Adverse Obstetric Outcome in Low- and High-
Risk Pregnancies: Predictive Value of Maternal
Serum Screening
M. VAN RIJN, MD, Y. T. VAN DER SCHOUW, PhD, A. M. HAGENAARS, MSc,
G. H. A. VISSER, MD, PhD, AND G. C. M. L. CHRISTIAENS, MD, PhD
Objective: To determine whether the relationship between
adverse pregnancy outcome and elevated maternal serum
alpha-fetoprotein (MSAFP) and/or maternal serum hCG lev-
els in women whose fetuses have no chromosomal abnor-
malities or neural tube defects is restricted to pregnancies
with a priori elevated risk for pathology or also present in
low-risk pregnancies.
Methods: The outcomes of pregnancy in two groups of
patients with elevated MSAFP and/or maternal serum hCG
values were compared with the outcomes of a reference
group with normal serum values. The first study group
consisted of 83 women without pre-existing risk for poor
outcome as defined by the guidelines of the Dutch Society of
Obstetrics and Gynecology. The second study group con-
sisted of 62 women with a priori elevated risk according to
these guidelines.
Results: Fetal or neonatal death, pregnancy-induced hy-
pertension, placental abruption, placenta previa, preterm
delivery, delivery of infants with birth weights in the 2.3rd
percentile, and complications during the third stage of labor
occurred significantly more often in patients with elevated
values and low a priori risk than in women with normal
values and without pre-existing risk factors. There was no
significant increase in adverse pregnancy outcome in women
with elevated values and high a priori risk compared with
women with normal values and elevated a priori risk.
Conclusion: In women at low risk, elevated MSAFP and/or
maternal serum hCG values are predictive of adverse preg-
nancy outcome. In women with a priori elevated risk,
abnormal serum values do not increase this risk. (Obstet
Gynecol 1999;94:929 34. 1999 by The American College
of Obstetricians and Gynecologists.)
From the Department of Obstetrics and Gynecology, Utrecht Univer-
sity Medical Center, Utrecht; the Julius Center for Patient-Oriented
Research, University Utrecht, Utrecht; and the Diagnostic Laboratory
for Infectious Diseases and Perinatal Screening, National Institute of
Public Heatlh and the Environment, Bilthoven, The Netherlands.
The authors thank A. C. C. van Oppen, MD, PhD, for assistance in
determining the a priori risk in the 290 patients and H. W. Bruinse, MD,
PhD, for his valuable comments.
VOL. 94, NO. 6, DECEMBER 1999
Women with elevated second-trimester maternal serum
alpha-fetoprotein (MSAFP) levels whose fetuses do not
have neural tube defects are known to have an in-
creased risk of fetal death, delivery of a low birth
weight infant, and preterm delivery.1,2 A similar asso-
ciation exists between high second-trimester maternal
serum hCG levels and fetal death, preeclampsia, preg-
nancy-induced hypertension, preterm delivery, and
placental pathology.3 6 The elevated levels of MSAFP
and maternal serum hCG are thought to reflect early
placental pathology that may be associated with prob-
lems later in pregnancy. Increased obstetric surveillance
in women with unexplained elevated MSAFP and/or
maternal serum hCG values has been recommend-
ed.711
The goal of this study was to determine whether
elevated MSAFP and/or maternal serum hCG values
are as predictive of adverse outcome in women with a
priori high obstetric risk as in women with a priori low
risk. This question is clinically relevant because in The
Netherlands, as elsewhere, healthy women with un-
eventful pregnancies are cared for by midwives, general
practitioners, nurse practitioners, and nurse midwives,
whereas pregnant women who are at risk for adverse
outcome are cared for by obstetricians.
Materials and Methods
Between March 1991 and January 1997, 7380 pregnant
women underwent serum screening for neural tube
defects and/or Down syndrome between 15 and 20
weeks gestation at the Utrecht University Medical
Center, Utrecht, The Netherlands. Gestational ages
were determined by first-trimester ultrasound. After
exclusion of pregnancies with unknown outcome (n
1164), twin gestations (n 172), and pregnancies with
fetuses with congenital anomalies associated with ab-
0029-7844/99/$20.00 929
PII S0029-7844(99)00467-6
Table 1. Indicators of Elevated Obstetric Risk, Determined at the Onset of Pregnancy (Based on Guidelines of the Dutch
Society of Obstetrics and Gynecology)
Medical
Asthma treated with medication
Blood group sensitization
Diabetes
Epilepsy treated with medication
Hemorrhagic diathesis
Heart disease with hemodynamic consequences
