Fetal growth restriction: Evaluation

INTRODUCTION — 

Fetal growth restriction (FGR) is broadly defined as an estimated fetal weight (EFW) or abdominal circumference (AC) <10^th percentile for gestational age. Severe FGR is generally defined as an EFW or AC <3^rd percentile for gestational age; the presence of fetal umbilical artery (UA) Doppler abnormalities also suggests that FGR is severe. However, sonographic criteria for diagnosis of FGR vary (table 1) [1-3]. None of these criteria is ideal for identification of FGR as all have poor performance for predicting adverse neonatal outcome [4]. (See "Fetal growth restriction: Screening and diagnosis", section on 'Diagnosis'.)

Identification of FGR is an integral component of prenatal care as it is a leading cause of perinatal morbidity and mortality [5]. When FGR is suspected, the obstetric provider needs to confirm the suspected diagnosis, determine the probable cause, assess the severity, counsel the pregnant person, closely monitor fetal growth and well-being for the remainder of the pregnancy, and determine the optimal time for and route of birth.

Although FGR is not a homogeneous entity, suboptimal placental function (placental insufficiency) is a common pathway to many forms of FGR. It can be present in patients with pregnancy-associated hypertension, chronic hypertension, chronic kidney disease, maternal or fetal infection, diabetes with vasculopathy, and fetal aneuploidy. In these cases, the fetus is closely monitored to identify those who are at highest risk of perinatal demise and thus may benefit from early delivery.

This topic will discuss the evaluation of FGR in singleton pregnancies. Screening, diagnosis, pregnancy management, and outcome are reviewed separately. (See "Fetal growth restriction: Screening and diagnosis" and "Fetal growth restriction: Pregnancy management and outcome" and "Fetal growth restriction (FGR) and small for gestational age (SGA) newborns".)

FGR in twin pregnancies is also reviewed separately. (See "Twin pregnancy: Routine prenatal care", section on 'Screening for fetal growth restriction and discordance' and "Selective fetal growth restriction in monochorionic twin pregnancies".)

INITIAL EVALUATION — 

The diagnosis of FGR is established sonographically (see "Fetal growth restriction: Screening and diagnosis"). The pregnancy is then evaluated to determine whether fetal growth is impaired as a result of maternal, fetal, or placental processes (table 2). However, this determination cannot always be made antenatally, despite the following evaluation. When no maternal and/or fetal predisposing factors are found, FGR may be termed idiopathic or isolated [6,7].

All cases

Determine the size percentile — Fetuses <3^rd percentile are at greatest risk of adverse outcome. Most fetuses with EFW or AC between the 5^th and 10^th percentiles are constitutionally small and thus have normal neonatal outcomes [8,9]. However, they still need to be monitored closely because a proportion are FGR and at increased risk of adverse outcome.

●In a population-based retrospective cohort study composed of all singleton term pregnancies in Scotland between 1992 and 2008, the overall association between birth weight percentile and risk of perinatal death had a reverse J-shaped distribution [10]. Birth weight <3^rd percentile had the highest relative risk of antepartum stillbirth and the absolute risk of stillbirth in this group was approximately 1 percent.

●In a retrospective study of 834 prenatally suspected FGR cases, composite neonatal morbidity at <5^th percentile was 29 percent versus 15 percent at the 5^th to 9^th percentile (adjusted odds ratio 2.22, 95% CI 1.34-3.67) [9].

●In the Prospective Observational Trial to Optimize Pediatric Health (PORTO), which included over 1100 nonanomalous fetuses with EFW <10^th percentile at 24+0 to 36+6 weeks of gestation, only 2 percent of those at the 3^rd to 10^th percentile (5 of 254) experienced adverse perinatal outcome, while 6.2 percent of those <3^rd percentile (51 of 826) had an adverse outcome and all eight mortalities were in this group [8]. Adverse perinatal outcome was defined as intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, or death.

Identify maternal and obstetric factors associated with FGR — The medical and obstetric history and physical examination help to identify maternal and obstetric factors that have been associated with restricted fetal growth (table 2).

