Fetal growth restriction: Pregnancy management and outcome

INTRODUCTION — 

Identification of fetal growth restriction (FGR) is an integral component of prenatal care as it is a leading cause of perinatal morbidity and mortality [1]. When diagnostic criteria for diagnosis of FGR are met (table 1), the obstetric provider needs to assess the severity, determine the probable cause, counsel the pregnant patient (eg, regarding fetal testing; risk for preterm birth, perinatal morbidity/mortality; preeclampsia; long-term maternal and pediatric outcomes), closely monitor fetal growth and well-being for the remainder of the pregnancy, and determine the optimal time for and route of birth. Management is complicated because FGR is not a homogeneous entity and the cause cannot always be determined prenatally. Regardless of the cause, birth timing needs to balance the consequences of iatrogenic preterm birth with the risk of stillbirth in ongoing monitored pregnancies.

This topic will discuss pregnancy management and outcome of FGR in singleton pregnancies. Screening and diagnosis of FGR and evaluation to determine the probable cause are reviewed separately. (See "Fetal growth restriction: Screening and diagnosis" and "Fetal growth restriction: Evaluation".)

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".)

PRENATAL CARE

Goal — The focus of prenatal care in pregnancies with FGR is to identify those fetuses at the highest risk of perinatal demise, as they may benefit from early delivery. Distinguishing the constitutionally small fetus from the fetus with pathologic growth can help avoid unnecessary interventions for the former and lead to appropriate monitoring and delivery timing of the latter. Unfortunately, this distinction is not always possible.

Fetal surveillance — The key parameters for fetal surveillance are:

●Estimated fetal weight (EFW)

●Doppler ultrasonography

●Fetal behavior (biophysical profile [BPP] and nonstress test [NST]/cardiotocography [CTG])

Fetal surveillance in FGR is initiated at the gestational age when delivery for perinatal benefit would be considered [2,3]. Patients should receive comprehensive counseling on neonatal morbidity and mortality, ideally by a team including the primary obstetric provider, maternal-fetal medicine, and neonatology services, before fetal surveillance is initiated. This is particularly important when nonreassuring fetal findings would lead to delivery of an extremely preterm neonate.

The cardiovascular (Doppler) and behavioral (BPP and NST) manifestations of fetal deterioration in FGR can occur largely independently of each other. For example, an abnormal BPP can occur before the appearance of the late Doppler changes (eg, reversed umbilical artery [UA] Doppler flow, ductus venosus [DV] a-wave abnormalities) [4]. This is the reason for monitoring the fetus with multiple modalities. Observational data suggest that the adoption of a protocol to detect and monitor FGR can reduce stillbirth [5].

Fetal weight — Sonography is typically performed every three weeks to assess the change in EFW over time [2,3]. It is not performed more frequently than every two weeks because the inherent error associated with ultrasonographic measurements can preclude an accurate assessment of interval growth [3]. A stable fetal growth trajectory is reassuring, while a fall in the EFW percentile for gestational age is associated with increased perinatal morbidity and mortality [6,7].

Doppler ultrasonography, nonstress test/cardiotocography, and biophysical profile — Several protocols for fetal monitoring are used in different areas of the world, all aiming to ensure the healthiest possible outcomes for both the mother and infant. Surveillance strategies that include Doppler velocimetry to determine the frequency of fetal behavioral testing (such as NST/CTG, BPP) are associated with better neonatal outcomes and lower stillbirth rates compared with empirically determined surveillance strategies (stillbirth: 0 to 4 percent versus 8 to 11 percent) [8]. However, the type and frequency of Doppler ultrasound used for fetal surveillance to predict adverse neonatal outcomes in FGR are not standardized. For example, some experts do not consistently recommend MCA Doppler in the fetal surveillance of FGR due to its low predictive value for adverse perinatal outcomes [9]. The Society for Maternal-Fetal Medicine (SMFM), American College of Obstetricians and Gynecologists (ACOG), and American Institute of Ultrasound in Medicine (AIUM) suggest not using Doppler assessment of the ductus venosus (DV) or the middle cerebral artery (MCA) for the routine clinical management of FGR [2]. In contrast, other experts, along with the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) and the Royal College of Obstetricians and Gynaecologists (RCOG), support their use [10]. The ISUOG includes the use of the MCA in the definition of late FGR [11], while the RCOG states that in term small fetuses with normal UA Doppler, an abnormal MCA Doppler (PI <5^th percentile) has moderate predictive value for acidosis at birth and should be used to time delivery [12].

