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Fetal growth restriction: current knowledge

Article  in  Archives of Gynecology and Obstetrics · March 2017

DOI: 10.1007/s00404-017-4341-9

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Arch Gynecol Obstet
DOI 10.1007/s00404-017-4341-9
REVIEW
Fetal growth restriction: current knowledge
Luciano Marcondes Machado Nardozza1 · Ana Carolina Rabachini Caetano1 · Ana Cristina Perez Zamarian1 ·
Jaqueline Brandão Mazzola1 · Carolina Pacheco Silva1 · Vivian Macedo Gomes Marçal1 · Thalita Frutuoso Lobo1 ·
Alberto Borges Peixoto1,2 · Edward Araujo Júnior1 
Received: 3 January 2017 / Accepted: 28 February 2017
© Springer-Verlag Berlin Heidelberg 2017
Abstract  the condition and adequate monitoring of the fetal status,
Background  Fetal growth restriction (FGR) is a condi-
tion that affects 5–10% of pregnancies and is the second
most common cause of perinatal mortality. This review
presents the most recent knowledge on FGR and focuses
on the etiology, classification, prediction, diagnosis, and
management of the condition, as well as on its neurological
complications.
Methods  The Pubmed, SCOPUS, and Embase databases
were searched using the term “fetal growth restriction”.
Results  Fetal growth restriction (FGR) may be classified
as early or late depending on the time of diagnosis. Early
FGR (<32 weeks) is associated with substantial alterations
in placental implantation with elevated hypoxia, which
requires cardiovascular adaptation. Perinatal morbidity and
mortality rates are high. Late FGR (≥32 weeks) presents
with slight deficiencies in placentation, which leads to mild
hypoxia and requires little cardiovascular adaptation. Peri-
natal morbidity and mortality rates are lower. The diagno-
sis of FGR may be clinical; however, an arterial and venous
Doppler ultrasound examination is essential for diagnosis
and follow-up. There are currently no treatments to control
FGR; the time at which pregnancy is interrupted is of vital
importance for protecting both the mother and fetus.
Conclusion  Early diagnosis of FGR is very important,
because it enables the identification of the etiology of
* Edward Araujo Júnior
araujojred@terra.com.br
1
Department of Obstetrics, Paulista School of Medicine,
Federal University of São Paulo (EPM-UNIFESP),
Rua Belchior de Azevedo, 156 apto. 111 Torre Vitoria,
São Paulo‑SP CEP 05089‑030, Brazil
2
Mario Palmério University Hospital, University of Uberaba
(UNIUBE), Uberaba‑MG, Brazil
thereby minimizing risks of premature birth and intrauter-
ine hypoxia.
Keywords  Fetal growth restriction · Placental
insufficiency · Prediction · Doppler · Management ·
Neurological development
Introduction
Fetal growth restriction (FGR) occurs when the fetus does
not reach its intrauterine potential for growth and devel-
opment as a result of compromise in placental function.
Fetuses with FGR present with a greater risk of perina-
tal morbidity and mortality and long-term health defects.
These include impaired neurological and cognitive devel-
opment and cardiovascular or endocrine diseases in adult-
hood. FGR is an intercurrence in 5–10% of pregnancies
[1]. It is the second leading cause of perinatal mortality
and is responsible for 30% of stillborn infants; it is also the
most common cause of premature births and intrapartum
asphyxia.
At present, there is no gold standard for the diagnosis
of FGR. It is generally defined by a statistical deviation
from fetal size in the population of reference, with percen-
tile limits of 10, 5, or 3. These limits, however, are better
understood as indicative of fetuses that are small for gesta-
tional age (SGA). In addition to fetuses that have true FGR,
SGA includes healthy but constitutionally small fetuses that
have a lower risk of abnormal perinatal outcomes. Approxi-
mately 70% of fetuses are classified as weighing below
the 10th percentile because of constitutional factors such
as female gender and the parents’ ethnicity, which are not
13
Vol.:(0123456789)