History of thromboembolic processes
Hyperthyroidism and hypothyroidism
Hypertension
Inflammatory bowel disease
Renal disorders
Systemic disease
Use of illicit drugs or alcohol
Perineal repair surgery
normal MSAFP and/or maternal serum hCG values
(n 29), there remained 6015 pregnancies for analysis.
The Dutch Society of Obstetrics and Gynecology
developed guidelines for risk assignment to help phy-
sicians decide whether a pregnant woman should re-
ceive secondary or primary care during pregnancy. The
most frequent conditions and histories indicating pre-
existing elevated obstetric risk are summarized in Table
1. The guidelines were used to divide women with
elevated MSAFP and/or maternal hCG levels into two
groups: those with low a priori risk and those with high
a priori risk. All medical and obstetric history informa-
tion was obtained from hospital records and referring
physicians or midwives. Because it would not have
been feasible to collect the same detailed information
for all 5870 women with normal MSAFP and maternal
serum hCG values, the random sample function of
the SPSS (SPSS, Inc., Chicago, IL) software package was
used to create a reference group of 145 women with
normal serum values. Two staff obstetricians, masked to
serum values and pregnancy outcome, independently
examined the medical histories of the patients and
listed the 290 pregnancies as low risk or high risk. The
two lists were cross-checked, and a third observer (the
head of the department) made the final decisions in the
case of the 81 patients (28%) whose pregnancies had
been classified differently by the first two observers.
Discrepancies in risk classification occurred in the case
of patients with obstetric or medical histories not ex-
plicitly listed in the national guidelines (eg, assisted
reproduction by intracytoplasmic sperm injection). The
final risk classification of these pregnancies was based
as much as possible on evidence-based medicine.
Pregnancy outcome was defined as adverse if one of
the following had occurred: fetal death, pregnancy-
induced hypertension, placental abruption, placenta
930 van Rijn et al Serum Screening and Outcome
Obstetric
Cervical incompetence
History of abruptio placentae
History of cesarean delivery
History of complete perineal tear
History of hemorrhage postpartum
History of fetal growth restriction
(birth weight in 2.3rd percentile)
History of perinatal asphyxia or perinatal mortality
History of pregnancy-induced hypertension
History of retained placenta
Last delivery an assisted vaginal delivery
Premature delivery at end of last pregnancy
Pre-existent gynecologic disease
previa, preterm delivery (delivery at less than 34 weeks
gestation), delivery of an extremely small for gesta-
tional age (SGA) infant (birth weight in the 2.3rd
percentile), or complications during the third stage of
labor (retained placenta and/or loss of at least 1000 mL
of blood during or after vaginal delivery). A distinction
was made between fetal death close to the time of blood
sampling (at less than 20 weeks gestation) and later
fetal death (at 20 weeks or more). A pregnancy resulting
in an infant who remained alive 8 days after delivery
was described as ending with a live-born child. Preg-
nancy-induced hypertension, pre-existent (or chronic)
hypertension, and preeclampsia were classified accord-
ing to the definitions of Davey and MacGillivray.12
Hemolysis, elevated liver enzymes, low platelets
(HELLP) syndrome was defined as a serum level of
liver enzymes of more than 70 IU/L and a platelet count
of less than 100 109/L.13
Serum tests were performed with the use of Amer-
lex-M kits (alpha-fetoprotein) (Amerlex IM4304), un-
conjugated estriol (Amerlex IM4044B), and whole hCG
(Amerlex IM4094)) (Amersham Pharmacia Biotech UK
Ltd, Buckinghamshire, UK). Second-trimester maternal
serum levels of the markers were expressed as multi-
ples of the median (MoM). Least-squares regression
analysis was performed for weight correction of
MSAFP and maternal serum hCG levels.14 The defini-
tion of elevated serum marker levels was based on their
99th percentiles in the screened population (2.66 MoM
for MSAFP and 3.96 MoM for maternal serum hCG).
These values were rounded off to 2.5 MoM for MSAFP
and 4.0 MoM for maternal serum hCG, comparable
with cutoff levels used in other studies. Until March
1996, obstetric management was not changed when
elevated serum levels were found. Thereafter, women
without elevated a priori risk and high values were seen
Obstetrics & Gynecology
Table 2. Obstetric History and Maternal Characteristics
MSAFP (MoM)