Maternal characteristics have a major influence on fetal growth potential. For example, when race/ethnicity was taken into account, the 5^th percentiles for White, Hispanic, Black, and Asian populations at 39 weeks of gestation were 2790, 2633, 2622, and 2621 grams, respectively, in a prospective study of over 2300 healthy individuals with low-risk, singleton pregnancies from 12 medical centers in the United States [11]. Using biometric standards derived solely from the group of fetuses from the White population, as many as 15 percent of the fetuses from other groups would have been classified as growth restricted (<5^th percentile).

Although pregnancy-associated hypertensive disorders are commonly considered causal factors of FGR, a study by the National Institute of Child Health and Human Development (NICHD) found that only preeclampsia with severe features, especially when it begins before 34 weeks of gestation, was associated with a significant and consistent impairment in fetal growth compared with normotensive pregnancies [12]. Growth impairment was observed as early as 22 to 23 weeks of gestation and could precede the maternal symptoms that characterize the disorder.

Perform a detailed fetal anatomic survey — A detailed fetal anatomic survey should be performed in all cases since approximately 10 percent of FGR is associated with congenital anomalies [13] and 20 to 60 percent of anomalous infants are small for gestational age [14]. These anomalies include omphalocele, gastroschisis, diaphragmatic hernia, skeletal dysplasia, some congenital heart abnormalities, and rarely congenital portosystemic shunts [15]. Although omphalocele and gastroschisis can be associated with FGR, the AC is distorted by the anomaly in these cases, limiting the utility of biometric measurements for diagnosis of FGR. (See "Gastroschisis", section on 'Assessment of fetal growth and amniotic fluid volume' and "Omphalocele: Prenatal diagnosis and pregnancy management", section on 'Fetal follow-up'.)

A fetal echocardiogram is indicated if there is uncertainty about normal cardiac development on a detailed ultrasound examination or when standard indications are present (eg, fetal chromosomal or anatomic abnormalities) [16]. (See "Congenital heart disease: Prenatal screening, diagnosis, and management".)

Selected cases

Work-up for genetic abnormalities

●Genetic causes of FGR – Genetic causes of FGR are listed in the table (table 3) and selectively discussed in more detail below:

•Aneuploidy – In a systematic review, the risk of chromosomal abnormalities in apparently isolated FGR was 6.4 percent [17]. Trisomy 21 and 18 accounted for five and three cases, respectively, of the 22 cases with numeric abnormalities. However, the authors emphasized that the small number of cases and low quality of evidence limited an accurate estimate for chromosomal abnormalities in pregnancies with isolated FGR. Others have also reported an increased risk of FGR in trisomy 21 pregnancies without severe structural anomalies [18] and with trisomy 13 [19].

Triploidy of paternal origin (diandric) is characterized by symmetric FGR with associated structural abnormalities in most cases and an enlarged placenta with hydropic and cystic changes (often a partial mole) [20,21]. Triploidy of maternal origin (digynic) is nonmolar and characterized by asymmetric FGR and a small placenta; holoprosencephaly may be present. Both types of triploidy may have oligohydramnios and abnormal Doppler velocimetry [21]. Fetuses with digynic triploidy are more likely to survive to the second trimester than those with diandric triploidy.

•Monogenic disorders – Fetuses with FGR related to monogenic disorders (eg, Cornelia de Lange, Smith-Lemli-Opitz, Meier-Gorlin, Noonan syndromes [19]) often have other findings, including thickened nuchal fold, congenital heart disease, and limb reduction defects. The pediatric outcome is often due to the abnormalities present in each case, and neurodevelopment may be either normal or show moderate to severe intellectual disability.

•Confined placental mosaicism – CPM increases the risk for FGR at least three-fold [22,23] and is present in about 10 percent of cases with unexplained FGR [24,25]. CPM of chromosomes 2, 7-10, 13-18, 21, and 22 is disproportionately found in FGR fetuses. CPM for trisomy 16 deserves special consideration as it is estimated to complicate approximately 1 percent of all pregnancies and is associated with FGR in 43 to 58 percent of cases [21]. It has also been associated with fetal anomalies, preeclampsia, and preterm birth.

•Uniparental disomy – Genes related to fetal growth are differentially expressed depending on the parent of origin. Imprinted genes control placental development, nutrient exchange, and growth rate. Uniparental disomy is rare and can lead to dysregulation of imprinted genes. The most common of these is uniparental disomy of chromosome 7 leading to Silver-Russell syndrome. Other causes are listed in the table (table 3).