involved in the increase in perinatal morbidity and mortal-
ity rates [2].
In clinical practice, FGR is defined on the basis of the
weight percentile relative to the gestational age. The World
Health Organization (WHO) defines FGR as an estimated
fetal weight below the third percentile. However, the
American College of Obstetrics and Gynecology (ACOG)
defines FGR as an estimated fetal weight below the 10th
percentile for gestational age and states that it is frequently
associated with placental insufficiency [3]. This is the most
commonly used classification.
In this chapter, we will address the current knowledge on
the etiology, classification, prediction, diagnosis, and man-
agement of FGR as well as its neurological complications.
Etiology
The etiology of FGR is multifactorial and may be subdi-
vided into maternal causes, fetal causes, and causes involv-
ing uteroplacental vascular insufficiency. It is not uncom-
mon for etiological factors to overlap.
Fetal factors
1. Chromosomal abnormalities, particularly those in tri-
somies 13, 18, and 21: These contribute to 5–20% of
FGR cases, particularly in cases of early FGR [4].
2. Genetic syndromes These include genetic mutations
such as a mutation in the gene responsible for insulin-
like growth factor production; it has been experimen-
tally shown that mutations in the insulin-like growth
factor 1 receptor gene determine pre- and post-natal
growth restriction [5].
3. Intrauterine infections These include infections with
viruses that cause placentitis, vascular endothelial
lesions, fetal viremia with direct inhibition of cell mul-
tiplication, angiopathy obliterans, chromosomal rup-
tures, and cytolysis. It is estimated that fetal infectious
diseases are present in 5–10% of FGR cases, particu-
larly those caused by rubella virus, cytomegalovirus,
varicella zoster virus, and Toxoplasma gondii [6].
4. Multiple gestation pregnancies In total, 15–30% of
multiple pregnancies develop FGR; the condition is
more common in monochorionic twins affected by
twin-to-twin transfusion syndrome. Up to the 28th to
30th week of pregnancy, fetuses in multiple pregnan-
cies have growth rates similar to those of fetuses in
single pregnancies; however, after this phase, there is a
15–20% decrease in the growth rate [7].
5. Inborn errors of metabolism Although rare, these may
be involved in the etiology of FGR [5].
13
Arch Gynecol Obstet
Maternal factors
1. Clinical diseases All forms of hypertensive pregnancy
diseases increase the incidence of FGR by two to three-
fold as a result of reduced uteroplacental perfusion.
There is a strong association between pre-eclampsia
and FGR due to deficient trophoblast invasion [8].
Other diseases such as insulin-dependent diabetes mel-
litus with vasculopathy, congenital cyanotic heart dis-
eases, restrictive pneumopathies, severe renal diseases,
autoimmune diseases (collagenoses, antiphospholipid
antibody syndrome), hereditary or acquired thrombo-
philia, hyperhomocysteinemia, and severe anemia are
associated with FGR [9, 10].
2. Nutritional disorders Chronic malnutrition prior to
pregnancy is associated with 40% of cases of under-
weight newborns. It leads to both premature births and
FGR, with a 400% increase in mortality rates during
the first year of life [11].
3. Drug use This category predominantly includes smok-
ing, which is a preventable cause of FGR. Expo-
sure to carbon monoxide reduces the ability of fetal
hemoglobin to carry oxygen, and nicotine induces the
release of maternal catecholamines, thereby reduc-
ing placental perfusion. There is a direct correlation
between the number of cigarettes consumed and the
degree of FGR. Similarly, second-hand smoke; the use
of narcotics such as cocaine, heroin, and alcohol; expo-
sure to ionizing radiation; residence at high altitudes;
and the inadvertent use of teratogenic substances such
as anti-seizure medications, warfarin-type anticoagu-
lants, antineoplastic agents, and folic acid antagonists
serve as etiological factors of FGR [12].
4. Other factors These include constitutional factors, eth-
nicity, stress levels, and depression.
Uteroplacental factors
The placenta, a complex organ with a biologically short
existence, is the only organ formed by cells from two dif-
ferent organisms. Because of the presence of paternal anti-
gens, the fetus and the fetal part of the placenta represent
an allograft to maternal tissues. The placenta is an essen-
tial organ for the transfer of nutrients and gases from the
mother to fetus and for the elimination of products resulting
from fetal metabolism. Blood flows to the uterus through
the uterine arteries, irrigating and providing nutrients to the
intervillous space (which is composed of 100–200 utero-
placental arteries). It also includes 75–175 veins, which
provide oxygenated blood to the fetus in a low-resistance
circuit [13]. It also functions as a barrier that protects
the fetus from pathogens. It has the ability to act as an
endocrine organ, because it is active in the synthesis and
Arch Gynecol Obstet
secretion of hormones, growth factors, and cytokines [14].
The interaction between maternal and fetal circulations in
the placenta is fundamental for adequate exchange of nutri-
ents and oxygen. It is hypothesized that this adaptation
comes from a physiological process referred to as “waves
of trophoblast migration”. Between the sixth and 12th
weeks of pregnancy, cytotrophoblast invasion is established
in the decidual tissue, including the intradecidual segments
of the spiral arteries. The second wave occurs between the
16th and 18th weeks, when endovascular invasion extends
to the intramyometrial segments of the spiral arteries that
lose the musculoskeletal layer, which is replaced by the
fibrin matrix. This process leads to an accentuated drop
in vascular resistance, in addition to less responsiveness
to local vasoconstricting agents [15, 16]. At present, it is
believed that trophoblast invasion is continuous; thus, the
references to first and second waves are incorrect.
Inadequate placentation, i.e., the absence of destruc-
tion of the musculoskeletal portion of the spiral arteries
in trophoblast migration, creates an area with high resist-
ance to blood flow and resultant decreased nutrition of the
intervillous space and possible increased vasoconstricting
agent activity, because intervention is not affected. Abnor-
mal placentation has been defined as a condition in which
trophoblast invasion of the myometrial portion of the spiral
arteries does not occur [17]. Reduced uteroplacental perfu-
sion associated with maternal vascular disease is responsi-
ble for 25–30% of FGR cases; it is the most common cause
in non-anomalous fetuses.
Structural abnormalities and changes in placental
implantation and attachment may also be involved in the
etiology of FGR, including bilobed placenta, low-insertion
placenta, chorioangioma, velamentous insertion of the
umbilical cord, and presence of a single umbilical artery.
Classification
Normal fetal growth reflects the interaction between geneti-
cally pre-determined growth potential and fetal, placental,
and maternal health. Normal fetal growth has a primary
phase of cellular hyperplasia in the first 16 weeks of the
pregnancy. Between 16 and 32 weeks, there is a concomi-
tant phase of hyperplasia and cellular hypertrophy, with an
increase in the number and size of cells. From week 32,
there is a cellular hypertrophy phase, with a rapid increase
in cell size. This pattern of normal fetal growth is the basis
for the clinical classification of FGR.
Campbell [18] used the head circumference/abdominal
circumference (HC/AC) ratio to differentiate between sym-
metrical or proportionally small fetuses and asymmetrical
fetuses, i.e., those with a disproportionately slower growth
of AC, and classified FGR into types I, II, and III. Type I:
This type is symmetrical harmonic, defined by a reduced
intrinsic potential of fetal growth. These fetuses exhibit a
proportional decrease in the size of the head and abdomen.
Etiological factors affect the growth pattern of these fetuses
at an early stage, during the cellular hyperplasia phase.
Type II: This is characterized by a late onset of changes
in growth, after 30 or 32 weeks, in the cellular hypertro-
phy phase, generally resulting in asymmetry and dishar-
mony. Head circumference and femur length (FL) are less
affected, corresponding to the gestational age. However,
AC is commonly most seriously affected, decreasing the
estimated fetal weight. These fetuses are markedly dys-
trophic. The main etiological factor of asymmetric FGR
is placental insufficiency. Type III: This includes an asso-
ciation of the previous mechanisms (types I and II). The
change occurs in the second trimester, which is when the
hyperplasia and hypertrophy phases occur. It occurs at an
early stage of pregnancy; therefore, the fetuses show semi-
harmonious growth with a hypotrophic appearance. Eti-
opathogenesis is associated with embryonic infections such
as those caused by rubella virus, cytomegalovirus, and Tox-
oplasma gondii as well as with toxic agents that affect the
fetus, such as pharmaceuticals, illegal drugs, and toxins.
At present, the chronological classification of FGR,
which is based on the time of onset, is the most commonly
used classification. It has greater clinical applicability,
because it involves the management and prognosis of the
fetus. Figueras and Gratacós [19] and Baschat [20] have
reported different pathophysiological behaviors in fetuses
with FGR before and after 32 weeks. Those with early FGR
(<32 weeks) exhibit a deciding factor: a substantial change
in placental implantation, which often leads to increased
resistance in the uterine artery and an increased risk of
developing pre-eclampsia. Thus, the resulting fetal hypoxia
is high and requires fetal cardiovascular adaptation. As a
defense mechanism, the fetus exhibits a high tolerance to
low levels of oxygen as well as hypoxemia. Perinatal mor-
bidity and mortality rates are high. In late-onset FGR (≥32
weeks), there are slight placentation deficiencies that lead
to mild hypoxia and require little cardiovascular adaptation
by the fetus. However, the degree of tolerance to hypoxia
is low; in contrast to cases of early onset FGR, the fetus
cannot tolerate this low oxygen supply for long. The major
challenge in early onset FGR is management, while the
problem associated with late-onset FGR is early diagnosis,
because the umbilical artery Doppler findings may still be
normal, thereby masking the disease.
In 2016, specialists established a consensus to define,
classify, and diagnose FGR using the Delphi procedure
[21]. In this process, the 32nd week of gestation was estab-
lished as the cut-off point for early versus late-onset FGR
classification, and fetuses with congenital anomalies were
excluded from this classification. Thus, in early onset FGR,
13