The author of this topic monitors the UA Doppler in both early- and late-onset FGR (ie, onset <32 versus ≥32 weeks of gestation). For outpatients with FGR, he also monitors the MCA Doppler if the UA Doppler is normal, as the MCA may become abnormal before the UA Doppler, indicating a need to increase the frequency of fetal surveillance. For inpatients, he uses MCA and DV Doppler results as additional factors to consider during counseling and shared decision-making, but not for determining delivery timing.

The following approach aligns with major guidelines and is commonly used in the United States. Fetal monitoring is not usually performed before 24 weeks, as delivery at this gestational age is primarily due to maternal indications. Monitoring between 24 and <26 weeks is performed if the EFW is greater than 500 grams, following a discussion with the patient, the neonatologist, and the obstetric provider if delivery is considered in the event of nonreassuring testing. The author's protocol for monitoring fetuses ≥26 weeks of gestation or with an estimated weight greater than 500 grams is as follows:

●If both the UA and MCA Doppler are normal (UA pulsatility index [PI] ≤95^th and MCA PI ≥5^th percentile), then UA and MCA Doppler tests, along with a BPP, are performed at weekly intervals. This approach is reasonable even in pregnancies with severe FGR (EFW or AC <3^rd percentile), as progression from normal Doppler results to absent or reversed UA end-diastolic flow was unlikely until four weeks after diagnosis of severe FGR, according to one study [13]. Outside of the United States, computerized cardiotocography (cCTG) is preferred over the BPP.

●If either the UA or MCA Doppler is abnormal, but the UA has diastolic flow (UA PI >95^th and or MCA PI <5^th percentile), the amniotic fluid volume is normal, and there are no concerning maternal or fetal comorbidities, then UA and MCA Doppler tests are performed twice a week. Additionally, a BPP is performed during one of the visits, and an NST is performed during the other visit (eg, perform a BPP and Doppler on Monday and an NST on Thursday).

●Patients with abnormal UA or MCA Doppler results but with UA forward diastolic flow, along with concerning comorbidities (eg, oligohydramnios, preeclampsia), are admitted to the hospital. After 24-hour inpatient observation and fetal monitoring, care is individualized and may include inpatient or outpatient monitoring or proceeding with delivery.

●If the UA Doppler shows absent or reversed diastolic flow, the patient is admitted to the hospital for convenient access to frequent fetal surveillance and to allow for prompt fetal evaluation in case of decreased fetal activity or other pregnancy complications. NSTs are performed every 12 hours, a BPP is performed daily, and UA and MCA Doppler are performed two to three times per week. The reason of this strategy is that both a reassuring NST and/or a BPP in case of severe FGR provide information on the fetal status at the time of testing, but they do not predict outcomes 24-hour posttest [14,15].

These fetuses are also monitored with DV Doppler. An absent or reversed DV a-wave in this context indicates an advanced stage of fetal compromise and can be an additional factor to consider during counseling and shared decision-making [4,16-19]. The author uses the DV Doppler to assess the severity of FGR, but not for timing delivery. Outside of the US, DV Doppler is also used for timing delivery. (See 'Delivery' below.)

In the near future, the gestational age for initiating fetal monitoring may change as medical advancements continue to improve survival rates for neonates delivered at the lower limit of neonatal viability (between 22 and <24 weeks). In cases of early FGR, a model combining gestational age at diagnosis, EFW in multiples of the median (MoM), and UA PI MoM could help predict perinatal mortality [20]. However, further study is required before implementing this tool to support decision-making at the lower limit of neonatal viability. In addition, a recent study reported that a successful BPP can be achieved between 20 and <24 weeks of gestation in 80 percent (63 out of 79) of appropriately growing fetuses within 30 minutes and in 97 percent (77 out of 79) within 43 minutes [21]. However, in the author's practice, we do not routinely monitor FGR before 24 weeks, and we proceed with delivery at these early gestational ages only for maternal indications.