•Epigenetic changes – Although epigenetic changes (modification of gene expression rather than differences in the DNA coding sequence) are emerging as key regulators of placental function, methods and utility of clinical testing for these changes as a cause of FGR remain investigational. Many cases of Silver-Russell syndrome are due to epigenetic alterations involving hypomethylation of an imprinting control region that regulates expression of the insulin-like growth factor 2 gene or others on 11p15.5 chromosome.

●Candidates for genetic studies – We suggest offering fetal genetic testing to patients in any of the following settings:

•Early FGR – Isolated FGR diagnosed before 32 weeks of gestation, especially if <3^rd percentile, in the absence of an identifiable nongenetic cause of the growth restriction. Fetal genetic testing is typically not performed when isolated FGR develops later in pregnancy since the risk is low in such cases [17,20,21].

•Anomalous fetus – FGR with major fetal structural abnormalities or ultrasound markers associated with an increased risk of aneuploidy, such as a thickened nuchal fold or findings suggestive of trisomy 18 or triploidy. (See "Sonographic findings associated with fetal aneuploidy".)

•Polyhydramnios – FGR with polyhydramnios. In a retrospective study, chromosomal anomalies accounted for most cases of FGR with polyhydramnios (64 out of 153, 41.8 percent) [26]. Other etiologies included complex malformation syndromes (24.1 percent), isolated malformations (15.7 percent), and musculoskeletal disorders (9.2 percent); 9.2 percent of cases had no identified anomaly.

This approach generally aligns with that of the American College of Obstetricians and Gynecologists (ACOG), which suggests genetic counseling and offering diagnostic testing for patients with a diagnosis of FGR before 32 weeks or FGR in combination with polyhydramnios or a fetal anatomic abnormality [27].

●Testing modality – Genetic counseling is useful in helping patients understand the benefits, risks, and limitations of the various genetic testing modalities, including whether to begin with a noninvasive screening test (cell-free DNA [cfDNA]) or a diagnostic test that requires amniocentesis, and when to pursue advanced genetic testing (exome and genome sequencing). In the author's practice, patients with nonanomalous FGR are counseled by a maternal-fetal medicine specialist and a genetic counselor. If the patient chooses to undergo amniocentesis, the author favors chromosomal microarray analysis. If the microarray analysis is nondiagnostic, performing additional genetic testing is controversial; however, exome and genome sequencing are promising approaches.

Genetic testing modalities include:

•Cell-free DNA of maternal blood – Cell-free DNA (cfDNA) is a screening test for trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), trisomy 13 (Patau syndrome), and selected sex chromosome aneuploidies. It has the advantage of being noninvasive, but it is not diagnostic. Test performance is reviewed separately. (See "Prenatal screening for common fetal aneuploidies: Cell-free DNA test".)

•Microarray or karyotype – Microarray or karyotype is performed on cells in amniotic fluid obtained by amniocentesis. Compared with a karyotype, microarray analysis has a higher diagnostic yield as it detects both aneuploidy and microdeletions and duplications, thus it can improve the detection of genetic anomalies, especially in fetuses with nonanomalous FGR [27,28]. In a meta-analysis to estimate the incremental yield of microarray analysis over karyotyping in FGR, microarray had a 4 percent (95% CI 1-6) incremental yield in nonanomalous FGR and a 10 percent (95% CI 6-14) incremental yield in FGR with associated anomalies [29]. The most common pathogenic copy number variants in growth restricted fetuses were 22q11.1 duplication, Xp22.3 deletion, and 7q11.23 deletion. (See "Prenatal diagnosis of chromosomal imbalance: Chromosomal microarray".)

Microarray or karyotype can also be performed on trophoblast obtained by chorionic villus sampling (CVS); however, this test is typically restricted to first-trimester pregnancies and thus before a diagnosis of FGR is typically made. Although CVS will detect confined placental mosaicism (CPM), which can be associated with FGR, we do not perform placental biopsy in the second or third trimester to identify this abnormality antepartum because antenatal diagnosis of CPM would not change pregnancy management and the procedure is associated with a small risk of pregnancy complications.