the estimated fetal weight and/or AC is less than the third
percentile or the umbilical artery Doppler which shows
absent and/or zero diastolic flow. Early onset FGR can
also be classified and diagnosed when two of the follow-
ing three parameters are present: (1) estimated fetal weight
and/or AC < the tenth percentile, (2) pulsatility index (PI)
of the uterine artery > the 95th percentile, and (3) PI of the
umbilical artery > the 95th percentile. Late-onset FGR is
determined by only one parameter: estimated fetal weight
and/or AC < the third percentile. Late-onset FGR can also
be classified and diagnosed when two of the following three
parameters are present: (1) estimated fetal weight and/or
AC < the tenth percentile, (2) fetal growth two “quartiles”
lower during fetus monitoring, and (3) cerebroplacental
ratio (CPR) < the fifth percentile.
Doppler follow-up of the umbilical artery has a major
importance in early onset FGR. In cases of late-onset FGR,
umbilical artery Doppler can be normal or only become
abnormal in advanced stages of the disease. In late-onset
FGR, placental dysfunction is less severe and we can
observe decreasing of middle cerebral artery Doppler and
cerebral placental ratio (CPR) with normal or minimal
uterine artery Doppler abnormalities.
Prediction
Although FGR is one of the most important obstetric dis-
eases, its prediction rate is still very low, with values rang-
ing from 12 to 47% and a false positive rate of 10% [22].
One of the first ultrasound markers studied for predicting
FGR was the uterine artery Doppler. Velauthar et  al. [23]
performed a meta-analysis that reviewed studies that used
the uterine artery Doppler in the first trimester to predict
FGR. PI and/or resistance index (RI) > the 90th percentile
or the presence of a unilateral or bilateral diastolic notch
was used the criterion to consider an abnormal Doppler
finding of the uterine arteries. The FGR prediction rate
was 15.4%; for early onset FGR, the rate was higher, with
39.2% sensitivity.
Several studies have evaluated biochemical markers
in FGR. Zamarian et  al. [24] compared biochemical fac-
tors between FGR and adequate for gestational age (AGA)
fetuses between 24 and 40 weeks. Fetuses with FGR
showed higher serum levels of fms-like tyrosine kinase-1
(sFlt-1), soluble endoglin (sEng), and pregnancy-associated
plasma protein A (PAPP-A) with lower levels of angiopoi-
etin-2 than AGA fetuses [24].
Cignini et  al. [25] analyzed the PAPP-A and free-beta
human chorionic gonadotropin (β-hCG) maternal serum
levels in 3332 pregnant women in the first trimester. They
observed that low level of PAPP-A and high value of free
β-hCG are associated with SGA newborns [25].
13
Arch Gynecol Obstet
A recent study demonstrated that the addition of
angiogenic factors to the FGR prediction algorithms
increased the detection sensitivity to 67% [26]. A model
was created for the prediction of SGA fetuses based on
the maternal characteristics, mean arterial pressure,
nuchal translucency measurement, β-hCG, PAPP-A, pla-
cental growth factor (PlGF), placental protein 13 (PP13),
metalloprotease and disintegrin 12 (ADAM12), and PI
of the uterine arteries at 11–13 weeks of gestation. This
model achieved a 73% detection rate, with a false positive
rate of 10% for SGA fetuses before 37 weeks of gestation
[26].
Crovetto et al. [22] developed an algorithm in the first
trimester of pregnancy for predicting early and late-onset
FGR. Maternal characteristics, mean arterial pressure, PI
of uterine arteries, PlGF, and fms-like tyrosine kinase-1
(sFlt-1) were included. Early onset FGR was detected
at a rate of 86.4% with a false positive rate of 10%, and
the sensitivity increased to 94.7% if early restriction was
associated with pre-eclampsia. In cases of late-onset
FGR, the detection rate was 65.8% and it increased to
70.2% when associated with pre-eclampsia, both with
false positive rates of 10%. In another study, the same
group compared the prediction in the first trimester of
pregnancy of SGA fetuses with that of FGR. SGA fetuses
were defined by birth weight < the tenth percentile, and
FGR was defined as estimated weight < the tenth percen-
tile associated with a change in umbilical artery Doppler
findings or birth weight < the third percentile. Maternal
characteristics, mean arterial pressure, Doppler of the
uterine arteries, PlGF, and sFlt-1 were the included varia-
bles. Detection rates for SGA and FGR were 42 and 67%,
respectively, each with a false positive rate of 10% [27].
Three-dimensional placental volume in the first tri-
mester has also been studied for the prediction of SGA
fetuses. A systematic review of the literature by Farina
et  al. [28] included 12 studies on placental volume
between 11 and 14 weeks. The authors concluded that
placental volume as a single marker has very low rates
of prediction (detection rate of 24.7% with 10% of false
positive), but it can be used better integrated into a multi-
variable screening method [28].
Screening can also be performed in the second trimes-
ter. A study including maternal characteristics (age, body
mass index, and ethnicity), fetal biometry, birth weight,
and PI of the uterine arteries in the second trimester
between 19 and 24 weeks, showed that all combined
markers had a detection rate of 40, 66, and 89% for SGA
fetuses at term, preterm, and early preterm, respectively,
with a false positive rate of 10% [29].
Arch Gynecol Obstet
Diagnosis
Accurate determination of the gestational age is essential
for the confirmation of FGR. The isolated assessment based
on the last menstrual period (LMP) may have an error of
14 to 28 days [30]. The gestational age is more accurate
when confirmed by ultrasound, particularly when the test
is performed in the first trimester of pregnancy. The crown-
rump length (CRL) has a 5–7  day error in determining
the gestational age. Therefore, there is always a need for
confirmation of the gestational age according to LMP and
ultrasound, preferably in the first trimester. Proper diagno-
sis enables fetuses with growth restriction that are at risk of
adverse perinatal outcomes to have an adequate follow-up.
Clinical aspects
In prenatal clinical history, we seek to identify risk fac-
tors for FGR, such as maternal complications, previous
obstetric history, occurrence of newborns with a low birth
weight, restricted growth or congenital malformations, and
current history, with possible exposure to an etiological
factor involved in FGR. An evaluation of the parents’ bio-
types also helps to differentiate between an SGA fetus and
a fetus with FGR, particularly in the absence of umbilical
artery Doppler changes.
During the physical examination, careful and prospec-
tive measurement of uterine height and maternal weight
gain may help in FGR screening. The measurement of uter-
ine height using a tape measure is simple and can detect
FGR during pregnancy. In general, the first sign of FGR is
uterine height lower than that expected for the gestational
age. The most common criterion is a difference greater
than 3.0 cm between the value observed and the gestational
age in weeks (sensitivity 86% and specificity 90%) [31].
Another proposed evaluation method for determining the
uterine height is the use of the percentile curve [32], which
considers FGR screening to be positive when its value
is < the tenth percentile for gestational age (sensitivity 78%,
specificity 77.1%, positive predictive value 47.6%, and
negative predictive value 92.9%) [33]. However, the accu-
racy of the measurement of uterine height for screening and
diagnosis remains controversial, because there are factors
that can affect the sensitivity of this method, such as the
body mass index, maternal bladder volume, amniotic fluid
index, parity, and ethnic group [34, 35]. Ideally, every preg-
nant woman should perform at least one ultrasound exami-
nation on the third trimester for estimated fetal weight.
However, measurement of uterine height may be a possibil-
ity for screening of FGR in counties which the ultrasound
examination is not available for all pregnant women on the
third trimester.
Ultrasonography
If FGR is suspected, ultrasonography should be used to
confirm the diagnosis. The estimated fetal weight accord-
ing to the ultrasound is one of the methods of FGR screen-
ing and diagnosis; it provides data to determine etiology.
The measurement of AC is lower in the presence of FGR
because of decreased liver size, reduced glycogen storage,
and depletion of adipose tissue in the abdominal region.
In isolation, AC measurement is the most sensitive param-
eter for detecting FGR [36, 37]. Specificity (89.8%) and
negative predictive value (90.7%) of AC measurement are
higher than those of estimated fetal weight for the detection
of FGR, which indicates that when AC measurements are
within the normal range, the presence of FGR is extremely
unlikely [30]. Estimates of fetal weight using in equations
measurements of AC, HC, biparietal diameter (BPD), and
FL are more accurate. Biometric ratios are also important
for the evaluation of FGR, and the HC/AC and FL/AC
ratios are more accurate for the detection of FGR associ-
ated with asymmetrical placental insufficiency [38, 39].
Prospective evaluation of the individual fetal growth
curve is also a tool used to differentiate SGA fetuses from
those with FGR. Fetuses with consistent growth percen-
tiles in subsequent evaluations associated with the umbili-
cal artery Doppler and a normal amniotic fluid index have
lower chances of adverse events. The sensitivity of isolated
fetal weight to predict FGR and adverse outcomes asso-
ciated with FGR is higher for fetuses with severe growth
restriction and estimated fetal weight < the third percentile
[40].
In addition to the anthropometric parameters, ultra-
sounds can assess fetal viability through the biophysical
fetal profile (BPF). The sequence of changes in the bio-
physical activities of the fetus in the presence of hypoxia
follows the inverse order of its establishment during embry-
ogenesis. Therefore, the fetal heart rate is the first param-
eter to deteriorate, followed by respiratory movements,
bodily movements, and the tonus, in that order. These are
considered acute markers of fetal vitality. The decrease in
amniotic fluid is a chronic marker of vitality. The proposed
mechanism is the decreased production of fetal urine due to
hypoxia induced by the redistribution of blood flow to vital
organs, to the detriment of others [41]. The presence of oli-
goamnios may suggest a diagnosis of FGR and the asso-
ciated extent to which the fetus is compromised when the
rupture of membranes, genitourinary malformations, and
post-term pregnancy are excluded.
Doppler velocimetry
The Doppler enables the non-invasive detection of signs of
placental insufficiency and of fetal hemodynamic changes
13

