Association, The Norwegian Medical Association, and Unexpected Child Death Society of Norway. Address reprint requests to J. Frederik Fren, MD, PhD, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo, Norway. E-mail: frederik.froen@fhi.no

(DFM). In a Western society such as Norway, as many as 51% of women report that they were concerned for DFM once or more in pregnancy.1 Not all these concerns are brought to the attention of health care professionals, but in different populations, between 4 and 15% will contact care providers with such concerns in the third trimester.2 Contemporary guidelines for the management of uncomplicated pregnancies provide little guidance for pregnant women and their care providers on DFM. While existing guidelines acknowledge the importance of DFM by recommending that women should be informed about the need to contact health care professionals when they perceive DFM, little, if any, provide further guidance in how to dene or manage DFM.3-5 DFM has a well-established role as an adaptive response to the various stages of placental insufciency and hypoxia. In early stages, DFM may represent compensatory adaptations in line with the redistribution of blood ow to essential organs as the brain, heart, and adrenals, and in later stages, a sign of decompensation warning imminent injury and death. Details of this pathophysiology are beyond the scope of this review, but in terms of management, it is important to acknowledge the signicant association between DFM and fetal growth restriction (FGR) across difference denitions of 307

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308 both DFM and FGR.6-16 A dose dependency is also seen between hypoxia/acidemia and DFM in FGR.17-22 In accordance with the association between DFM and FGR, studies have reported associations between DFM and low birth weight,15,23 oligohydramnios,24-26 preterm birth,13-15,23,27 threatening preterm labor,15,23 congenital malformations and chromosomal abnormalities,15,23,28 fetomaternal transfusion,29 perinatal brain injuries and disturbed neurodevelopment,30,31 intrauterine infections,32 low Apgar scores and acidemia,19,33 hypoglycemia,15,23 umbilical cord complications and placental insufciencies,13,15,23 emergency deliveries, inductions of labor and cesarean sections, stillbirths, and neonatal deaths.10,14,27,33,34 The incidence of adverse outcomes in pregnancies with DFM is signicant. In a population-based prospective cohort of 38,728 pregnancies in Norway, 2348 cases presented with DFM and in a quarter of these a suboptimal pregnancy outcome was recorded. These adverse outcomes included the following: FGR, preterm birth, severe neonatal depression, death or immediate admission for observation, induction, or emergency delivery.14,27

J.F. Fren et al
test, maternal hemoglobin, amnioscopy if 37 weeks of gestation, and repeated ante partum testing after discharge.13 The tools used for assessment reect efforts to detect acute fetal distress, subacute and chronic placental insufciency, and other specic pathologies associated with DFM. While some authors present observational estimates of true and false-positive and -negative tests, these estimates may have little value. In obstetrics, a positive test may indeed be false, but the lack of adverse outcome after a positive test is not equivalent to a false-positive test. The suspicion of future complications will lead to iatrogenic delivery, and the perfect ante partum tests would therefore have 100% falsepositive tests. As an alternative to interpret the value of testing in observational studies, we have chosen the perceived clinical utility indicated by the individual practitioner. In a prospective population-based cohort of 46,132 births in Norway (consecutive to the one described above), guidelines including both NST/CTG and ultrasound scanning for consultations for DFM were implemented. All delivery units in eastern Norway and the city of Bergen were included in the study over a 17-month period, ending April 1, 2007. As part of a quality improvement project, pregnancies where women reported DFM were registered prospectively without maternal consent to avoid recruitment bias. All health care for pregnant women is free of charge in Norway; there are no private delivery units, and the population is accustomed to contacting their delivery unit with any acute concerns for DFM. The study was approved by the Regional Committees for Medical Research Ethics and advised by the Personal Data Act of The Norwegian Data Inspectorate. The study included 3014 pregnancies with DFM in which the mother presented to hospital with her concerns. A NST/ CTG was performed in 97.5% of cases, and ultrasound scanning was performed in 94.0% of cases (Table 1). According to the guidelines of the study, the ultrasound scanning was intended for the estimation of fetal weight, amniotic uid volume, and fetal movements (FM). A standardized biophysical prole was not requested, and umbilical artery Doppler examinations were not indicated by the subjective concerns for DFM alone. The obstetrician managing the individual woman would indicate, on a preregistered form, whether the examination detected abnormalities (fetal growth restriction, fetal distress, oligohydramnios, malformations, or other), and if so, what investigational tool detected the anomaly.

Evaluations in Pregnancies with Decreased Fetal Movements

As we discuss elsewhere in this issue of Seminars in Perinatology, there is no widely accepted denition of DFM, as natural variation restricts the value of any rigid limits. Most published data on DFM in total populations have been based on womens own perception of decreased and in practice management is likewise largely based on that subjective denition. There are no randomized controlled trials on any aspect of the initial evaluation or further management of pregnancies with decreased fetal movements. As a result of this lack of evidence, management varies signicantly between populations, institutions, and practitioners within single institutions.6,9,13,16,26,27,35-37 These approaches to DFM range from a nonstress test (NST) or cardiotocography (CTG) as sole screening tool,27 to the hospitalization of all women with DFM for clinical examination, NST/CTG every 8 hours for 48 hours, ultrasound examination including a structured biophysical prole, umbilical artery Doppler, KleihauerBetkes

Table 1 The Use and Perceived Usefulness of Tests in Pregnancies Presenting with Decreased Fetal Movements (n Perceived as Useful in Detecting Abnormalities in Total 3.2% 11.6% 1.9% Perceived as Useful When Abnormality Was Found 23.4% 86.2% 14.1% Only Finding in Detecting Abnormalities in Total 1.2% 8.7% 0.2%

3014)

Test NST/CTG Ultrasound Doppler

Usage 97.5% 94.0% 47.3%

Only Finding When Abnormality Was Found 9.9% 71.3% 1.7%

Note. The obstetrician managing the patient has scored whether abnormalities were detected, and if so, what tool(s) was useful in detecting it. Only nding denotes the frequency of a useful test when the NST/CTG and/or ultrasound was negative. Only NST/CTG and ultrasound were recommended initial evaluations, while Doppler was used selectively.

Management of decreased fetal movements

Overall, NST/CTG and ultrasound scanning identied abnormalities in 3.2 and 11.6% of cases, respectively. In cases where both the ultrasound and the NST/CTG was performed, the ultrasound detected abnormalities in 8.7% of cases despite a normal NST/CTG, and conversely the NST/CTG identied abnormalities in 1.2% of cases despite a negative ultrasound scanning. Among all cases in which one or more abnormality was detected, ultrasound was the sole tool to identify it in 71.3% of cases. In 47.3% of cases, a Doppler examination was performed as well. Despite the preselection of cases that would be subjected to Doppler, Doppler only identied abnormalities in 0.2% of cases in which both the NST/CTG and the ultrasound scanning were normal. Of these three pregnancies, two appeared to be false-positive tests leading to uncomplicated outcomes more than 7 weeks later and the remaining case was induced for delivery the next day at 33 4 weeks of gestation with a severely growth restricted baby (1900 g; 2.5 centile), which should have been detected by the ultrasound scanning, suggesting either that ultrasound was not performed according to guidelines or an underreporting of actual ndings. In summary, with normal and adequately performed NST/CTG and ultrasound scanning, umbilical artery Doppler did not provide uniquely valuable information in any of the 3014 cases of DFM in a real-life setting in Norwegian public hospitals. While the effectiveness of each individual tool for ante partum testing in risk pregnancies is discussed in detail elsewhere in this issue of Seminars in Perinatology, these results are consistent with the evidence for ante partum testing in other risk pregnancies. The use of NST/CTG as the sole screening tool in risk pregnancies has been largely abandoned. Although studies are old, the likely benet effect, if any, would be a discouragement of such practice.38 The use of Doppler evaluation of ow patterns in umbilical arteries in risk pregnancies may reduce mortality, but there is no evidence of benet when FGR and hypertensive disorders are excluded.39 Others have also published no additional benet of Doppler in the evaluation of DFM.6 The use of ultrasound for the initial assessment of growth and amniotic liquor volume in pregnancies at risk of FGR has remained unchallenged as the gold standard.