•Exome and genome sequencing – The appropriate use of exome and genome sequencing in FGR without anatomic abnormalities is under investigation. In a prospective study of 19 small-for-gestational-age newborns without a known cause and with normal karyotype and microarray, three were subsequently found to have a genetic cause with genome sequencing [30]. In a meta-analysis of prospective and retrospective studies, prenatal exome sequencing had 4 percent incremental yield over karyotype or microarray in isolated FGR (7 diagnoses in 70 cases with exome sequencing versus 4 diagnoses in 70 cases with standard karyotype/microarray; pooled risk difference 0.04, 95% CI -0.05-0.12), but was much more informative (30 percent incremental yield) in cases with multisystem anomalies (23 diagnoses in 48 cases with exome sequencing versus 9 diagnoses in 48 cases with standard karyotype/microarray; pooled risk difference 0.30, 95% CI 0.13-0.47), and especially in fetuses with skeletal abnormalities (short long bones and other signs suggestive of skeletal dysplasia) [31]. Another meta-analysis reported exome sequencing had a 12 percent incremental yield in isolated FGR [32].

Work-up for infection — The author obtains serology studies for infection when FGR is associated with sonographic markers of fetal infection (echogenicity and calcification of the brain and/or liver, hydrops) or when a careful maternal history and physical examination suggest the possibility of maternal infection and vertical transmission. He does not perform routine TORCH serology in the evaluation of isolated FGR. If the patient chooses to have diagnostic fetal infection testing for isolated FGR, he performs amniocentesis for polymerase chain reaction (PCR) of amniotic fluid for cytomegalovirus (CMV). In patients who live in or travel to areas where malaria is endemic, malaria should be considered a possible etiology of FGR and excluded (see "Malaria in pregnancy: Epidemiology, clinical manifestations, diagnosis, and outcome"). Similarly, in patients at increased risk for Zika virus infection, congenital Zika virus infection should be considered a possible etiology of FGR and excluded (see "Zika virus infection: Evaluation and management of pregnant patients"). Screening for syphilis one or more times is a routine prenatal test recommended for all pregnant patients. In a literature review of 161 cases of congenital syphilis, 23 (14 percent) had FGR. (See "Syphilis in pregnancy", section on 'Timing of initial and repeat screening'.)

Although infections such as CMV, toxoplasmosis, rubella, varicella, and herpes simplex may be associated with FGR (refer to individual topic reviews on specific fetal infections during pregnancy for a description of the ultrasound findings), use of maternal serology should be limited because, when positive, the time of occurrence of the primary infection is often difficult to determine. This may lead to unnecessary invasive procedures with associated parental anxiety and cost. Due to its low yield, the Society for Maternal-Fetal Medicine recommends against TORCH serology for isolated FGR and recommends PCR of amniotic fluid for CMV in patients with unexplained FGR who elect to have diagnostic testing [1]. In a systematic review including 2538 pregnancies in eight studies, 496 TORCH serologies were performed in patients with FGR (EFW <10^th percentile) [33]. Of this group, 12 were positive (2.4 percent, 95% CI 1.4-4.2%) and 10 congenital infections were detected (eight CMV, two parvovirus B19), but only 2 of the 10 fetuses had isolated FGR (CMV infection was found in both cases). The studies included in this review did not differentiate between early and late FGR (ie, onset <32 versus ≥32 weeks) and there were no cases of rubella or herpes simplex virus.

Maternal COVID-19 does not appear to be associated with an increased risk of FGR [34,35]. However, data on perinatal outcomes when the infection is acquired in early pregnancy are limited, and any condition that results in prolonged maternal hypoxia or placental dysfunction places the fetus at risk for growth restriction. (See "The placental pathology report", section on 'Chronic histiocytic intervillositis'.)

Other

●Antiphospholipid antibodies – Routinely testing for antiphospholipid antibodies (aPLs) is not recommended as there is insufficient evidence to support evaluating all pregnancies with FGR for antiphospholipid antibody syndrome (APS). However, APS has been associated with early-onset placental insufficiency (eg, FGR) resulting in the birth of a morphologically normal neonate before 34 weeks of gestation. Selective aPL testing is reasonable in patients with this obstetric history who also manifest livedo, valvular heart disease, neurologic findings such as cognitive deficits and white matter lesions, a systemic autoimmune disease (especially systemic lupus erythematosus) with appropriate clinical symptoms, and/or laboratory abnormalities such as otherwise unexplained mild thrombocytopenia, prolongation of the activated partial thromboplastin time (aPTT), or a history of a false-positive serologic test for syphilis (Venereal Disease Research Laboratory [VDRL] or rapid plasma reagin [RPR] tests). The table (table 4) shows the most recent classification criteria for APS developed by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) for use in research studies [36]. (See "Antiphospholipid syndrome: Diagnosis", section on 'When to suspect the diagnosis' and "Antiphospholipid syndrome: Diagnosis", section on 'Diagnostic evaluation' and "Antiphospholipid syndrome: Obstetric implications and management in pregnancy".)