that occur during oxygen deprivation. This analysis can
be performed using the uterine arteries (maternal circula-
tion), umbilical arteries (feto-placental circulation), and
other fetal vessels [cerebral artery, abdominal aorta, renal
artery, ductus venosus (DV), and transverse sinus]. Using
the Doppler, it is possible to identify restricted fetuses at
risk of hypoxia, which corresponds to approximately 40%
of cases [40]. In addition, it enables the differential diagno-
sis of pathological restrictions, i.e., between fetuses that are
deficient in nutrients or have hypoxia and require intensive
management and those that are constitutionally small, in
which case, a more conservative treatment can be adopted.
In addition, it contributes to the investigation of possible
etiological such as aneuploidy and congenital syndromes.
There is consensus that its use significantly reduces perina-
tal mortality as well as iatrogenic prematurity and its com-
plications [42].
Uterine artery Doppler
The uterine artery Doppler plays a key role in the diagno-
sis of abnormal placentation. A previous study aimed to
evaluate this technique between 11 and 14 weeks, particu-
larly for the prediction of pre-eclampsia, a condition that
is very frequently associated with FGR. The authors used
the mean PI uterine artery Doppler as parameter using
a cutoff >2.35 (sensitivity for isolated prediction of FGR
and needed for delivery <32 weeks due FGR of 11.7 and
27.8%, respectively) [43]. It can also be re-evaluated during
Fig. 1  Uterine artery Doppler
with increased resistance and
diastolic notch
13
Arch Gynecol Obstet
the second trimester, because it identifies pregnancies with
a risk of placental failure, pre-eclampsia, and SGA through
increased resistance (mean PI uterine artery > 95th centile)
with or without the presence of unilateral or bilateral dias-
tolic notch [44] (Fig. 1).
A recent consensus established the importance of evalu-
ation using a uterine artery Doppler, particularly in cases
of early onset FGR (<32 weeks). PI of the uterine arter-
ies > the 95th percentile associated with estimated fetal
weight or with AC < the 10th percentile represents a suffi-
cient parameter for FGR diagnosis [21].
CPR
The classic model of Doppler abnormalities described
by Carrera [45] involves four sequential periods of fetal
response to hypoxia, clearly defined as follows: (1) a silent
period of increased vascular resistance; (2) a reduction in
umbilical flow; (3) centralization of flow; and (4) decen-
tralization of flow. This sequence of progressive changes in
the process of fetal hemodynamics centralization has been
questioned, and new methods of the diagnosis and predic-
tion of adverse outcomes have been proposed.
Recent publications have showed that even fetuses with
FGR with normal uterine artery Doppler are of risk for
adverse perinatal outcomes [46].
Thus, CPR calculated as the product of PI of the medial
cerebral artery and PI of the umbilical artery is another
tool to assist assessment and management. First, described
Arch Gynecol Obstet
in 1980, an abnormal CPR has recently been associated
with adverse perinatal outcomes, higher admission rates in
intensive care units (NICUs), post-natal neurological defi-
cits, and lower Apgar scores. DeVore [47] reviewed stud-
ies in which CPR was evaluated in both normal and SGA
fetuses to determine whether the test should be conducted
in clinical practice. An abnormal CPR was a better predic-
tor of adverse events than the biophysical profile in cases
of early onset FGR. In normal for gestational age fetuses,
an abnormal CPR could predict fetal distress during labor.
The high specificity of CPR could help in the selection of
fetuses at risk that require closer monitoring.
The recent consensus over the Delphi method has also
extended the concept to identify the largest share of fetuses
that are at risk of an unfavorable outcome using severe
FGR (estimated fetal weight < the third percentile), CPR,
and the uterine artery Doppler as the main factors [21].
There are some studies with different abnormal CPR
(ratio <1.00, ratio <1.08, <5th centile for gestational age,
MoM < 0.6765) [47]. In our service, we consider an abnor-
mal CPR < 1.08.
Umbilical artery, medial cerebral artery, and fetal
hemodynamic centralization
The umbilical artery Doppler reflects placental vascu-
lar resistance, which is strongly correlated with placental
insufficiency. Under normal conditions, umbilical artery
resistance gradually decreases during pregnancy, and the
reverse occurs under placental insufficiency conditions
[40]. During the silent period and despite poor placen-
tal adaptation, fetal hemodynamics are normal, even with
the obliteration of up to 50% of placental vessels, with no
increase in resistance in the umbilical arteries [48]. The
reduction in placental flow is the first hemodynamic signal
of a placental lesion, with impaired villi microcirculation
[49]. Thus, placental lesions are associated with a decrease
in umbilical artery perfusion, increasing PI and RI uterine
artery Doppler values (Fig. 2).
Fetal hemodynamic centralization is the next step in fetal
deterioration in response to placental insufficiency. There is
selective vasodilation to preserve major organs (the brain,
heart, and adrenals) and vasoconstriction in other organs
(the kidney, lung, intestine, skin, and bones) in fetuses with
hypoxemia [42] (Fig. 3). Figure 4 shows the process of bio-
physical and hemodynamic changes in the context of FGR.
Thus, the fetal hemodynamic centralization process wors-
ens umbilical artery PI, with a loss of its diastolic com-
ponent until it becomes inverse, in addition to increasing
the resistance in the distal thoracic aorta with a higher PI.
Next, the ratio between PI of the medial cerebral artery and
the umbilical artery becomes smaller than 1.0 because of
cerebral vasodilation, determined by the decrease in PI of
the medial cerebral artery.
DV plays an important role in delaying the fetal hemo-
dynamic centralization process by redirecting a significant
amount of blood from the fetal liver to the heart, thereby
ensuring more blood flow to the heart and brain [50]. Dur-
ing this period, many fetuses with FGR have more intrapar-
tum stress, and consequently, the rate of cesarean delivery
is higher, but there is no acidosis. The increase in DV flow
is enabled by two factors: the existence of innervation and
that of musculature in the anastomosis of the umbilical vein
in the hepatic portal system, leading to the enlargement of
DV and increase in resistance in the right hepatic vein [51].
In addition, there are more α-adrenergic receptors in the
affluent vessels of the hepatic veins than in DV, which can
contribute to a functional difference, i.e., the response of
hepatic veins to catecholamines is greater than that of DV
[52].
The occurrence of decelerations in antepartum cardioto-
cography has a 2-week delay between the onset of hemo-
dynamic centralization and changes in formation. It can be
concluded that Doppler abnormalities precede changes in
the biophysical profile. The presence of abnormalities in
cardiotocography corresponds to 77% of fetal hypoxia or
acidosis cases. In addition, there are changes in the amni-
otic fluid index and in the loss of cardiac automatism,
with decreased reactivity. The period in which these find-
ings appear depends on the ability of the fetus to reduce
its metabolic rate [53]. The disappearance of the diastolic
component on the umbilical artery Doppler coincides with
changes in the acid–base balance [54, 55]. Perinatal mortal-
ity is higher in this group, with several neonatal complica-
tions due to vasoconstriction in several organs [54].
Preceding fetal death, there is generalized vasoplegia
and irreversible hemodynamic changes, a period referred to
as flow decentralization [38]. Cerebral edema is the result
of the accumulation of lactic acid during the period of
hypoxia and anaerobic respiration, altering cell membrane
permeability and increasing intracellular osmotic pressure
with the appearance of necrosis and edema [39]. Because
of edema, difficulty in cerebral perfusion occurs, with the
appearance of highly resistant flow rate waves on the Dop-
pler of the medial cerebral arteries, even without the dias-
tolic component. Concomitantly, changes in the umbilical
area persist, and in some cases, a false normalization of this
area may occur, while persistent changes in the venous sys-
tem persist.
Venous Doppler velocimetry
The flow rate wave in DV is clearly pulsatile, with three
components. The flow rate is high during ventricular sys-
tole (S wave) and ventricular diastole (D wave), with two
13