309 in admissions, preterm births, and stillbirths.41 We have implemented the following consensus-based strategy.

Clinical Evaluation
A standard clinical evaluation should be undertaken for all women reporting certain DFM, including measurement of blood pressure, to reevaluate her risk prole.

Nonstress Test/Cardiotocography
The CTG/NST may provide immediate reassurance, a recording of maternal perception of activity, and often a valuable opportunity for the woman to focus on fetal activity.

Ultrasound Measurements
Fetal Activity As for any other symptom in pregnancy, the actual complaint should be assessed and documented objectively, in particular to exclude absence of FM. Amniotic Fluid Volumes Estimates of amniotic uid volumes have become standard in antenatal testing of risk pregnancies, and in the U.S. even medicolegally essential.42 The traditional understanding of oligohydramnios as a predictor of perinatal outcome has recently been challenged, and the relation between isolated oligohydramnios and adverse outcomes in total populations at term may be weaker than previously assumed.43,44 Still, amniotic uid has signicant impact on fetal health45 and estimations of the amniotic uid volume or index adds to the clinical information in cases where impaired fetal well-being is suspected. Fetal Growth As previously discussed, DFM in risk pregnancies is associated with high risk of FGR, with reported odds ratios (OR) ranging from 4.4 to 13.3.2 In total populations the OR is about 3.2 The latter is in the range seen for risk of FGR in hypertensive disorders in pregnancy,46,47 in which fetal growth assessment in a newly identied risk pregnancy for growth failure is standard. As evidence for effective interventions is limited, antenatal detection of FGR does not decrease the risk of FGR at birth. However, a Swedish institution-based study demonstrated how perinatal outcomes deteriorated signicantly in 573 cases where FGR remained undetected in pregnancy, compared with 681 cases identied antenatally (OR 4.1, 95% condence intervals, 2.5 to 6.8).48 Ultrasound measures may provide valuable documentation in circumstances where growth failure may be present before identiable FGR. Fetal Anatomy In populations screened for fetal anomalies in early pregnancy, undetected anomalies in pregnancies with DFM are rare. In previously unscreened pregnancies, DFM represent additional indication for evaluation. If polyhydramnios or FGR is found, a more detailed examination of fetal anatomy is warranted.

Management of Women with Decreased Fetal Movements

The goal of ante partum fetal surveillance in cases of DFM is to exclude imminent fetal jeopardy40 and to identify those pregnancies at increased risk of stillbirth and other adverse pregnancy outcome and to provide appropriate care to reduce this risk while avoiding unnecessary interventions.3 While improved denitions and randomized controlled trials are needed to identify the optimal management of pregnancies with DFM, current knowledge does inform the choices for a basic initial evaluation of DFM. In our clinical quality improvement project in Norway for the management of decreased fetal movements, we have seen signicant reductions

310

J.F. Fren et al
3. American Academy of Pediatrics, The American College of Obstetricians and Gynecologists. Guidelines for perinatal care. Washington, DC. AAP and ACOG, 2002 4. National Collaborating Centre for Womans and Childrens Health: Antenatal CareRoutine Care for the Healthy Pregnant Women (ed 2). London, UK, RCOG Press, 2008 5. Klovning A, Backe B, Eide BI, et al: Sosial- og Helsedirektoratet. Retningslinjer for svangerskapsomsorgen. Oslo, Sosial- og Helsedirektoratet, 2005 6. Dubiel M, Gudmundsson S, Thuring-Jonsson A, et al: Doppler velocimetry and nonstress test for predicting outcome of pregnancies with decreased fetal movements. Am J Perinatol 14:139-144, 1997 7. Ehrstrom C: Fetal movement monitoring in normal and high-risk pregnancy. Acta Obstetr Gynecol Scand Suppl 80:1-32, 1979 8. Fischer S, Fullerton JT, Trezise L: Fetal movement and fetal outcome in a low-risk population. J Nurse Midwifery 26:24-30, 1981 9. Heazell AE, Sumathi GM, Bhatti NR: What investigation is appropriate following maternal perception of reduced fetal movements? J Obstet Gynaecol 25:648-650, 2005 10. Pearson JF, Weaver JB: Fetal activity and fetal wellbeing: an evaluation. BMJ 1:1305-1307, 1976 11. Rayburn WF, McKean HE: Maternal perception of fetal movement and perinatal outcome. Obstet Gynecol 56:161-164, 1980 12. Sadovsky E, Ohel G, Havazeleth H, et al: The denition and the significance of decreased fetal movements. Acta Obstet Gynecol Scand 62(5): 409-413, 1983 13. Sergent F, Lefevre A, Verspyck E, et al: [Decreased fetal movements in the third trimester: what to do?] Gynecol Obstet Fertil 33:861-869, 2005 14. Tveit JV, Saastad E, Brdahl PE, et al: The epidemiology of decreased fetal movements. Proceedings of the Norwegian Perinatal Society Conference, November 2006. 2006 15. Valentin L, Marsal K: Pregnancy outcome in women perceiving decreased fetal movement. Eur J Obstet Gynecol Reprod Biol 24:23-32, 1987 16. Whitty JE, Garnkel DA, Divon MY: Maternal perception of decreased fetal movement as an indication for ante partum testing in a low-risk population. Am J Obstet Gynecol 165:1084-1088, 1991 17. Bekedam DJ, Visser GH: Effects of hypoxemic events on breathing, body movements, and heart rate variation: a study in growth-retarded human fetuses. Am J Obstet Gynecol 153:52-56, 1985 18. Gagnon R, Hunse C, Fellows F, et al: Fetal heart rate and activity patterns in growth-retarded fetuses: changes after vibratory acoustic stimulation. Am J Obstet Gynecol 158:265-271, 1988 19. Ribbert LS, Nicolaides KH, Visser GH: Prediction of fetal acidaemia in intrauterine growth retardation: comparison of quantied fetal activity with biophysical prole score. Br J Obstet Gynaecol 100:653-656, 1993 20. Sival DA, Visser GH, Prechtl HF: The effect of intrauterine growth retardation on the quality of general movements in the human fetus. Early Hum Dev 28:119-132, 1992 21. Vindla S, James DK, Sahota DS, et al: Computerised analysis of behaviour in normal and growth-retarded fetuses. Eur J Obstet Gynecol Reprod Biol 75:169-175, 1997 22. Vindla S, James D, Sahota D: Computerised analysis of unstimulated and stimulated behaviour in fetuses with intrauterine growth restriction. Eur J Obstet Gynecol Reprod Biol 83:37-45, 1999 23. Valentin L: Fetal movements in late pregnancy. Detection of fetal jeopardy by objective recording and by maternal counting. Lund, Sweden, University of Lund, 1986 24. Sherer DM, Spong CY, Minior VK, et al: Decreased amniotic uid volume at 32 weeks of gestation is associated with decreased fetal movements. Am J Perinatol 13:479-482, 1996 25. Sival DA, Visser GH, Prechtl HF: Does reduction of amniotic uid affect fetal movements? Early Hum Dev 23:233-246, 1990 26. Ahn MO, Phelan JP, Smith CV, et al: Ante partum fetal surveillance in the patient with decreased fetal movement. Am J Obstet Gynecol 157: 860-864, 1987

Timing of the Initial Evaluation and Advice to Women

Timely exclusion of imminent and serious risk to the fetus depends on the apparent severity (absence or only decreased) and maternal certainty in perception of DFM. Maternal concern due to being in doubt of whether fetal activity has been decreasing should not automatically dictate a rapid response by health care professionals, but guidance and observation to resolve these doubts seems reasonable. We have suggested that if there is doubt the women should be advised to continue observation for up to 12 hours. However, if there is possible absence of FM, observation should not be continued longer than 2 hours before contacting her care provider and subsequent evaluation. (See discussion of denitions of DFM elsewhere in this issue of Seminars in Perinatology.) We suggest the same minimum standards in the timeliness of assessment of fetal health on presenting at a health care facility with DFM, within 2 hours if suspected absence, otherwise within 12 hours. When imminent risk to the fetus is excluded, growth assessment is not an emergency. Completing all examinations in sequence is convenient for most, but at inconvenient times, growth assessment may be postponed. We have suggested within 12 hours in cases of DFM, and 2 hours in the absence of detectable fetal movements.