2.5 2.5 2.5 2.5

Maternal serum hCG (MoM)

4.0
All women with
All women Reference group 2.5 4.0 2.5 abnormal values

No. of women 5870 145 72 51 22 145

Maternal age (y) 31 4.9* 30 4.7 32 5.3* 32 5.0 31 6.0 32 5.3*
No. of Amniocenteses performed after blood sampling 591 (10) 15 (10) 24 (33) 37 (73) 16 (73) 77 (53)
No. of nulliparous women 54 (37) 32 (44) 27 (53) 11 (50) 70 (48)
No. of parous women 91 (63) 40 (56) 24 (47) 11 (50) 75 (52)
No. of women with low a priori risk 111 (77) 41 (57)* 29 (57)* 13 (59)* 83 (57)*
No. of women with high a priori risk 34 (23) 31 (43)* 22 (43)* 9 (41)* 62 (43)*
MSAFP maternal serum alpha-fetoprotein; MoM multiples of the median.
Data are presented as n, mean standard deviation, or n (%).
* Significant (P .05) difference compared with the reference group.

by obstetricians at 24 weeks for blood pressure (BP)
measurement, urinanalysis, ultrasound, and Doppler
measurement of the umbilical arteries. The frequencies
of prenatal consultations (and hence the opportunities
for diagnosing fetal death before the woman was
alerted herself by lack of fetal movement) therefore
were largely unaltered because of serum values.
The 2 test and unpaired t test were used for statisti-
cal analysis of obstetric history and maternal character-
istics in serum marker level categories. A two-tailed P
value of less than .05 was considered statistically sig-
nificant. Associations between pregnancies with spe-
cific outcomes and serum marker levels were expressed
as relative risks (RRs; the proportion of women with a
certain outcome in the study group divided by the
proportion of women with the same outcome in the
reference group) and 95% confidence intervals (CIs).
Relative risks were calculated separately for the two
subgroups (high and low a priori risk).
To compare our results with previous studies, we
consulted the MEDLINE database. References in this
database date back to 1966. Used keywords were feto-
protein, AFP, gonadotrophin, and hCG, preg-
nancy outcome, death, and pregnancy complica-
tions.
Results
Table 2 shows the maternal characteristics of the 6015
women. One hundred forty-five women (2.4%) had
elevated MSAFP and/or maternal serum hCG values.
Women with high MSAFP and/or maternal serum hCG
values more often had pre-existing risk factors com-
pared with women with normal MoM values (43%
compared with 23%, P .001).
Nine hundred fifty-five women (15%) had one or
more adverse outcomes. Relative risks and 95% CIs for
each outcome in the study groups are presented in
Table 3. Overall, women with elevated MSAFP or
maternal serum hCG values had a three-fold increase in
risk for adverse pregnancy outcome (RR 3.1, 95% CI 2.5,
3.7). If both MSAFP and maternal serum hCG levels
were elevated, there was an almost five-fold increase in
risk compared with the risk in women with normal
values (RR 4.7, 95% CI 3.4, 6.5). Women with elevated
MSAFP and/or maternal serum hCG values were at
greater risk for fetal death, delivery before 34 weeks,
delivery of an extremely SGA infant, placental abrup-
tion, and complications in the third stage of labor than
were women with normal MSAFP and maternal serum
hCG values. Additionally, women with elevated mater-
nal serum hCG values (and with or without elevated
MSAFP values) had a significantly higher risk for
pregnancy-induced hypertension, preeclampsia, or
HELLP syndrome. The median gestational age at which
fetal death was detected was 28 weeks (range 17 41
weeks) for the group with normal MSAFP and maternal
serum hCG values and 20 weeks (range 16 30 weeks) in
the group with elevated values (P .004). Isolated
elevated MSAFP levels were predictive mainly of im-
minent fetal death and not of fetal death beyond 20
weeks gestation. The positive predictive value of ele-
vated MSAFP and/or maternal serum hCG values for
adverse pregnancy outcome when the described cutoff
values were used was 41% (95% CI 33%, 49%) and the
negative predictive value was 86% (95% CI 86%, 87%).
When data from patients with a priori low risk and
data from patients with a priori high risk were analyzed
separately, abnormal MSAFP and/or maternal serum
hCG levels were found to be predictive of an increase in
risk for adverse outcome in the former group only
(Table 4). Overall, women without a priori elevated risk