Fig. 2  Normal umbilical artery
Doppler (a) and reversed dias-
tolic component (b)
anterograde components. The third component is still
anterograde, with a lower speed than the others during
arterial contraction (A wave). Ductus venosus can have
its wave flow adjusted by the A wave (atrial contraction),
making it reverse (Fig.  5). In this context, the umbilical
vein Doppler may present abnormal pulsations.
13
Arch Gynecol Obstet
The venous area provides information on the cardiovas-
cular response of the fetus. Fetuses experiencing hypoxia
and an altered hemodynamic profile or hemodynamic
centralization have gradual changes in venous flow. The
peripheral vasoconstriction that develops in the fetal flow
centralization process promotes increased pressure in the
Arch Gynecol Obstet
Fig. 3  Normal medial cerebral
artery Doppler (a) and Doppler
with low resistance (b)
heart chambers, followed by changes in the venous area.
There is an increase in reverse flow in the inferior vena
cava up to 30% of the total flow; under normal conditions,
it reaches only 10% [56]. Increase in blood flow through
ductus arteriosus due to hepatic vasoconstriction is associ-
ated with hypoxic myocardium and consequent reverse or
absent flow in DV Doppler during atrial contraction.
The importance of the venous Doppler, and of the DV
Doppler in particular, should emphasized in the prediction
of adverse perinatal outcomes in fetuses with FGR and in
premature infants. All neonatal complications have been
found to increase in the presence of abnormal DV Doppler
findings [57]. Fetal acidosis is present when DV is changed,
which increases the incidence of neonatal complications.
Carvalho et al. [58] analyzed 47 pregnancies with placental
insufficiency to evaluate the DV Doppler and its ability to
predict fetal acidosis at birth. The cut-off PI of DV for pre-
dicting acidosis was 0.76. The percentile curve of PI of DV
is also a tool that can be used to determine the management
strategy, particularly in cases of extreme prematurity and
13