Follow-Up and Delivery

Findings at the initial consultation should guide further action. No studies of follow-up of women reporting DFM in apparently normal pregnancies exist. In view of the high number of adverse outcomes associated with DFM, increased vigilance is recommended. We suggest that women with denite absence of FM should not be discharged undelivered before the cause is found and managed appropriately. Reassurance by antenatal testing is time limited, and persistent DFM should be reevaluated after the period of reassurance has passed, earlier if further decrease or absence of FM is perceived. All women with DFM who remain undelivered should have adequate antenatal care. The advantages and disadvantages of induced delivery versus continued surveillance should be considered for women with a term otherwise uncomplicated pregnancy with persistent DFM, and certainly in postterm pregnancies where induction of labor at 41 completed weeks reduces the risk of perinatal death.49 The rising risk of unexplained stillbirths from about 36 weeks of gestation, the diminishing hazard of inductions at these gestations, and the possibility that active management of risk may be benecial should be considered in the decision-making process.50-52

References
1. Saastad E, Ahlborg T, Froen JF: Maternal awareness towards fetal activity associated with SGA. J Midwifery & Womens Health 2008 (in press) 2. Fren JF: A kick from withinfetal movement counting and the cancelled progress in antenatal care. J Perinat Med 32:13-24, 2004

Management of decreased fetal movements

27. Fren JF, Saastad E, Tveit JV, et al: [Clinical practice variation in reduced fetal movements]. Tidsskr Nor Laegeforen 125:2631-2634, 2005 28. Lin CC, Adamczyk CJ, Sheikh Z, et al: Fetal congenital malformations. Biophysical prole evaluation. J Reprod Med 43:521-527, 1998 29. Giacoia GP. Severe fetomaternal hemorrhage: a review. Obstet Gynecol Surv 52:372-380, 1997 30. Naeye RL, Lin HM: Determination of the timing of fetal brain damage from hypoxemia-ischemia. Am J Obstet Gynecol 184:217-224, 2001 31. James DK, Telfer FM, Keating NA, et al: Reduced fetal movements and maternal medicationnew pregnancy risk factors for neurodevelopmental disability in childhood. J Obstet Gynaecol 20:226-234, 2000 32. Goldstein I, Romero R, Merrill S, et al: Fetal body and breathing movements as predictors of intraamniotic infection in preterm premature rupture of membranes. Am J Obstet Gynecol 159:363-368, 1988 33. Yogev Y, Ben-Haroush A, Horowitz ER, et al: PGE2 induction of labor for consistent decreased perception of fetal movements at term. Int J Gynaecol Obstet 82:173-178, 2003 34. Sadovsky E, Yaffe H: Daily fetal movement recording and fetal prognosis. Obstet Gynecol 41:845-850, 1973 35. Korszun P, Dubiel M, Kudla M, et al: Doppler velocimetry for predicting outcome of pregnancies with decreased fetal movements. Acta Obstet Gynecol Scand 81:926-930, 2002 36. Olesen AG, Svare JA: Decreased fetal movements: background, assessment, and clinical management. Acta Obstet Gynecol Scand 83:818826, 2004 37. Heazell AE, Green M, Wright C, et al: Midwives and Obstetricians knowledge and management of women presenting with decreased fetal movements. Acta Obstet Gynecol Scand 87:331-339, 2008 38. Pattison N, McCowan L: Cardiotocography for ante partum fetal assessment. Cochrane Database Syst Rev CD001068, 2000 39. Neilson JP, Alrevic Z: Doppler ultrasound for fetal assessment in high risk pregnancies. Cochrane Database Syst Rev CD000073, 1996 40. ACOG practice bulletin. Ante partum fetal surveillance. Number 9, October 1999 (replaces Technical Bulletin Number 188, January

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1994). Clinical management guidelines for obstetrician-gynecologists. Int J Gynaecol Obstet 68:175-185, 2000 Fren JF, Tveit JVH, Saastad E, et al: Stillbirths and decreased fetal movements: prevention by improved information and management. Proceedings of the International Stillbirth Alliance Conference 2007, Birmingham, UK. 2007 Moore TR: Sonographic screening for oligohydramnios: does it decrease or increase morbidity? Obstet Gynecol 104:3-4, 2004 Ott WJ: Reevaluation of the relationship between amniotic uid volume and perinatal outcome. Am J Obstet Gynecol 192:1803-1809, 2005 Sherer DM, Langer O: Oligohydramnios: use and misuse in clinical management. Ultrasound Obstet Gynecol 18:411-419, 2001 Underwood MA, Gilbert WM, Sherman MP: Amniotic uid: not just fetal urine anymore. J Perinatol 25:341-348, 2005 Odegard RA, Vatten LJ, Nilsen ST, et al: Preeclampsia and fetal growth. Obstet Gynecol 96:950-955, 2000 Xiao R, Sorensen TK, Williams MA, et al: Inuence of pre-eclampsia on fetal growth. J Matern Fetal Neonatal Med 13:157-162, 2003 Lindqvist PG, Molin J: Does antenatal identication of small-for-gestational age fetuses signicantly improve their outcome? Ultrasound Obstet Gynecol 25:258-264, 2005 Gulmezoglu AM, Crowther CA, Middleton P: Induction of labour for improving birth outcomes for women at or beyond term. Cochrane Database Syst Rev CD004945, 2006 Fren JF, Arnestad M, Frey K, et al: Risk factors for sudden intrauterine unexplained death: epidemiologic characteristics of singleton cases in Oslo. Norway, 1986-1995. Am J Obstet Gynecol 184:694-702, 2001 Fretts RC, Elkin EB, Myers ER, et al: Should older women have ante partum testing to prevent unexplained stillbirth? Obstet Gynecol 104: 56-64, 2004 Nicholson JM, Kellar LC, Cronholm PF, et al: Active management of risk in pregnancy at term in an urban population: an association between a higher induction of labor rate and a lower cesarean delivery rate. Am J Obstet Gynecol 191:1516-1528, 2004

41.

42. 43.

44. 45. 46. 47. 48.

49.

50.

51.

52.

New Indications for Antepartum Testing: Making the Case for Antepartum Surveillance or Timed Delivery for Women of Advanced Maternal Age
Ruth C. Fretts, MD, MPH,* and Ugonna A. Duru, MD
Maternal age is an independent risk factor for stillbirth; a moderate number of these occur in normally formed babies near term. For a woman 40 years of age or older giving birth, her risk of having a chromosomal anomaly is 1/66. What is not appreciated is that even without medical risk factors, her risk of having a stillbirth after 37 weeks of gestation is 1/116. This article reviews the risks and benets of the strategy of antepartum testing and timed delivery and discusses the limitations of the available data in this eld. Semin Perinatol 32:312-317 2008 Elsevier Inc. All rights reserved. KEYWORDS advanced maternal age, late stillbirth, antepartum testing, active management of risk

Indications for Antepartum Testing

ntepartum testing cannot directly reduce the risk of stillbirth, but it can inform as to when to deliver the patient. Delivering the fetus incurs both maternal and fetal risks and benets. The goal is to minimize perinatal mortality (ie, the sum of stillbirths and neonatal deaths) and include a measure of maternal morbidity, mortality, and patient preference. The current management of the most common risk conditions such as diabetes mellitus requiring insulin, the hypertensive disorders, and intrauterine growth restriction already include various schedules for antepartum testing. This proactive, comprehensive approach has led to the reduction of stillbirth risk, albeit at the cost of an increased risk of iatrogenic preterm birth. The role of antepartum testing in women with these conditions is summarized elsewhere in this edition of Seminars in Perinatology. In less prevalent diseases that may contribute to fetal loss, such as systemic lupus erythematosis, or in patients with a history of a previous stillbirth, there is little doubt that the clinician will include multiple modalities of antepartum testing to assess the ongoing health of the

fetus. Many questions remain however. For example, should we treat women with common risk factors for stillbirth as a high-risk pregnancy and initiate antepartum testing and or timed delivery and, if so, what are the potential risks and benets of this approach?