Antenatal corticosteroids

●Timing – Ideally, a course of antenatal betamethasone (or dexamethasone) is given to pregnancies <34+0 weeks of gestation in the seven days before preterm birth is anticipated. The efficacy of antenatal steroids for reducing neonatal morbidity and mortality in the preterm growth-restricted neonate remains controversial, with two large studies showing conflicting results [22,23]. Until definitive information is available, a course of betamethasone (or dexamethasone) should be administered.

The author of this topic individualizes the precise day of administration of corticosteroids based on multiple factors, including the severity of FGR, Doppler findings, comorbid conditions, rate of deterioration in fetal status, and discussions involving the primary obstetrician, the neonatologist, and the patient. A study of pregnancies with FGR <32 weeks between 2012 and 2021 compared administration when the UA PI was above the 95^th centile with positive end-diastolic flow versus administration when end-diastolic velocity became absent or reversed [24]. Three hospitals followed the first strategy and three followed the second strategy. Although not statistically significant, the second strategy was associated with higher rates of the composite of perinatal and in-hospital mortality.

Administration between 34+0 and 36+6 weeks does not appear to decrease the need for respiratory support and increases the rate of neonatal hypoglycemia [25] but is recommended by some guidelines [3]. The administration of antenatal corticosteroids, including the potential harms on neurodevelopment, is reviewed in detail separately. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)

●Effect on Doppler findings – Three studies observed that growth-restricted fetuses with absent end-diastolic flow often show transient improvement in blood flow after betamethasone administration [26-28]. Fetuses that did not show increased flow appeared to have poorer neonatal outcomes. The reason sicker fetuses are unable to mount a vascular response to betamethasone administration is unclear. One action of glucocorticoids is to enhance the tropic effect of catecholamines on heart muscle. It is hypothesized that inotropy does not improve in sicker fetuses because they have impaired cardiac wall compliance.

Maternal interventions

●In an otherwise healthy pregnant patient with FGR, there is no strong evidence that any intervention improves fetal growth and outcome. Information is available on the following interventions.

•Statins – Use of a statin appears promising. A pilot trial in 38 patients with singleton pregnancies and FGR diagnosed at ≤28 weeks of gestation observed that administration of pravastatin 40 mg improved birth weight compared with no treatment (1300 versus 1040 grams), although the difference was not statistically significant [29]. The pravastatin group had significant improvement in angiogenic profiles but not in Doppler parameters.

•Phosphodiesterase-5 enzyme inhibitors – Use of a phosphodiesterase-5 enzyme inhibitor (eg, tadalafil, sildenafil) appeared promising and was under investigation [30]. However, a multicenter Dutch trial of sildenafil for treatment of poor prognosis early-onset growth restriction was halted early because of a higher than expected rate of pulmonary hypertension in the intervention group with no benefit in the primary outcome (perinatal mortality or major neonatal morbidity) at the time the trial was stopped [31].

A concurrent trial in Australia and New Zealand reported sildenafil had no effect on fetal growth velocity after diagnosis of growth restriction before 30 weeks but no adverse effects on newborns [32]. At follow-up at 2.5 years corrected age, the sildenafil group did not have less neurosensory impairment than the placebo group [33]. A similar trial from the United Kingdom reported sildenafil therapy did not prolong pregnancy and did not improve perinatal outcomes or neurodevelopment at age two years [34].

In a meta-analysis of phosphodiesterase-5 inhibitors in FGR (six trials using sildenafil, one using tadalafil), the intervention improved uteroplacental, but not fetal cerebral, blood perfusion [35].

•Other – Numerous other approaches have been tried, including maternal nutritional supplementation (eg, balanced protein energy bars, L-arginine, lipid-based nutrients), oxygen therapy, and interventions to improve blood flow to the placenta (eg, plasma volume expansion, nitroglycerin, bed rest, low-dose aspirin, anticoagulation), but the quality of evidence is low and none has been proven effective [36-45]. Recommending for low-intensity activities or against physical activity is a common practice, particularly with increased severity/complexity of FGR; however, this is a common-sense approach in the absence of research identifying the risks and benefits of physical activity or activity limitations based on FGR severities and comorbidities [46].

●In patients with reversible risk factors for FGR, targeted intervention may be beneficial. Information is available on the following interventions.