●Inherited thrombophilias – Assessment for inherited thrombophilic disorders is not recommended as evidence of an association between the inherited thrombophilias and FGR is weak. (See "Inherited thrombophilias in pregnancy", section on 'Adverse pregnancy outcome risk'.)

SUBSEQUENT EVALUATION — 

After the initial evaluation, additional assessments are performed over time to help distinguish the fetus at increased risk of adverse outcome from the constitutionally small fetus or the fetus who is minimally impacted from a placenta-mediated disorder or other pathologic factors that impair fetal growth and at low risk of adverse outcome. The modalities are described below; our approach to obtaining these assessments and managing the pregnancy based on the findings is provided separately. (See "Fetal growth restriction: Pregnancy management and outcome".)

Novel approaches to risk assessment are being investigated. A probabilistic graphical model (PGM) is a type of artificial intelligence that provides a framework for modeling large collections of random variables with complex interactions. One group is studying PGMs to discriminate cases of FGR resulting in significant composite perinatal morbidity from those that do not [37].

Fetal weight — Fetal weight is calculated using various published equations and formulae. Most clinicians use the Hadlock formula [38]. The computed EFW is then compared with Hadlock standards for fetal weight across gestation or plotted on a population-based or customized growth curve [39]. The rate of adverse perinatal outcomes are inversely related to the percentile [40].

Doppler velocimetry — The hemodynamic physiology of FGR is the basis for the use of Doppler ultrasound to monitor and manage affected pregnancies. The classic progressive sequence of Doppler changes in the peripheral and central circulatory systems leading to fetal compromise or death in FGR are shown in the figure (figure 1) but other patterns of Doppler deterioration also exist [6,41-44]. This sequence is most likely to progress quickly (within days) when the onset of FGR is earlier in gestation and with increasing severity of placental insufficiency [45]. Doppler abnormalities in late gestational FGR may progress slowly (within weeks) or not at all or along a different pathway [42]. The reason is that FGR is not a homogeneous entity and different phenotypes of FGR behave differently. For example, FGR associated with preeclampsia with severe features may have a more rapidly deteriorating clinical course than idiopathic FGR [7].

The following figures (figure 2 and figure 3) compare the Doppler changes observed from the time of initial diagnosis of FGR until delivery or fetal demise in a series of pregnancies with idiopathic FGR versus those with FGR associated with preeclampsia diagnosed at <32 weeks of gestation. It is important to emphasize that not all fetal vessels described in the figures are used in current clinical practice. (See "Fetal growth restriction: Pregnancy management and outcome", section on 'Doppler ultrasonography, nonstress test/cardiotocography, and biophysical profile'.)

Umbilical artery Doppler — UA Doppler is the primary surveillance tool for monitoring pregnancies with FGR [1,3,27,46]. UA diastolic flow normally increases with advancing gestational age (waveform 1). UA indices become abnormal when 30 percent of the placental villous vasculature is obliterated [47,48]. When 60 to 70 percent is obliterated, flow in the UA can become absent or even reversed at the end of the cardiac cycle (waveform 2).

The most common UA Doppler indices used in clinical obstetric practice are:

●Pulsatility index (PI = peak systolic velocity - end-diastolic velocity/time-averaged maximum velocity) [49]

●Resistance index (RI = peak systolic velocity – end-diastolic velocity/peak systolic velocity) [50]

●S/D ratio: Peak systolic velocity/end-diastolic velocity [51]

Reference ranges for the three UA indices have been reported in many studies, including a longitudinal study [52]. The PI is preferred because it gives a better estimate of the characteristics of the waveform than the RI or S/D ratio [53]. A value above the 95^th percentile for gestational age is considered abnormal.