Fig. 4  Flowchart of the process of biophysical and hemodynamic
changes in the context of fetal growth restriction
limited fetal viability. When PI is above the 95th percentile,
there is a greater risk of hypoxia [59].
Adaptive cardiac mechanisms
The heart is the central organ in the adaptive process and
increased atrial natriuretic peptide and echocardiographic
abnormalities in SGA newborns have been reported [55].
Another study showed that these fetuses had early cardiac
impairment, including changes in ejection fraction and in
the myocardial performance index (MPI), which often pre-
ceded hemodynamic centralization [60]. Some epidemio-
logical studies have shown that FGR and low birth weight
are risk factors for cardiovascular disease and hyperten-
sion in adulthood, probably because of cardiac underde-
velopment and cardiovascular adaptations of these fetuses
in utero, including left ventricular hypertrophy due to
increased flow, which is a consequence of fetal hemody-
namic centralization.
Ischemia leads to cell necrosis and the release of pro-
teins that are in the contractile apparatus of the myocar-
dial striated muscle, which can be measured in the blood.
Among these proteins, the troponin complex, particularly
cardiac troponin I, can diagnose microscopic lesions due to
its high tissue specificity and high sensitivity [61]. When
there is severe impairment of uteroplacental circulation, the
compensating hemodynamic and metabolic mechanisms
in the fetus reach their limits, and myocardial oxygenation
is insufficient to provide adequate contractility and effec-
tive blood ejection. Hypoxic myocardiopathy occurs with
ventricular dysfunction and a consequent decrease in car-
diac output. Recent studies have shown that plasma con-
centrations of troponin I, which are detectable in umbili-
cal cord blood, are associated with fetal hemodynamic
13
Arch Gynecol Obstet
centralization, with changes in the DV Doppler, with aci-
dosis at birth, and with SGA fetuses. These findings may
represent another parameter to be considered when making
a decision regarding the best time for the birth of fetuses
with placental insufficiency and growth restriction. There-
fore, it is very important to monitor the cardiac function of
fetuses with growth restriction to assess severity and pre-
vent adverse perinatal outcomes, including future cardiac
sequelae.
Fetal growth restriction (FGR) leads to cardiac dysfunc-
tion in the fetus that may persist after birth. In this situa-
tion, fetuses redistribute their circulation and oxygenation
to prioritize the brain. New cardiovascular parameters are
being proposed for the evaluation of fetal well-being, such
as the evaluation of the aortic isthmus and MPI. The fetal
aortic isthmus (FAI) is an arterial connection between
brain and placental circulations, and the quantification of
its flow has been proposed as a method for assessing fetal
hemodynamic centralization in clinical practice [62]. Cer-
ebral vasodilatation plays an important role in the reduc-
tion of the diastolic flow of FAI, and abnormal impedance
indices are intermediaries between hypoxemia–placental
insufficiency and cardiac decompensation, with potential
application in clinical practice [63]. However, other clinical
studies have suggested that the flow pattern in FAI is simul-
taneously influenced by placental peripheral resistance and
cerebral resistance [64–67]. Canadilla et al. [62] observed
that with the progression of the FGR, the diastolic flow of
FAI decreased, and in very severe cases, it became mark-
edly reversed. Based on this finding, FAI can be considered
to be a good predictor of poor perinatal neurodevelopment
and of a high risk for adverse perinatal outcomes and mor-
tality [68–70].
Myocardial performance index (MPI), a global cardiac
parameter that assesses both systolic and diastolic functions
of the myocardium, has also been found to be elevated in
fetuses with FGR [71–73], with a linear correlation with
stages of hemodynamic severity [74]. Hernandez-Andrade
et  al. [69] evaluated MPI, the FAI Doppler, and the DV
Doppler to predict mortality in fetuses with early onset
FGR. They determined that the combination of MPI and
the DV Doppler is a better predictor of fetal mortality.
Management
Because there is no effective treatment to reverse or stop
the progression of placental insufficiency, the evaluation
of fetal vitality and the decision regarding when delivery
should take place are the main strategies in the manage-
ment of these fetuses [75]. Studies have been conducted
in an attempt to develop a treatment for FGR, including
maternal nutritional supplementation, bed rest, oxygen
Arch Gynecol Obstet
Fig. 5  Flow rate waves on a
normal ductus venosus Doppler
(a) and an abnormal Doppler
(b)
therapy, the use of aspirin, and the use of sildenafil, but
there has been no evidence of benefits in the natural course
of the disease [76]. In pregnant smokers, smoking cessation
may be beneficial [76].
In a clinical trial entitled “The Growth Restriction Inter-
vention Trial”, women with fetuses with FGR between
24 and 36 weeks of gestation were randomly classified
into two groups, namely immediate delivery (n = 291)
and expectant management (n = 291), when obstetricians
were in doubt about when to indicate delivery. Of these
patients, 40% had zero or reversed diastolic flow on the
umbilical artery Doppler. The immediate delivery group
had fewer stillbirths (2 versus 9 in the expectant group);
however, it had more neonatal and infant deaths (27 ver-
sus 18), particularly in patients with gestations <31 weeks
[77]. The 13-year follow-up of children showed no dif-
ferences between groups in terms of cognition, language
skills, motor skills, or behavioral development [78]. These
13