Late Stillbirths and Candidate Risk Factors for Antepartum Screening

The best opportunity for stillbirth reduction is to identify patients who have an increased risk of stillbirth, late in pregnancy, where the downside of antepartum testing and early delivery, if warranted, can be minimized. Candidate risk factors include obesity, socio-economical or racial risk factors, and advanced maternal age. Obesity has many detrimental obstetrical and maternal consequences. In a recent metaanalysis of prepregnancy maternal obesity and stillbirth, Chu and colleagues estimated the risk of stillbirth to be 1.4-fold higher in overweight women (ie, a body mass index (BMI) 25-29.9 kg/m2), and 2.1 times higher in women with a BMI of 30 or over, when compared women with a BMI of 25.1 In a Danish population, the risk of stillbirth associated with prepregnancy obesity appeared to increase late in pregnancy, and this additional risk could not be attributed to hypertension or diabetes.2 Indeed, Salihu and coworkers found obesity associated with many social, medical, and obstetric factors, which placed women at increased risk for adverse outcomes. In their study of Missouri births from 1978 to

*Harvard Vanguard Medical Associates, Brigham and Womens Hospital and Newton Wellesley Hospital, Wellesley, MA. Brigham and Womens Hospital, Boston, MA. Address reprint requests to Ruth C. Fretts, MD, MPH, Assistant Professor, Harvard Medical School, Harvard Vanguard Medical Associates, Brigham and Womens Hospital and Newton Wellesley Hospital, 230 Worchester St., Wellesley, MA 02481. E-mail: Rfretts@vmed.org

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0146-0005/08/$-see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2008.04.016

New indications for antepartum testing

1997, they found that women with a prepregnancy BMI of 30 or greater conferred a 1.4-fold risk of stillbirth.3 This increase in risk appears to be dose dependent, and black women faired worse in all weight categories when compared with whites. Black women who were extremely overweight (dened as a BMI of 40 or greater) had a 2.7-fold risk above that of normal weight white women, while similarly overweight white women had a 1.8-fold risk of stillbirth. Unfortunately, however, because cause and timing of the stillbirths associated with obesity is not well known in the American population, there are insufcient data at this time to make a recommendation for routine antepartum testing based on maternal weight alone. For now, the strategies necessary to manage these patients and minimize adverse perinatal outcomes need to be individualized, based on obesity and other comorbid conditions. In the United States, perinatal statistics are stratied by race. Obvious differences in neonatal and stillbirth rates may be due to many factors including access to obstetrical care, quality of care, stress, diet, and biological factors. Black women in the US, for example, experience a two-fold risk of stillbirth when compared with whites with a higher rate of stillbirth both early in gestation and late in gestation.4 There are no trials specically addressing the potential role of antepartum testing and timed delivery in black women, although Yuan and colleagues using US data compared induction and stillbirth rates in 1997 versus 1991.4 Comparing the two time periods, they noted a 20% decrease in the number of stillbirths after 40 weeks of gestation, which was largely attributed to an increase in the rate of inductions after 41 weeks. These authors did note however that black women were less likely that white women to be induced before 43 weeks.4 This is one area in which earlier intervention could ameliorate the disproportionate stillbirth rate that is experienced by black women late in pregnancy. Currently in the United States, approximately 15% of women giving birth are 35 years of age or older, and 2.5% are 40 years of age or older. Indeed, the birth rate to women 35 to 39 years of age has increased every year since 1978 and has risen 43% since 1990. The rate of women giving birth who are 40 years of age or older has also continued to rise. For example, based on the nal birth statistics from 2003 and 2004, the rate for women 40 years of age or older rose from 8.7 births per 1000 women to 8.9 per 1000. Interestingly, the Centers for Disease Control now reports birth rates for women aged 45 to 49 and 50 to 54, but these births represent only a small fraction of total births (0.15%).5 Many patients and practitioners alike have the belief that if older women are without medical problems such as diabetes or hypertension, the additional risk of conferred by advancing age is probably relatively low for adverse outcomes. Indeed small studies directed at this issue have been generally reassuring.6 However, a large Canadian study by Fretts and coworkers, after controlling for many factors that occur more often in older women (eg, hypertension, diabetes, previous abortion, previous stillbirth, multiple gestation, placenta previa, placental abruption, parity, and martial status), they found that advanced maternal age remained an independent risk factor for stillbirth. Women 35 to 39 years of age had a 1.8-fold risk of stillbirth when compared with women less

313 than 30 years of age; for women 40 years of age or older the risk was 2.4-fold higher.7 Using the McGill Obstetrical Neonatal database, which had over 100,000 births, Fretts and Usher found that the causes of stillbirth in older women has changed over the past three to four decades. Historically, the only specic cause of fetal death that occurred signicantly more often in women 35 years of age or older, compared with younger women, was stillbirths related to congenital anomalies (OR, 3.2; 95% CI, 1.6-6.5).8 Later in the study period after the introduction of routine prenatal screening, diagnosis, and the availability of abortion, the number of stillbirths due to anomalies in older women reduced almost statistically below that of younger women (OR, 0.2; 95% CI, 0.003-1.5). Of course these are still signicant losses, but they no longer appear in the stillbirth statistics. What was notable in the 1978-1995 period was that the unexplained stillbirth rate (ie, an appropriately grown fetus and without obstetrical or maternal risk factors) was 2.2-fold higher in women 35 years of age or older when compared with younger women.8 Froen and coworkers, using a Norwegian database of over 500,000 women, found that women 35 years of age or older to be at a 5.1-fold increased risk of having an unexplained stillbirth when compared with women less than 25 years of age (95% CI, 1.319.6).9 Huang and coworkers, also using the McGill Obstetrical Neonatal database, found that 60% of the unexplained stillbirths occurred after 36 weeks of gestation.10 In a separate study, this group showed that the increased risk of unexplained stillbirth late in pregnancy was notably higher in women 35 years of age or older.11 Reddy and colleagues using US data from 36 states from 2001 and 2002 (N 5,458,735) performed an analysis of the risk of stillbirth by maternal age throughout pregnancy for nonanomalous singleton pregnancies.12 In their study, 10.4% of their population was 35 to 39 years of age, with 8.1% reported to have a concomitant medical condition (eg, hypertension and diabetes, which were the most commonly reported conditions). Women 40 years of age or older constituted 2.2% of births, 14.4% of which reported a medical condition. The risk of stillbirth for women 40 years of age or older was higher at all gestational ages, but the risk difference was accentuated after 38 weeks of gestation (Fig. 1).12 This gure demonstrates that older women have stillbirth risks usually associated with postdates but this occurs earlier in gestation. For example, at 41 weeks of gestation, the risk of stillbirth is approximately 0.95/1000 for women 30 to 34 years of age; this is the equivalent rate for women 35 to 39 years of age at 40 weeks of gestation, and for women 40 years of age and older this rate of stillbirth occurs at 39 weeks of gestation. Only about 10% women who were 35 years of age or older had reported a medical condition that might increase the risk of stillbirth, so it is useful to remember than 90% did not. When women with known medical problems were eliminated from the analysis, the results regarding stillbirth rates were unchanged. It is also important to note that primiparous women had the highest risk of stillbirth and black women had a higher rate than white women (Table 1).12 These observations support a case for treating these pregnancies in a

314

R.C. Fretts and U.A. Duru

Figure 1 The risk of stillbirth for singleton births without congenital anomalies by gestational age. Adapted from Reddy and colleagues.13 (Color version of gure is available online.)

manner similar to postdates pregnancies, by considering the options of antepartum testing and/or timed delivery. However, there are no prospective clinical trials however that specically address this issue for older women, and for reasons of logistics and statistical power, it unlikely that there will be good, Level 1 evidence in the near future. For now, the clinicians must use their clinical judgment to weigh the risks and benets of such a strategy. In this setting, it is a useful exercise to compare the risk of a late stillbirth to other adverse outcomes that occur in women of advanced maternal age (Table 1).12,13 Much emphasis has been placed on prenatal diagnosis to reduce the risk of having a live-born infant with a signicant chromosomal anomaly. Indeed, if a woman had not been sufciently counseled that her risk of a chromosomal anomaly was estimated to be 1/66 at the age of 40, and had not been offered invasive testing, she (and her lawyer) could easily demonstrate that her care fell outside the bounds of the standard of care. It appears that if an older woman has been able to achieve pregnancy, has been lucky enough to not have an early miscarriage, and has navigated through the many options of prenatal screening and invasive diagnostic testing, that the risk of having a late stillbirth in a normally formed baby after 37 weeks of gestation has not caught the attention

of both the provider and the patient. For women 40 years of age or older having her rst birth, the risk of late stillbirth after 37 weeks of gestation is 1/116 (Table 1). Given that older women have fewer reproductive opportunities, it is worth reviewing these risks with the patient and reviewing the options available to her (eg, expectant management with kick-counting, formal antepartum testing, and/or timed delivery). It is also worth mentioning that there is no standardof-care or consensus practice guideline at the present time.