The severity of UA Doppler abnormalities correlates with prognosis: Reversed diastolic flow is associated with fivefold higher perinatal mortality compared with absent flow [54]. Numerous randomized trials and well-designed observational studies have established that monitoring UA Doppler can significantly reduce perinatal death by prompting early delivery when it is abnormal. In addition, a normal Doppler is infrequently associated with significant perinatal morbidity or mortality and is strong evidence of fetal well-being; thus, this finding provides support for delaying the delivery of preterm gestations when it is important to gain further fetal maturity.

●In a systematic review of 19 trials comparing the use of mostly UA Doppler with no Doppler in over 10,000 high-risk pregnancies, Doppler use reduced perinatal deaths (1.2 versus 1.7 percent; risk ratio [RR] 0.71, 95% CI 0.52-0.98; number needed to treat 203), labor induction (RR 0.89, 95% CI 0.80-0.99) and cesarean births (RR 0.90, 95% CI 0.84-0.97) [55].

●In the Prospective Observational Trial to Optimize Pediatric Health in FGR (PORTO) study, FGR with normal UA Doppler was associated with less perinatal mortality than FGR with abnormal Doppler (2 of 698 [0.3 percent] versus 6 of 418 [1.4 percent]) and a lower rate of overall adverse outcome (9 of 698 [1.3 percent] versus 48 of 418 [11.5 percent]) [8,56]. In addition, the combination of EFW <3^rd percentile and abnormal UA Doppler was a strong and consistent predictor of adverse outcome: 16.7 percent of these fetuses developed intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, or death. Abnormal UA Doppler was defined as a pulsatility index (PI) >95^th percentile or absent/reversed end-diastolic flow.

A detailed discussion of Doppler interrogation of the UA, including performance of the test, is available separately. (See "Doppler ultrasound of the umbilical artery for fetal surveillance in singleton pregnancies".)

Middle cerebral artery pulsatility index — In uncomplicated pregnancies, vascular resistance of the fetal brain changes with advancing gestation, thus the middle cerebral artery (MCA) PI is low at early gestational ages (<20 weeks), then gradually increases, before gradually decreasing in the third trimester [57,58]. However, in fetuses such as those with FGR experiencing progressive hypoxemia, cerebral blood flow increases to compensate for the decrease in available oxygen (brain-sparing effect) (waveform 3) [59], which results in a reduction in MCA PI [6,7,41,43,44]. Subsequent normalization of the MCA PI may occur and is considered an ominous sign because it indicates the loss of brain-sparing [60].

The MCA PI can be the first parameter to become abnormal in late FGR [61], followed by the UA PI. An abnormal MCA PI is found in approximately 20 percent of FGR cases with normal UA PI in the third trimester [62,63] and associated with a higher incidence of suboptimal neurodevelopmental outcome at two years of age compared with a normal MCA PI [62]. In a study of 856 FGR cases between 32 and 36.6 weeks, an abnormal MCA PI (<5^th percentile for gestational age) had higher relative risk of a composite adverse outcome compared with the UA PI [64]. Two fetuses died; in both cases, UA PI was normal while MCA PI was abnormal.

MCA Doppler results can be used to calculate two ratios sometimes used in the evaluation of FGR. (See 'Cerebroplacental ratio' below and 'Umbilicocerebral ratio' below.)

Ductus venosus Doppler — Normal flow in the fetal ductus venous (DV) is forward and uniform [65]. With progressively increasing UA resistance in FGR, fetal cardiac performance becomes impaired and atrial pressure increases, resulting in reduced diastolic flow in the DV a-wave. With progression of the severity of FGR, and late in the course of the disorder, the a-wave becomes absent or reversed (waveform 4) [6,7,41,43,44]. Absent or reversed DV a-wave is considered a sign of impending acidemia and fetal demise. It has overall sensitivity of 65 percent and specificity of 95 percent for fetal pH <7.20 [66]. The time from detection of absent or reversed DV a-wave to delivery or fetal demise is variable, and not all very preterm FGR fetuses with this finding are acidemic [67]. Neither neonatal death nor neonatal morbidity are predicted by its duration [68].

An absent or reversed a-wave is uncommon, occurring more often in early rather than late FGR, and is typically seen after reversed flow in the UA has been observed.

Biophysical profile and nonstress test/cardiotocography — Following the diagnosis of FGR, different regions and institutions follow distinct protocols, generally emphasizing close monitoring of fetal well-being.