VOL. 94, NO. 6, DECEMBER 1999 van Rijn et al Serum Screening and Outcome 931
Table 3. Relative Risks for Pregnancy Outcomes in Patients With Elevated Serum Marker Levels
MSAFP (MoM) All
2.5 2.5 2.5 2.5 women
with
Maternal serum hCG (MoM)
abnormal
Outcome 4.0 2.5 4.0 2.5 values

Live-born infant
No. (%) of women 5795 (99) 63 (88) 47 (92) 16 (73) 126 (87)
RR 1.00 (reference) 0.89 0.93 0.74 0.88
95% CI 0.81, 0.97 0.86, 1.00 0.57, 0.95 0.83, 0.94
Any adverse outcome
No. (%) of women 795 (14) 22 (31) 24 (47) 14 (64) 60 (41)
RR 1.0 (reference) 2.3 3.5 4.7 3.1
95% CI 1.6, 3.2 2.6, 4.7 3.4, 6.5 2.5, 3.7
Fetal death
No. (%) of women 50 (85.0) 6 (8.3) 3 (5.9) 4 (18.2) 13 (9.0)
RR 1.0 (reference) 9.8 6.9 21.0 11.0
95% CI 4.3, 22.0 2.2, 21.0 8.4, 54.0 5.8, 19.0
PIH, preeclampsia, or HELLP syndrome
No. (%) of women 397 (6.8) 5 (6.9) 14 (28.0) 6 (27.0) 25 (17.0)
RR 1.0 (reference) 1.0 4.1 4.0 2.5
95% CI 0.4, 2.4 2.6, 6.4 2.0, 8.0 1.8, 3.7
Placental abruption
No. (%) of women 29 (0.50) 4 (5.6) 0 2 (9.1) 6 (4.1)
RR 1.0 (reference) 11.0 18.0 8.4
95% CI 4.1, 31.0 4.7, 72.0 3.5, 20.0
Placenta previa
No. (%) of women 17 (0.29) 3 (4.2) 0 0 3 (2.1)
RR 1.0 (reference) 14.0 7.1
95% CI 4.3, 48.0 2.1, 24.0
Live-born* delivery before 34 wk
No. (%) of women 137 (2.3) 5 (6.9) 3 (5.9) 4 (18.0) 12 (8.3)
RR 1.0 (reference) 3.0 2.5 7.8 3.5
95% CI 1.3, 7.0 0.8, 7.7 3.2, 19.0 2.0, 6.3
Live-born* birth weight in 2.3rd percentile
No. (%) of women 74 (1.3) 2 (2.8) 3 (5.9) 3 (14.0) 8 (5.5)
RR 1.0 (reference) 2.2 4.7 11.0 4.4
95% CI 0.6, 8.8 1.5, 14.0 3.7, 32.0 2.2, 8.9
Complications in 3rd stage of labor
No. (%) of women 186 (3.2) 6 (8.3) 4 (7.8) 3 (14.0) 13 (9.0)
RR 1.0 (reference) 2.6 2.5 4.3 2.8
95% CI 1.2, 5.7 0.1, 6.4 1.5, 12.0 1.7, 4.8
RR relative risk; CI confidence interval; PIH pregnancy-induced hypertension; HELLP hemolysis, elevated liver enzymes, low platelets;
all other abbreviations as in Table 2.
Numbers in columns do not add up.
* Alive 8 days after delivery.

had a 3.8-times-higher risk for adverse outcome when Discussion

MSAFP and/or maternal serum hCG levels were ele-
vated (95% CI 2.0, 7.1) compared with women in the
same risk category who had normal marker levels.
Adverse outcome occurred in 25% of the patients at low
risk who had unexplained high MSAFP levels only, in
41% of those with high maternal serum hCG levels
only, and in 69% of those in whom both MSAFP and
maternal serum hCG levels were elevated. In women at
high risk, unexplained elevated MSAFP and/or mater-
nal serum hCG levels were not associated with change
in risk for any adverse pregnancy outcome (RR 0.99,
95% CI 0.6, 1.6).
Reports on the relationship between elevated MSAFP
levels and adverse pregnancy outcome date back to the
start of maternal serum screening programs for neural
tube defects in the 1970s.1517 In seven studies with
designs similar to ours, RR for an adverse outcome
ranged from 1.6 to 3.8 in cases of elevated MSAFP levels
and from 1.5 to 5.0 in cases of elevated maternal serum
hCG levels.5,6,18 22 Both leakage of MSAFP through a
defective placental barrier and an increased placental
villous surface have been mentioned as explanations for
the association between elevated MSAFP levels and