A Strategy of Antepartum Testing at Term

By choosing a strategy of antepartum testing, the benet of such a strategy depends on the underlying risk of stillbirth and the sensitivity and specicity of the test. Currently there are no data to permit the generalization that antepartum testing typically used for a postdates pregnancy will function in a similar way for older women at earlier gestational ages. In general, for a postdates pregnancy, the available data to date are insufcient to guide as to which intervention(s) has contributed most to the observed reduction of stillbirths after 41 weeks of gestation. Has the often routine induction after 41

Table 1 Rates of Chromosomal Abnormalities in Live-Born Compared to the Age-Related Risk of Stillbirth Maternal Age at Delivery 20 to 34 35 to 39 40 Risk of Trisomy 21 Risk of Any Risk of Stillbirth Risk of Stillbirth Risk of Stillbirth for All Black Chromosomal After 37 Weeks After 37 Weeks Women After 37 Weeks with Abnormality Multipara Nulliparous No Known Medical Problems 1/775 1/502 1/304 1/269 1/156 1/116 1/326 1/247 1/230

1/1667 to 1/485* 1/562 to 1/238* 1/378 1/192 1/106 1/66

*Estimates range from 20 years to age to 34 years of age. Adapted from Reddy and colleagues,12 and Hook.13

New indications for antepartum testing

Table 2 Effect of Unexplained Stillbirth Risk on Outcomes of Weekly Antepartum Testing Starting at 37 Weeks Outcome Fetal deaths per 1000 with no testing Fetal death per 1000 with testing Fetal deaths averted with testing Tests per pregnancy Tests per fetal death averted Inductions per fetal death averted Cesarean deliveries per fetal death averted OR 1 1.6 0.4 1.2 3.4 2862 233 44 OR 2 3.2 0.8 2.4 3.4 1418 116 22 OR 3 4.7 1.2 3.5 3.3 950 78 15 OR 4 6.2 1.5 4.7 3.3 711 58 11

315

OR 5 7.8 1.9 5.9 3.3 569 47 9

Outcomes from week 37 through 41 weeks assumes test characteristics to be 70% sensitive and 90% specic. Adapted from Fretts and colleagues.15

weeks contributed more to the stillbirth reduction or was it a less-than-perfect evaluation of fetal well-being that led to an induction? Crowley, for example, has estimated that, in the general population at 41 weeks, it would take 400 inductions to prevent one stillbirth.14 Since all estimates of a truepositive test and a false-positive test are driven by the fact that our interventions are designed to prevent stillbirth, a clinician will probably never know which of the 400 interventions saved a baby. In an attempt to quantify the risks and benets of antepartum testing late in pregnancy, Fretts and colleagues designed a decision analysis based on the week-specic risk of unexplained stillbirth (the most frequent type of loss) in women 35 years of age or older having their rst birth.15 Estimates of relative risk of unexplained stillbirth by maternal age were obtained from the McGill Obstetrical Neonatal Database (ie, a Canadian hospital-based data). To estimate the possible increased risk of cesarean delivery, they used the week-specic difference of cesarean delivery in labors that occurred spontaneously versus those that were induced, in two large Boston teaching hospitals.16 A sensitivity analysis of the characteristics of the test was included, varying both the sensitivity and the specicity from 70 to 90%. For the main model it assumed that the testing would begin in the 37th week, and it was assumed that 10% of women would have an abnormal test and that this would lead to an induction, regardless of cervical status. It also assumed that, despite testing, 30% of babies would die anyway and that there were no intrapartum deaths. In this model, the odds ratio for stillbirth was the most important factor in stillbirth reduction (Table 2). Women who had an underlying ve-fold increased risk, using a strategy of antepartum testing, would theoretically reduce the rate

of unexplained stillbirth from 1/128 to 1/526 ongoing births. It is also useful to note women at low risk (ie, an OR 1.0) using a similar strategy would have a more limited benet, reducing the risk of late unexplained stillbirth from1/625 to 1/833. For example, women 35 years of age or older having her rst birth, who have an estimated rate of late unexplained stillbirth of 5.2/1000 after 37 weeks of gestation, the model predicts that the rate of unexplained stillbirth could be reduced to as low as 1.3/1000. This strategy however would entail 863 antepartum tests per fetal death averted, 71 inductions per fetal death averted, and 14 additional cesarean deliveries per fetal death averted (Table 3). It is interesting when one compares this approach to a strategy of no testing, but with a planned induction at 41 weeks. In this scenario, the rate of induction and cesarean delivery per fetal death averted is much greater (429 and 219, respectively) than with a strategy of antepartum testing. That is because a large portion of the stillbirths have already occurred, before 41 weeks.15 Of course this is only a model and is limited by many factors. As previously stated, it is not known if antepartum testing in women of advanced maternal age late in pregnancy will reveal abnormalities before a demise. However, if parallels can be drawn to other high-risk conditions, a strategy of implementing antepartum testing has been associated with a reduction in the risk of stillbirth in women with hypertension and diabetes to that just slightly above the general population. Another limitation is that the study model did not employ twice weekly testing (a standard protocol used for postdates pregnancies) nor did it account for the effect of serial testing. Typically, if one test is abnormal, it would be routine to perform a second, follow-up test. This would be especially true in the setting where the patient was 35 years of age or

Table 3 Base-Case Results for Nulliparous Women Aged 35 Years and Older Outcome of Unexplained Fetal Deaths Fetal deaths/1000 Fetal deaths averted Test per pregnancy Test per fetal death averted Induction per fetal death averted Cesarean deliveries per fetal death averted No Testing 5.2 Weekly Testing Starting at Week 37 1.3 3.9 3.3 863 71 14 Induction at 41 Weeks 4.3 0.9 469 219

Outcomes from week 37 through 41 weeks assumes test characteristics to be 70% sensitive and 90% specic. Adapted from Fretts and colleagues.15

316 older, at 37 weeks, with an unfavorable cervix. Contrast this with the threshold to induce in the setting of a 43-year-old woman with mild oligohydramnios at term, where the clinician might be relieved that at 39 weeks there is now an indication for delivery. This decision analysis does not address the type and the cost of antepartum testing, the potential maternal risks of additional cesareans, nor the effect of antepartum testing on maternal anxiety and condence. In summary, the sensitivity and specicity of antepartum testing has been greatly debated. In this model, however, if the specicity were lowered from 90 to 70% (thereby increasing the false-positive rate to 30%, and consequently increasing the induction rate), there was a reduction of stillbirths, reminding us once again that if the patient is delivered, she is no long at risk for stillbirth.15

R.C. Fretts and U.A. Duru

for low-risk women, 39 2/7 to 40 1/7 weeks for women with hypertension, and for women 35 years of age or older, the optimal timing of delivery was 38 5/7 to 39 6/7 weeks of gestation. Interestingly their model did not work well for diabetic women, because a large proportion of babies born to diabetics spent time in the neonatal intensive care unit, presumably to monitor the babys glucose, monitoring that was not routinely performed on infants born to nondiabetic mothers. This study, while interesting, did not assess the impact of antepartum testing or induction. There were also many questions on how competing outcomes should be weighed and how patient preference might have altered these outcomes.