data suggest that expectant management of very premature
restricted fetuses, when there are questions about the time
of delivery, will result in some fetal deaths, but immedi-
ate delivery results in a similar number of neonatal deaths.
Neither of the two methods produced a better neurological
outcome.
In a study entitled “TRUFFLE: A trial of umbilical and
fetal randomized flow in Europe”, neurodevelopment was
assessed at 2 years after delivery for cases of fetuses with
early onset FGR born before 32 weeks. The patients were
divided into three groups on the basis of the delivery time
and different fetal vitality assessment strategies, such as
reducing the short-term variation in computerized cardi-
otocography, early changes in DV (95th percentile), and
late changes in the DV (zero wave). Most deliveries were
recommended for reasons other than changes that recom-
mended delivery in each group. The groups that were based
on the DV Doppler used cardiotocography as a safety cri-
terion, whereas in the cardiotocography group, a safety
criterion was not applied to the DV Doppler. The hypoth-
esis was that a slight worsening in the prognosis of the
cardiotocography group could be explained by the lack of
information from the DV Doppler. Therefore, the authors
concluded that to optimize the decision regarding the time
of delivery in cases of early onset FGR, fetuses should be
monitored longitudinally using a DV Doppler and comput-
erized cardiotocography [79].
Although many studies have been conducted, there is
a lack of consistent evidence to safely recommend a spe-
cific time of delivery in cases of FGR. The objective of a
clinical protocol for the management of FGR is to com-
bine the existing evidence on various methods for assess-
ing fetal vitality (cardiotocography, biophysical profile, and
Doppler) to achieve better growth and lung maturity and
minimize the risk of morbidity as well as fetal and neo-
natal mortality. This decision is often based on the gesta-
tional age, etiology of growth restriction, extent to which
the fetus is compromised, and experience and technologi-
cal resources available for the evaluation of the fetus and
for neonatal treatment. The delivery should be prefer-
ably performed in a tertiary hospital. In the management
of these fetuses, the first important step is to try to distin-
guish cases of true FGR, which is associated with placen-
tal insufficiency and worse perinatal outcome, from cases
of constitutionally small fetuses, which have normal peri-
natal outcomes overall [46]. Cases of early and late-onset
FGR are easily distinguishable when considered in groups.
However, when dealing with fetuses individually, clinical
features may overlap, particularly in terms of borderline
gestational ages. Therefore, the same management protocol
can be used to monitor and decide the delivery time in both
the groups [6].
13
Arch Gynecol Obstet
A type of management described in the literature is to
group patients into stages of development on the basis of
the follow-up results, birth time, and similar fetal risks
[46]. Based on the evidence available in the literature and
the characteristics of our practice, of our patient population,
and of our obstetricians in the Department of Gynecology
of the Paulista Medical School at the Federal University of
São Paulo (UNIFESP), we follow the management protocol
based on the stages of FGR development.
SGA fetuses
These are fetuses with an estimated weight between the
third and tenth percentiles, without Doppler changes. The
evaluation of fetal vitality (Doppler and biophysical profile)
and growth may be performed every 2 weeks. If the patient
does not go into labor spontaneously, labor may be induced
at 40 weeks. It is recommended to avoid the use of pros-
taglandins in the induction of labor because of the risk of
hyperstimulation in fetuses that may have some degree of
placental injury [46].
FGR with normal Doppler: stage 1
For fetuses in which the estimated fetal weight is below the
third percentile without Doppler changes, the evaluation of
fetal vitality (Doppler and biophysical profiles) and growth
may be performed every week. Birth may be induced care-
fully at 38 weeks, but the use of prostaglandins should be
avoided [46]. If the estimated weight percentile is less than
1, delivery should be considered at 37 weeks.
FGR with moderate placental insufficiency (with
Doppler changes): stage 2
In case of the presence of umbilical artery PI > the 95th
percentile, median cerebral artery PI < the fifth percentile,
or CPR < the fifth percentile on the Doppler, the evaluation
of fetal vitality (Doppler and biophysical profile) may be
performed every week. In our practice, we monitor vital-
ity twice a week and consider the hospitalization of patients
after 34 weeks to optimize clinical management. Evidence
suggests a low risk of fetal impairment before the end of
the term, but it does not show benefits in maintaining preg-
nancy after the term is reached. The induction of birth at 37
weeks is acceptable, but the use of prostaglandins should
be avoided. Furthermore, there is also the risk of intrapar-
tum fetal distress [19]. If it is not possible rigorous fetal
monitoring or there is suspected or abnormal test, CTG or
biophysical profile, delivery should be considered between
34 and 37 weeks of gestation to avoid adverse perinatal
outcome.
Arch Gynecol Obstet

FGR with severe placental insufficiency (Doppler
of the umbilical artery with zero diastolic flow): stage 3
In case of zero diastolic flow on the umbilical artery Dop-
pler or reversed diastolic flow on the FAI Doppler, fetal
monitoring every 2 or 3 days is acceptable [79]. To opti-
mize the control of fetal well-being in our practice, patients
are hospitalized and evaluated daily (Doppler, fetal bio-
physical profile, and cardiotocography). Delivery at 34
weeks by the elective cesarean section is recommended,
because the risk of fetal distress in labor induction exceeds
50% [46].
FGR with advanced fetal deterioration (umbilical
artery Doppler with reversed diastolic flow or dv
with pi > 95th percentile): stage 4
In case of the presence of reversed diastolic flow on the
umbilical artery Doppler or PI > the 95th percentile on the
DV Doppler, there is a high risk of fetal death and impaired
neurological development. Hospitalization and daily fetal
monitoring (Doppler, biophysical profile, and cardiotocog-
raphy) are recommended. Delivery is recommended at 30
weeks [46]; however, in our practice, we perform delivery
by the elective cesarean section, depending on the avail-
ability of NICUs.
FGR with high probability of fetal acidosis and high
risk of fetal death (Doppler of dv with reversed wave,
computerized cardiotocography <3 ms, or decreased
fetal heart rate): stage 5
receive counseling according to the data of viability with-
out sequelae and their opinion should be taken into consid-
eration in the delivery decision [46].
At any stage, when any change indicates an accelera-
tion in disease progression, for example the presence of
pre-eclampsia or a sign indicating fetal deterioration, the
frequency of fetal monitoring should be increased until the
gestational age for delivery is reached. Fetal monitoring
should begin between 24 and 26 weeks and should prefer-
ably be performed by combining the available tests (Dop-
pler, fetal biophysical profile, and cardiotocography) to
improve the prediction of acidosis and fetal death [80].
The prenatal use of corticosteroids should occur
between 24 and 34 weeks, preferably in the week preced-
ing the scheduled date for delivery, to accelerate fetal lung
development and to reduce the risk of intracranial hemor-
rhage [76]. However, shortly after the use of corticoster-
oids, the Doppler indices may present an improvement that
is only transitory. The responsible mechanisms for Doppler
alterations after corticosteroids administration are not well
established. Experimental and human studies have showed
increased blood pressure after corticosteroids administra-
tion. Another possible reason is a reduced placental resist-
ance as result of nitric oxide mediated vasodilatation nitric
oxide mediated as consequence of increased secretion of
placental corticotropin releasing hormone [81].
For deliveries before 32 weeks, the use of magnesium
sulfate is recommended for neuroprotection [76]. Table  1
presents the management of fetuses with FGR according to
the stages of evolution, as proposed by our practice.