932 van Rijn et al Serum Screening and Outcome Obstetrics & Gynecology
Table 4. Relative Risks for Adverse Outcome in Patients With Elevated Serum Level Markers Without and With A Priori
Elevated Obstetric Risk
MSAFP (MoM)

2.5 2.5 2.5 2.5

Maternal serum hCG (MoM)

All women with abnormal
4.0 (n 145) 2.5 (n 72) 4.0 (n 51) 2.5 (n 22) values (n 145)

Women with a priori

low risk
No. 11/111 (9.9) 10/41 (24.4) 12/29 (41.4) 9/13 (69.2) 31/83 (37.3)
RR 1.00 (reference) 2.46 4.18 6.99 3.77
95% CI 1.13, 5.36 2.06, 8.48 3.58, 13.60 2.01, 7.05
Women with a priori
high risk
No. 16/34 (47.1) 12/31 (38.7) 12/22 (54.5) 5/9 (55.6) 29/62 (46.8)
RR 1.00 (reference) 0.82 1.15 1.18 0.99
95% CI 0.47, 1.45 0.67, 1.95 0.60, 2.34 0.64, 1.55
RR relative risk; CI confidence interval; all other abbreviations as in Table 2.
Numbers in parentheses are percentages.

adverse pregnancy outcome.2,23 A considerable propor-
tion of pregnancy outcomes that are associated with
elevated MSAFP levels (such as preeclampsia, placental
abruption, placenta previa, and fetal growth restriction
[FGR]) are associated with abnormalities of the placenta
or placentation.23 The specific mechanism for maternal
serum hCG level elevation in pregnancies with adverse
outcomes is unknown, but placental immaturity (also
related to growth restriction and prematurity) and
uteroplacental underperfusion leading to placental vas-
cular changes have been suggested.4,24,25
Our study confirms previous findings regarding
the relationship between elevated MSAFP and/or
maternal serum hCG levels and adverse pregnancy
outcome.111,18 22 The higher risk of adverse preg-
nancy outcome if levels of one or both markers were
elevated was significant, but only in women with low
a priori risk. In women with pre-existing risk for
adverse pregnancy outcome, the presence of elevated
serum marker levels did not relate to further increase
in risk. This is in agreement with the results of
Phillips et al,26 who studied a high-risk urban popu-
lation and found that elevated MSAFP levels did not
have any additional predictive value with regard to
adverse perinatal outcome.
The negative predictive value of maternal serum
screening is too low for it to be useful as a screening
instrument for adverse pregnancy outcome. However,
the positive predictive value of 41% may justify inten-
sified obstetric surveillance in women with unexplained
elevated MSAFP and/or maternal serum hCG values.
Repeat ultrasound and Doppler flow measurements
from 24 weeks onward to rule out early-onset FGR or
placental pathology, close supervision of maternal BP,
and fetal monitoring are recommended.711 Whether
medical and psychologic costs and benefits are bal-
anced should be the subject of future studies.
Women with elevated MSAFP and/or maternal se-
rum hCG levels usually are referred for second-
trimester amniocentesis. This procedure involves a
small (0.5%) risk of iatrogenic loss. Several studies have
shown that the association between elevated marker
levels and fetal death is independent of amniocente-
sis.2729
Combining the guidelines of the Dutch Society of
Obstetrics and Gynecology with the determination of
marker levels improves differentiation between women
with low risk and those with high risk. Ten percent of
the women assigned to the low-risk group who had
normal serum marker levels had adverse outcomes,
compared with 43% of those with high a priori risk
and/or elevated serum marker levels. Consequently,
women with low risk who have unexplained elevated
MSAFP and/or maternal serum hCG values have an
increased risk of adverse pregnancy outcome and re-
quire intensified obstetric surveillance. Further studies
are necessary to determine whether intensified obstetric
surveillance can prevent all or some of these outcomes.
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Address reprint requests to:
G. C. M. L. Christiaens, MD, PhD
Department of Obstetrics and Gynecology
Utrecht University Medical Center
HP KE 04.123.1, PO Box 85090
3508 AB Utrecht
The Netherlands
E-mail: l.christiaens@dog.azu.nl
Received December 14, 1998.
Received in revised form May 10, 1999.
Accepted May 21, 1999.
Copyright 1999 by The American College of Obstetricians and
Gynecologists. Published by Elsevier Science Inc.
Obstetrics & Gynecology