Risk of Induction Near Term

While there is no measurable long-term neonatal mortality associated with delivery after 37 weeks, there is an increase in the incidence of neonatal respiratory distress and transient tachypnea at term, and the rate is higher before 38 weeks of gestation and with those having a cesarean delivery.20,21 Multiparous women of advanced maternal age are at an increased risk of stillbirth late in pregnancy, but for them induction near term does not materially increase the cesarean section rate.16,20 The greater management dilemma is for nulliparous women. There are many cohort studies addressing the role of induction in nulliparous women. While most have not included information on cervical status or the use of cervical ripening agents, there appears to be an approximately twofold increased risk of cesarean delivery when comparing women who present in spontaneous labor compared with those that are induced.16 The most appropriate comparison however is to compare elective induction (with cervical ripening) to expectant management. With the nadir of cesarean section being between 38 and 39 weeks, expectant management is associated with both larger babies and an increasing opportunity for late placental dysfunction.22 In an elegant analysis, Caughey and coworkers, using a retrospective cohort of women eligible for a vaginal delivery at University of California San Francisco, demonstrated how using the traditional comparison of spontaneous versus induced labor generated a two-fold increase in cesarean sections for nulliparous women.23 However, when the cesarean section rate of induced women was compared with the total risk of a cesarean delivery over the last weeks of gestation (ie, the prospective risk of cesarean similar to the prospective risk of stillbirth), it appears that induction may actually reduce the risk of cesarean delivery (Table 4). A novel approach called the Active Management of Risk in Pregnancy at Term (AMOR-IPAT), used by groups at the University of Pennsylvania, does show some promise.24 They published a cohort study comparing outcomes in AMOR-IPAT (N 100) and non-AMOR-IPAT groups (N 300). In the active management group, early dating was performed. At term, a riskassessment was performed that included the presence or absence of factors that might increase uterine and placental dysfunction (eg, hypertension, diabetes, advanced maternal age, smoking, size-less-than-dates, and other factors). They also included risk factors for cephalopelvic disproportion (eg, BMI 30, short stature, gestational diabetes, size-greater-than-dates,

Optimal Timing of Testing and Delivery

Theoretically, each medical condition has an optimal time to start antepartum testing, and an optimal time for delivery, after taking into account both fetal and maternal factors. For pregnant women with insulin-dependent diabetes, Rouse and colleagues estimated the optimal time to begin antepartum testing was about 34 weeks of gestation.17 Similarly, Weeks and colleagues, using results of antepartum testing in 300 women with a previous stillbirth, estimated in otherwise healthy women that antepartum surveillance be initiated after 32 weeks of gestation.18 Early interventions led to an increased risk of admission to the neonatal intensive care, but delaying fetal evaluation and delayed delivery can increase the risk of stillbirth or delivery of a baby in poor condition. Postdates pregnancies can also put the mother at risk for increased obstetrical trauma, because of the increased rate of fetal macrosomia. Nicholson and colleagues, for example, compared maternal and fetal outcomes in women with good dating, who were at term and who were eligible for a vaginal birth.19 The database included 11,724 women without any known risk factors, who were less than 35 years of age, and 2373 women who were 35 years of age or older. Six hundred thirty-ve women had a diagnosis of hypertension, and 460 women had diabetes. Women with multiple risk factors were included in each subgroup. The study was not powered to look at perinatal mortality. The investigators evaluated the maternal cesarean section rate, the newborn admission rate, the incidence of maternal 3rd- and 4th-degree tears, and the 5-minute Apgar of 0 to 6 rate. The most important component of this studys outcomes that dened the lower limits of the optimal time of delivery was the admission rate to the neonatal intensive care unit. The outcome that largely dened the upper limit of the optimal time of delivery was the maternal cesarean section rate. Given the design of this study, including the prespecied goals of minimizing both neonatal admissions and cesarean sections, these investigators described the optimal time of delivery to be where these risks intersected the 95% CI around these points. The optimal times of delivery were described as 37 1/7 to 41 0/7 weeks

New indications for antepartum testing

Table 4 Induction of Labor Compared to Expectant Management in Nulliparous Week of Induction 38 39 40 41 Induction of Labor C/S Rate 15.6% 18.6% 22.5% 29.3% Expectant Management C/S Rate 17.6% 19.9% 24.3% 33.1% Adjusts OR (95% CI)* 1.9 (1.3 1.5 (1.1 1.6 (1.2 1.3 (1.0 to to to to 2.9) 2.1) 2.2) 1.8)

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Spontaneous Labor C/S Rate 9.0% 11.6% 15.2% 19.3%

Expectant management group includes all women delivered beyond the particular gestational age of the induction of labor comparison group. *Controlling for maternal ethnicity, BMI, insurance, preeclampsia, diabetes, and epidural use. P value < 0.01 when comparing induction of labor group to the spontaneous labor group. Adapted from Reddy and colleagues,12 and Hook.13

etc). Cervical ripening was used for all women with a Bishop score less than 5. The AMOR-IPAT group had a median gestational age at delivery which was signicantly lower than the non-AMOR-IPAT group (38.9 versus 40.1 weeks; P 0.001), as well as a signicantly higher induction rate (63% versus 25.7%; P 0.001), but they also had a surprisingly low cesarean section rate (4% versus 16.7%). The active management group also had a statistically lower rate of 3rd- and 4th-degree tears and a lower NICU admission rate. If this approach were to be widely adopted, the result would be a sea of change for obstetrics, necessitating a very high induction rate. While the utility of this approach needs to be conrmed and validated, issues of patient acceptability will also be an important measure. Modern obstetrics is often accused of medicalization of the birthing process; it is not clear what proportion of women would embark on a strategy that would involve a 60% induction rate.

Summary
While there is no level 1 evidence to recommend antepartum testing or timed delivery in patients with an increased risk of stillbirth late in pregnancy, we need to appreciate that this a gap in our knowledge. Many times we as practitioners must function in the gray area of imperfect knowledge. It is important however to accurately assess risk. The 40-year-old woman having her rst baby should be told that her risk of stillbirth in late pregnancy is 1/116. When she and her practitioner travel down the gray roads together, it behooves the practitioner to describe the risks and benets of these approaches within the limits of our knowledge.

References
1. Chu SY, Kim SY, Lau J, et al: Maternal obesity and the risk of stillbirth: a metaanalysis. Am J Obstet Gynecol 2007. Available at: www. AJOG.org. Accessed September 12, 2007 2. Nohr EA, Bech BH, Davies MJ, et al: Prepregnancy obesity and fetal death: a study within the Danish National Birth Cohort. Obstet Gynecol 206:250-259, 2006 3. Salihu HM, Dunlop AL, Hedayatzadeh Alio AP, et al: Extreme obesity and the risk stillbirth among black and white gravidas. Obstet Gynecol 110:552-557, 2007 4. Yuan H, Platt RW, Morin L, et al: Fetal deaths in the United States, 1997 vs 1991. Am J Obstet Gynecol 193:489-495, 2005 5. Martin JA, Hamilton BE, Sutton PD, et al: National Vital Statistics Reports. Births: Final Data for 2004. Available at: www.cdc.gov. Accessed September 29, 2006