In case of a DV Doppler with a reversed wave, short-term Neurological complications

variation in computerized cardiotocography <3  ms or
decreased fetal heart rate, delivery by the elective cesar- Studies have shown that restricted fetuses and SGA fetuses
ean section is recommended, depending on the availability (even those without Doppler abnormalities) are at a high
of NICUs. For younger gestational ages, parents should risk of obstetric complications and neonatal sequelae in

Table 1  Management of fetuses with growth restriction according to stages of progression: protocol from the Department of Obstetrics of Pau-
lista Medical School, Federal University of São Paulo (EPM-UNIFESP)
Stage Description Viability monitoring Birth

SGA fetus 3rd > EFW < 10th Monitor viability every 2 weeks Birth at 40 weeks

Stage 1 EFW < 3rd Monitor viability every week Birth at 38 weeks
EFW < 1st Birth at 37 weeks
Stage 2 Abnormalities in UA, MCA, or CPR Monitor viability twice a week Birth at 37 weeks
Stage 3 Zero diastole in UA Hospitalization and daily monitoring Birth at 34 weeks (elective cesarean)
Stage 4 UA with reversed diastole or DV PI > 95th Hospitalization and induced labor Labor when viable (26–28 weeks) (elective
cesarean)
Stage 5 Reversed wave DV/STV in cCTG < 3 ms or Hospitalization and induced labor Labor when viable 26–28 weeks (elective
decreased FGR cesarean)

SGA small for gestational age, EFW estimated fetal weight, UA umbilical artery, MCA medial cerebral artery, CPR cerebroplacental ratio, PI pul-
satility index, DV ductus venosus, cCTG computerized cardiotocography, STV short-term variation, FGR fetal heart rate

13

both childhood and adulthood [82]. With regard to neural
development, it was thought that the fetal brain was pro-
tected (even in cases of abnormal umbilical artery Dop-
plers) because of the mechanisms of fetal hemodynamic
centralization. However, more recent studies, such as the
systematic review from 2012, found that full-term neonates
that were SGA experienced worse neurodevelopmental
scores than normal-weight neonates [83].
Baschat concluded that HC size is the single most
important factor in neurological prognosis. Smaller
cephalic pole and brain sizes are associated with psycho-
motor retardation, cognitive delay, and childhood behavior
disorders, followed by persistent cognitive delay, speech
delay, motor dysfunction, and impaired school performance
until adolescence. These changes have been documented in
cases of both early and late-onset FGR, regardless of Dop-
pler parameters [20]. Caetano et  al. [84] concluded that
the volumes of the intracranial structures, particularly the
frontal lobe volume/brain volume ratio, measured by three-
dimensional ultrasonography, were decreased in fetuses
with FGR  < the third percentile and normal umbilical
artery Doppler results [84]. Another study used magnetic
resonance spectroscopy to compare metabolic differences
between the brains of SGA fetuses and fetuses with FGR
near term and fetuses with appropriate weight for gesta-
tional age. Both SGA fetuses and those with FGR exhibited
significant metabolic changes in the brain [85].
A systematic review published in 2015 evaluated 38
studies on children between 1 month and 12 years of age.
The authors collected data on cognitive, behavioral, lan-
guage, motor, and visual development as well as on sleep
habits. They concluded that FGR increased the risk of
changes in neurological development during childhood.
Children with FGR who were born prematurely or with evi-
dence of intrauterine circulatory redistribution were more
severely affected [86]. Recent evidence shows that SGA
fetuses and fetuses with FGR have a higher risk of impaired
neurological development in childhood. Therefore, better
identification of these fetuses at an early gestational age
could benefit these children through monitoring and mul-
tidisciplinary treatment to reduce the possible impact on
neurological outcomes [86].
Critical analysis
In this study, current aspects of FGR are presented. Diag-
noses and management of FGR are still a challenge due
to not well established physiopathology. The main goal is
the difference SGA, which includes constitutionally small
and healthy fetuses, and FGR, which includes fetuses with
placental impairment and of high risk for adverse perina-
tal outcomes. In this article, we used the definition of FGR
13
Arch Gynecol Obstet
based on Delphis Consensus, which seems to be appro-
priated for us but still needs to be validated in the clinical
practice. Another important aspect presented in the present
review is the latest and most used classification of FGR
based on time of onset. Early and late-onset FGR show dif-
ferent pathogenesis, diagnosis, management, and prognosis.
As the FGR is a disease of difficult diagnosis, espe-
cially the late-onset, prediction is important to distinguish
pregnant women who should be closer monitored. Several
aspects have been studied about the FGR prediction; how-
ever, there is no single and effective marker for predicting
FGR. The set of clinical, biochemical, and Doppler param-
eters seem to be the most effective method for the predic-
tion of FGR.
Assessment of fetal well-being and time of delivery are
the main management strategies in the FGR, because it is
not an effective clinic treatment until at this moment. This
study brings the experience of Department of Obstetrics,
São Paulo Federal University, Brazil, and our management
proposal is based on the recent literature.
Conclusion
Fetal growth restriction (FGR) is a multifactorial syndrome
that may be defined as a condition in which the fetus does
not reach its intrauterine potential for growth and develop-
ment, which consequently compromises placental function.
The early diagnosis of FGR may enable etiological iden-
tification of the condition and adequate monitoring of the
fetal status, thereby minimizing risks of premature birth
and intrauterine hypoxia.
Author contributions  LMN Project development, Supervision.
ACRC—manuscript writing. ACPZ—manuscript writing. JBM—
manuscript writing. CPS—manuscript writing. VMGM—search on
the literatute. TFL—search on the literature. ABP—critical review.
EAJ—Critical review.
Compliance with ethical standards 
Funding  This study was not funding.
Conflict of interest  The authors declare no conflict of interest.
Ethical approval  This article does not contain any studies with
human participants or animals performed by any of the authors.
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