In the United States, both the nonstress test (NST; also called cardiotocography [CTG]) with amniotic fluid volume determination and the biophysical profile (BPP) are used to monitor fetal status as these tests evaluate both acute and chronic fetal physiologic parameters [27,46]. The tests are relatively easy to perform and are initiated at a gestational age where an abnormal finding would trigger intervention. The frequency of testing is determined by UA Doppler results and amniotic fluid volume. (See "Fetal growth restriction: Pregnancy management and outcome", section on 'Doppler ultrasonography, nonstress test/cardiotocography, and biophysical profile'.)

The rationale for including a BPP in FGR management is based on its superior reflection of current fetal acid-base balance, which is independent of fetal heart rate testing and multivessel Doppler assessment [69]. Specific concerns about the use of BPP in FGR surveillance arise from two studies. One is a meta-analysis that concluded that there is insufficient evidence from randomized trials to support the use of the BPP as a test of fetal well-being in high-risk pregnancies [70]. However, this analysis mainly included high-risk pregnancies with conditions other than FGR and did not assess acidemia and stillbirth rates concerning the surveillance strategy. The other is an observational study that specifically evaluated the use of a daily BPP in managing early severe FGR (<1000 g) with very abnormal Doppler parameters of the UA, MCA, and DV, both with and without maternal preeclampsia [71]. It found that a normal BPP score did not predict the outcome in the next 24 hours for this subgroup of FGR pregnancies. However, no randomized trial has compared the BPP with the NST in FGR management, and no study has shown that the NST is superior to the BPP (or vice versa) for the management of FGR. Between 30 and 70 percent of cases of FGR with a nonreactive NST require a BPP to verify fetal well-being. The BPP score is abnormal in 8 to 27 percent of these cases and identifies the need for delivery, which was not suspected based on Doppler findings alone [69]. These results underscore the importance of using multiple modalities for fetal surveillance and conducting frequent testing.

The BPP is not widely used in many countries outside of the United States. In these countries, computerized cardiotocography (cCTG) is often used instead of conventional CTG for fetal heart rate monitoring and interpretation [3].

It is important to emphasize that assessing FGR can be complex. This assessment should include coordinated care between maternal-fetal medicine and neonatology services, comprehensive patient counseling on neonatal morbidity and mortality, and shared decision-making with the parents regarding FGR evaluation.

Other evaluations

Growth velocity — The diagnosis of FGR on a single ultrasound based on an EFW <5^th percentile in a well-dated pregnancy, oligohydramnios, and abnormal Doppler indices does not require serial scans for confirmation; however, assessing growth velocity (trajectory) has the potential to assist in the diagnosis of less severe forms of FGR not captured by current diagnostic criteria [2,72-78]. A normal growth velocity (ie, parallel to the growth curve of fetuses with EFW or AC >10^th percentile) appears to be predictive of a favorable outcome, while an abnormal growth velocity (a percentile drop between consecutive ultrasound scans of >50 percentiles in EFW or AC [eg, from the 75^th percentile to the 20^th percentile]) appears to predict perinatal complications (eg, preterm birth, preeclampsia, neonatal morbidity).

The author does not routinely calculate growth velocity as studies have not established that determination of growth velocity substantially improves prediction of birthweight and perinatal outcome (morbidity and mortality) compared with EFW alone. Routine fetal growth velocity assessment is not endorsed by the American College of Obstetrics and Gynecology, Society for Maternal-Fetal Medicine, and American Institute of Ultrasound in Medicine (AIUM) for management of pregnancies affected by FGR [1,27] .

Cerebroplacental ratio — The cerebroplacental ratio (CPR) is the MCA PI divided by UA PI [79]. The CPR reflects both the placental status and fetal response and thus may be a sensitive Doppler index for predicting perinatal outcome [80]. In late-onset FGR, reduction in the CPR may be the only Doppler change present [81].

This parameter is used in the definition of FGR after 32 weeks by ISUOG; however, it is not included in the definitions by SMFM, ACOG, and AIUM (table 1). The controversy may be due in part to data from different studies that have used various threshold values for predicting adverse outcomes (CPR <1, <1.05, ≤1.08, <5^th percentile, etc) [82-89].