6. Berkowitz GS, Skovron ML, Lapinski RH, et al: Delayed childbearing and outcome of pregnancy. N Engl J Med 332:659-664, 1990 7. Fretts RC, Schmittdiel J, McLean FH, et al: Increased maternal age and the risk for fetal death. N Engl J Med 333:953, 1995 8. Fretts RC, Usher RH: Causes of fetal death in women of advanced maternal age. Obstet Gynecol 89:40-45, 1997 9. Froen JF, Arnestad M, Frey K, et al: Risk factors for sudden intrauterine unexplained death: epidemiological characteristics of singleton cases in Oslo. Norway, 1986-1995. Am J Obstet Gynecol 184:694, 2001 10. Huang DY, Usher RH, Kramer MS, et al: Determinants of unexplained antepartum fetal deaths. Obstet Gynecol 95:215, 2000 11. Fretts RC, Usher RH: Fetal death in women in the older reproductive age group. Contemp Rev Obstet Gynecol 9:173-179, 1997 12. Reddy UM, Ko CW, Willinger M: Maternal age and the risk of stillbirth throughout pregnancy in the Unites States. Am J Obstet Gynecol 195: 764-770, 2006 13. Hook EB: Rates of chromosome abnormalities at different maternal ages. Obstet Gynecol 58:282, 1981 14. Crowley P: Elective induction of labor at 41 weeks gestation. In: Enkin M, Keirse MJNC, Renfrew MJ, et al (eds): Cochrane Database of Systematic Reviews. Review 4144 15. Fretts RC, Elkin EB, Myers ER, et al: Should older women have antepartum testing to prevent unexplained stillbirth? Obstet Gynecol 104: 56, 2004 16. Heffner LJ, Elkin E, Fretts RC: Impact of labor induction, gestational age and maternal age on cesarean section delivery rates. Obstet Gynecol 120:287-293, 2003 17. Rouse DJ, Owen J, Goldenberg RL, et al: Determinants of the optimal time in gestation to initiate antenatal fetal testing: a decision-analytic approach. Am J Obstet Gynecol 173:1357-1363, 1995 18. Weeks JW, Asrat T, Morgan MA, et al: Antepartum surveillance for a history of stillbirth: when to begin? Am J Obstet Gynecol 172:486-492, 1995 19. Nicholson JM, Kellar LC, Kellar GM: The impact of the interaction between increasing gestational age and obstetrical risk on birth outcomes: evidence of a varying optimal time of delivery. J Perinatol 26: 392-402, 2006 20. Tylleskar J, Finnstrom O, Leijon I, et al: Spontaneous labor and elective inductiona prospective randomized study.I. Effects on mother and fetus. Acta Obstet Gynecol Scand 58:513, 1979 21. Morrison JJ, Rennie JM, Milton PJ: Neonatal respiratory morbidity and mode of delivery at term: inuence of timing of elective caesarean section. Br J Obstet Gynaecol 102:101, 1995 22. Stallmach T, Hebisch G, Meier K, et al: Rescue by birth: defective placental maturation and late fetal mortality. Obstet Gynecol 97:505509, 2001 23. Caughey AB, Nicolson JM, Cheng YM, et al: Induction of labor and cesarean delivery by gestational age. Am J Obstet Gynecol 195:700-705, 2006 24. Nicholson JM, Keller LC, Cronholm PF, et al: Active management of risk at term in an urban population: an association between a higher induction of labor rate and a lower cesarean delivery rate. Am J Obstet Gynecol 191:1516-1528, 2004

Antenatal TestingBenets and Costs

Christina M. Scifres, MD, and George A. Macones, MD, MSCE
Antenatal testing is a common component of care for the high-risk pregnancy. The goals of antenatal testing include the prevention of stillbirth and the detection of the hypoxic fetus to allow intervention before acidosis and long-term damage. Data regarding the efcacy of antenatal testing are limited by a lack of randomized controlled trials. The majority of available data hinge on observational studies with the inherent potential for bias. There is also a paucity of data comparing the various testing modalities and addressing the issue of the optimal timing of initiation of testing. As well, data are limited regarding the various conditions most likely to benet from testing and the frequency with which testing should be performed. The issue of cost relating to antenatal testing is an important one. Central to the issue of estimating cost is an understanding of the efcacy of the test. Given our current limitations, we have signicant difculty accurately estimating the cost of antenatal testing; however, rough estimates of cost are made. Semin Perinatol 32:318-321 2008 Elsevier Inc. All rights reserved. KEYWORDS antenatal testing, cost analysis, nonstress test, biophysical prole

ntenatal testing was introduced into clinical practice with the primary goal of stillbirth prevention. Multiple methods of antenatal testing have been studied, including the contraction stress test, nonstress test, biophysical prole, and modied biophysical prole. Little has been published regarding the benets and costs associated with each of these testing modalities. The rst step in any analysis of cost is to understand the efciency and effectiveness of an intervention. Signicant difculties in evaluating the costs of antepartum testing arise from limitations in the data addressing the usefulness of testing in preventing stillbirth as a primary goal. The purpose of this review is to discuss some of the data pertaining to the effectiveness of antenatal testing, to use this data to estimate the costs of antenatal testing, and to explore future research areas in this eld.

patient, and be easily and reliably interpreted by the clinician with good intra- and inter-observer variability, and with low false-positive rates. The rst goal of this review is to examine the available literature relating to the efcacy of antepartum testing. Importantly, we will also discuss some of the significant limitations present in this body of literature. From there, we discuss some of the issues relating to the costs associated with antenatal testing.

Efcacy of Antepartum Testing

There are a number of studies available addressing stillbirth rates following each of the various methods of antenatal testing, including the contraction stress test, nonstress test, biophysical prole, and modied biophysical prole (Table 1). However, strong evidence for the efcacy of antepartum testing is lacking. Many of the studies are observational studies, which do not report stillbirth rates in an untested group, compare tested to untested subjects at the same institution, or compare stillbirth rates before and after the initiation of testing. These observational studies leave large gaps in our understanding of the true sensitivity and specicity for each of the specic antenatal tests. The observational studies that compare tested to untested populations at the same institution are signicantly limited by the fact that little is known about the untested population. For example, in the work by Miller and coworkers,4 utilizing the modied biophysical prole for antenatal testing the uncorrected stillbirth rate in

Goals of Antepartum Testing

The optimal method of antepartum testing would have the ability to prevent stillbirth. An ideal test would also identify the hypoxic or acidemic fetus and allow intervention before the onset of either death or disability. This ideal test would also be inexpensive, require minimal effort of the part of the

Washington University, St. Louis, MO. Address reprint requests to Christina M. Scifres, MD, Department of Obstetrics and Gynecology, 4911 Barnes Jewish Hospital Plaza, Box 8064, St. Louis, MO 63110. E-mail: scifresc@wudosis.wustl.edu

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0146-0005/08/$-see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2008.04.017

Antenatal testing
Table 1 Corrected Stillbirth Rates Following Antepartum Tests Antepartum Test Nonstress test Contraction stress test Biophysical prole Modied biophysical prole Corrected Stillbirth Rate 1.9 to 3.2/10001,2 0.4/10002 0.7/10003 0.8/10004

319 impossible to distinguish how many of these cesarean sections were indicated or associated with improved fetal and neonatal outcomes. Another important consideration which is poorly understood is the potential contribution of antenatal testing to long-term outcomes in children. For example, a signicant consideration is whether or not antenatal testing allows us to identify the compromised infant and intervene before the onset of adverse neurologic outcomes. This is certainly a primary goal of antenatal testing, but there is a paucity of published long-term follow-up on these children. The general assumption in the literature is that our intervention for an abnormal antepartum test results in a good outcome. However, in the absence of data we cannot be assured that our interventions, even if they prevent stillbirth, may not involve a tradeoff between longterm neurologic dysfunction and fetal death. Such information would play a vital role in determining both the effectiveness and the cost of antenatal testing. Finally, another important question regarding the effectiveness of antepartum testing is whether or not there are data to support the use of one antepartum test over another. There are no adequately powered randomized trials to examine the efcacy of one testing modality over another, although, as noted earlier, the stillbirth rates following any of the antepartum testing modalities are overall quite low. Freeman and coworkers2 published a nonrandomized cohort study comparing the contraction stress test to the nonstress test which demonstrated overall low stillbirth rates for each test but this study design prohibits an accurate comparison. Platt and coworkers6 conducted a small quasi-randomized trial comparing management based on the results of nonstress testing versus the biophysical prole. They were unable to detect a difference in the stillbirth rates between the two populations. The above data leave the clinician with a paucity of information on which to base clinical choices among the various methods of antenatal assessment.

the untested population is 10.8/1000, while the corrected stillbirth rate (fetuses with lethal anomalies, mothers who refused intervention excluded) in patients who underwent antenatal testing is 0.8/1000. While the overall stillbirth rates following any of the antenatal tests are low, the question that naturally arises is thisif the patients undergoing testing are going to be compared with patients who were not undergoing testing, do the untested patients in the above study represent a high- or low-risk group of patients? If indeed they are truly a low-risk population, then the reduction in stillbirth achieved by antenatal testing may be notable. However, if the stillbirths in the untested population represent a high-risk group of patients who otherwise may not have been receiving care or if a large number of fetuses with lethal anomalies are included, then it remains highly possible, if not likely, that the differences in stillbirth rates may be secondary to other factors unrelated to the antenatal test. Four small randomized studies involving a total of 1588 pregnancies undergoing cardiotocography were included in a review by the Cochrane Collaboration.5 There was a trend toward increased perinatal deaths in the group undergoing monitoring (odds ratio, 2.85; 95% CI, 0.99-7.12) and the authors of the review concluded that there is not enough evidence to evaluate the use of antenatal cardiotocography for fetal assessment. In addition, another signicant limitation of the current available literature is the lack of information on potential adverse outcomes related to antenatal testing. Antenatal testing has the potential for not only false-negative results (stillbirth following a reassuring test) but also false-positive results. False-positive results have the potential to result in iatrogenic prematurity with downstream adverse neonatal outcomes and also unnecessary interventions with secondary adverse maternal outcomes. In much of the published literature regarding antenatal testing these important outcomes are not discussed. For one example, in the article by Miller and coworkers4 discussed above, the false-positive rate resulting in preterm delivery was 1.5% of the total population tested before 37 weeks. Many of these patients had testing initiated at 34 weeks, but it is intuitive that if earlier testing is utilized, the potential risks associated with iatrogenic preterm birth may increase. In addition, the overall false-positive rate was 60% if the false-positive rate was dened as an abnormal test that prompted delivery but was not associated with fetal distress, meconium-stained amniotic uid, low 5-minute Apgar score, or intrauterine growth restriction. The cesarean section rate was 24% in the tested population compared with a rate of 13.2% in the untested population but it is

Costs of Antenatal Testing

Economic analysis remains an important part of health care secondary to the fact that resources are limited and overall health care costs are rising quickly. For example, in 2002 total health care spending was $1.6 trillion dollars amounting to total expenditures of $5440/person. In addition, health care expenditures are growing 5.7% faster than the gross domestic product and overall account for 14.2% of the gross domestic product. As health care resources become limited, what is spent on programs such as antenatal testing diverts resources from other programs. That being said, we must ask whether or not cost is likely to drive our clinical decisionmaking when it comes to the utilization of antenatal testing. Currently, very little in obstetrics is driven solely by cost. For example, the utilization of Down syndrome screening has become widespread. Cost estimates per live birth of a child with Down syndrome avoided with screening programs range from 0.67 to 1.35 million dollars7 but cost has played very little in the decision to recommend screening.

320 The fundamental principles of cost assessment are related to the evaluation of the effectiveness and efcacy of a particular intervention. Effectiveness refers to the improvement in health as measured by explicit health outcomes in real world settings (eg, does the intervention work?), whereas efcacy refers to improvement in health as measured by these same health outcomes in ideal or research settings.8 The best and least biased way to establish efcacy is from randomized controlled trials but unfortunately this data are not available for the various methods of antenatal assessment, which limits our ability to perform a formal cost assessment. However, it does appear that the best data available from the literature to assess the costs pertaining to antenatal testing is the article by Miller and coworkers.4 We have discussed this particular article throughout this review but will now examine some of the details and how we can use this data to make at least rough estimates of costs associated with antenatal testing. This study involved 15,482 high-risk obstetric patients who underwent modied biophysical prole testing. A total of 54,617 exams were performed. The cost of a modied biophysical prole was estimated by assessing the professional and technical fees at our own institution and then applying a cost:charge ratio of 0.6. This leads to an estimate of cost for a nonstress test of $48.00, $236.00 for an amniotic uid index, and $295.00 for a biophysical prole. The estimated costs associated with testing are listed in Table 2. The total cost for this testing program was $17,192,661. If one calculates that 158 stillbirths were potentially prevented by antepartum testing, the cost per stillbirth averted is $108,814. As discussed throughout this article, there are many difculties with these calculations. It is unclear how many stillbirths are truly prevented by this, or any, antenatal testing program. In addition, it is difcult to estimate the potential costs associated with induction of labor, excess cesarean sections, and maternal complications directly related to intervention. The costs of antenatal testing depend highly on the efcacy of the test. For example, we can assume the extremes of effectiveness to further examine potential costs. In this same population of patients, if only 10 stillbirths are prevented, the cost per stillbirth averted is $1,719,000. At the other extreme, if testing prevents 300 stillbirths, the cost per stillbirth

C.M. Scifres and G.A. Macones

averted is $57,300. Even the high-end cost of $1,719,000 per stillbirth prevented may be quite reasonable if it results in delivery of a healthy neonate. The gestational age at initiation of testing plays a central role is estimation of cost as well. In the Miller article, testing was initiated at greater than 34 weeks in almost all cases. However, the earlier testing is initiated, the higher the potential for signicant costs related to the care of premature neonates as well as the increased likelihood of long-term sequelae of prematurity. This was addressed in a decision analysis performed by Rouse and coworkers,9 which examined relationship of fetal death, neonatal death, and moderate to severe disability in patients with diabetes over a range of gestational ages at which testing could be initiated. This model demonstrated that initiating testing around 34 weeks may provide the most favorable outcomes. Estimates of the cost of an antenatal testing program also hinge on how frequently testing should be performed.

Conclusions
As we have reviewed throughout this document, the efcacy of antepartum testing is uncertain. There is also a signicant lack of data relating to the comparative efcacy of each of the testing modalities and a paucity of information to guide us in determining the optimal time to initiate testing. The safety of antepartum testing clearly relates to the timing of initiation of testing. Given the lack of data pertaining to efcacy of testing, preventing iatrogenic prematurity seems to be an important goal of testing. Although we have explored issues of cost relating to antenatal testing, this is unlikely to drive decisionmaking regarding whether or not to test. If we could be assured that antenatal testing was highly effective in preventing stillbirth of an otherwise normal fetus, society would be likely to endorse testing even at very high cost. For example, if antenatal testing is highly effective, with low rates of falsepositive results, expanding indications for testing or even a policy of universal testing may be a reasonable approach to consider. However, with the current available data, the above remains speculative.

References
1. Freeman R, Anderson G, Dorchester W: A prospective multi-institutional study of antepartum fetal heart rate monitoring. Risk of perinatal mortality and morbidity according to antepartum fetal heart rate test results. Am J Obstet Gynecol 143:771-777, 1982 2. Freeman R, Anderson G, Dorchester W: A prospective multi-institutional study of antepartum fetal heart rate monitoring. Contraction stress test versus nonstress test for primary surveillance. Am J Obstet Gynecol 143:778-781, 1982 3. Manning F, Morrison I, Harman C, et al: Fetal assessment based on fetal biophysical proling: experience in 19,221 referred high risk pregnancies. Am J Obstet Gynecol 157:880-884, 1987 4. Miller D, Rabello Y, Paul R: The modied biophysical prole: antepartum testing in the 1990s. Am J Obstet Gynecol 174:812-817, 1996 5. Pattison N, McCowan L: Cardiotocography for antepartum fetal assessment. Cochrane Database of Systematic Reviews 1999;(1):CD001068. DOI:10.1002/14651858 6. Platt L, Walla C, Paul R, et al: A prospective trial of the fetal biophysical

Table 2 Costs Associated with an Antenatal Testing Program Utilize the Modied Biophysical Prole as an Initial Test Contributors to Cost 54,617 modied biophysical proles 4070 excess biophysical proles secondary to nonreactive nonstress test Hospital admissions secondary to abnormal testing 32 iatrogenic preterm deliveries (>34 weeks) Cost $15,551,228 $1,200,650

$393,120 $47,663

Antenatal testing
prole versus the nonstress test in the management of high-risk pregnancies. Am J Obstet Gynecol 153:624-633, 1985 7. Biggio JR, Owen J, Wenstrom KD, et al: An outcomes analysis of 5 prenatal screening strategies for trisomy 21 in women less than 35 years. Am J Obstet Gynecol 185:1016-1020, 2001

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8. Macones G, Goldie S, Peipert J: Cost-effectiveness analysis: an introductory guide for clinicians. Obstet Gynecol Surv 54:663-672, 1999 9. Rouse D, Owen J, Goldenberg R, et al: Determinants of the optimal time in gestation to initiate antenatal fetal testing: a decision-analytic approach. Am J Obstet Gynecol 173:1357-1363, 1995