Umbilicocerebral ratio — The umbilicocerebral ratio (UCR) is obtained by dividing the UA PI by the MCA PI, making it the inverse of the CPR. As fetal Doppler changes become more abnormal, resulting in lower MCA impedance and higher UA impedance, the CPR tends toward zero, while the UCR tends toward infinity [64]. Therefore, it has been suggested that the UCR might provide more information than the CPR.

A multicenter cohort study with a nested randomized trial assessed the association between UCR in FGR at 32+0 to 36+6 weeks of gestation and adverse perinatal outcomes, defined as perinatal death, birth asphyxia, or major neonatal morbidity [90]. Patients with an abnormal UCR were randomly assigned to immediate delivery when at least 34 weeks or expectant management until 37 weeks. An abnormal UCR was associated with a higher incidence of short-term perinatal adverse outcomes, thus it appeared to be a useful tool to discriminate between the constitutionally small fetus and FGR needing surveillance and timed delivery. The trial was halted prematurely due to low recruitment and thus was unable to evaluate any benefit of early delivery of FGR because of an abnormal UCR.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fetal growth restriction".)

SUMMARY AND RECOMMENDATIONS

●Overview – Identification of fetal growth restriction (FGR) is an integral component of prenatal care as it is a leading cause of perinatal morbidity and mortality. When FGR is suspected, the obstetric provider needs to confirm the suspected diagnosis, determine the probable cause, assess the severity, counsel the parents, closely monitor fetal growth and well-being for the remainder of the pregnancy, and determine the optimal time for and route of birth. Although FGR is not a homogeneous entity, uteroplacental insufficiency with suboptimal fetal nutrition and hypoperfusion is a common pathway to many forms of FGR. (See 'Introduction' above.)

●Initial evaluation – Sonographic criteria for diagnosis of FGR vary (table 1). After diagnosis of FGR, the pregnancy is evaluated to determine whether fetal growth is impaired as a result of maternal, fetal, or placental processes (table 2). However, this determination cannot always be made antenatally.

•Percentile – Fetuses <3^rd percentile are at greatest risk of adverse outcome. Most fetuses with estimated fetal weight (EFW) or abdominal circumference (AC) between the 5^th and 10^th percentiles are constitutionally small and thus have normal neonatal outcomes. However, they still need to be monitored closely because a proportion of these fetuses are FGR and at increased risk of adverse outcome.

•History and physical examination – The medical and obstetric history and physical examination help to assess for maternal factors that have been associated with FGR. (See 'Identify maternal and obstetric factors associated with FGR' above.)

•Fetal anatomic survey – A detailed fetal anatomic survey is performed in all cases since approximately 10 percent of FGR is accompanied by congenital anomalies and 20 to 60 percent of anomalous infants are small for gestational age. (See 'Perform a detailed fetal anatomic survey' above.)

•Genetic testing – We offer fetal genetic diagnostic tests to patients in any of the following settings (See 'Work-up for genetic abnormalities' above.):

-FGR without a known cause diagnosed before 32 weeks. After 32 weeks, we do not screen for fetal genetic abnormalities if anatomy is normal since the risk of aneuploidy is more common early in gestation and the yield would be low.

-FGR with major fetal structural abnormalities or ultrasound markers associated with an increased risk of aneuploidy, such as a thickened nuchal fold.

-FGR with polyhydramnios.

-Ultrasound findings suggestive of a triploid pregnancy.

Issues to consider are use of a noninvasive screening test (cell-free DNA) or a diagnostic test (microarray or karyotype) that requires amniocentesis, and when to pursue advanced genetic testing (exome or genome sequencing).

•Laboratory testing – We obtain serology studies for infection when FGR is associated with sonographic markers of fetal infection (echogenicity and calcification of the brain and/or liver, hydrops) or when a careful maternal history and physical examination suggest the possibility of maternal infection and vertical transmission. We do not perform routine TORCH serology in the evaluation of isolated FGR. (See 'Work-up for infection' above.)

●Subsequent evaluation – After the initial evaluation, periodic assessment of fetal weight and Doppler interrogation of the umbilical artery (UA) are performed to differentiate fetuses at increased risk of adverse outcomes from those that are constitutionally small or minimally affected by uteroplacental insufficiency or other pathologic factors that impair fetal growth and at low risk of adverse outcomes. (See 'Subsequent evaluation' above and "Fetal growth restriction: Pregnancy management and outcome".)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Robert Resnik, MD, who contributed to an earlier version of this topic review.