•Nutritional intervention – Patients with risk factors for or evidence of nutritional deficiencies (eg, pregnancies complicated by bariatric surgery or eating disorders) may benefit from referral to a registered dietician. Individuals in resource-limited settings with undernutrition may benefit from balanced energy and protein supplements. (See "Fertility and pregnancy after bariatric surgery" and "Eating disorders in pregnancy" and "Undernutrition in pregnancy: Evaluation, management, and outcome in resource-limited areas".)

•Smoking cessation – In smokers, an intensive smoking cessation program may be of value in improving fetal growth and has other pregnancy and health benefits [47,48]. (See "Cigarette and tobacco products in pregnancy: Screening and impact on pregnancy and the neonate" and "Tobacco and nicotine use in pregnancy: Cessation strategies and treatment options".)

•Antihypertensive therapy – In pregnant patients with chronic hypertension, antihypertensive therapy has maternal benefits but neither increases nor clearly decreases the risk of FGR [49]. (See "Chronic hypertension in pregnancy: Prenatal and postpartum care".)

DELIVERY

General approach to timing — There is little consensus about the optimal time to deliver the growth-restricted fetus. The timing and route of delivery of pregnancies with FGR is based on a combination of factors, including Doppler findings, biophysical profile (BPP) score, nonstress test (NST)/cardiotocography (CTG) result, gestational age, and fetal weight (table 2).

Early severe FGR is a major challenge because morbidity and mortality related to preterm birth are relatively high before 32 weeks [50,51]. Between 26 and 29 weeks of gestation, each day in utero was estimated to improve survival by 1 to 2 percent in one study [52] and by 50 percent per week in a second study [53]. When considering delivery for fetal indications, some authors have suggested a minimum threshold of 26 weeks of gestation, 500 g, or both; however, ongoing advances in neonatal care have enabled survival of younger and smaller neonates. Decision-making in these cases is complex and should include coordination of care between maternal-fetal medicine and neonatology services, along with comprehensive patient counseling on neonatal morbidity and mortality and shared decision-making regarding pregnancy management [2].

Evidence from major trials — The following key randomized trials attempted to answer the question of when to intervene in FGR pregnancies, without a clear conclusion:

●The Growth Restriction Intervention Trial (GRIT) randomly assigned pregnant patients between 24 and 36 weeks with FGR to immediate (n = 273) or delayed (n = 274) delivery if the obstetrician was uncertain about when to intervene [54]. In the delayed delivery group, delivery occurred when the obstetrician was no longer uncertain about intervening, which occurred at a median of 4.9 days from enrollment.

The immediate delivery group had fewer stillbirths (2 versus 9 with delayed delivery) but more neonatal and infant deaths (27 versus 18). Follow-up data up to age 13 years showed no differences between groups in cognition, language, motor, or parent-assessed behavior scores on standardized tests [55,56].

These data suggest that delaying delivery of a very preterm growth-restricted fetus in the setting of uncertainty results can lead to some stillbirths. However, immediate delivery may result in an almost equal number of neonatal deaths, and neither approach appears to improve long-term neurodevelopmental outcome.

●The Disproportionate Intrauterine Growth Intervention Trial At Term trial (DIGITAT) randomly assigned 650 pregnant patients over 36 weeks of gestation with suspected FGR to induction of labor or expectant monitoring [57-59]. The primary outcome was a composite measure of adverse neonatal outcome (death before hospital discharge, five-minute Apgar score <7, UA pH <7.05, or admission to the intensive care unit) [57]. Neonatal morbidity was analyzed separately using Morbidity Assessment Index for Newborns (MAIN) score [58].

The induction group delivered 10 days earlier and weighed 130 grams less (mean difference -130 grams, 95% CI -188 to -71) than the expectantly managed group, but had statistically similar composite adverse outcome (6.1 versus 5.3 percent with expectant management) and cesarean birth rates (approximately 14 percent) [57]. Developmental and behavioral outcomes at two years of age were also similar for both groups [59]. The authors concluded that both approaches were reasonable, and the choice should depend on patient preference. However, in a subanalysis of data, they reported that neonatal intensive care unit admissions were lower when growth restricted fetuses were delivered after 38 weeks of gestation [58], which suggests a benefit of deferring delivery until 38 weeks of gestation, as long as the fetus is closely monitored and in the absence of other indications for an early delivery.

●The Trial of Randomized Umbilical and Fetal Flow in Europe (TRUFFLE) assessed whether changes in the fetal DV Doppler waveform could be used to guide timing of delivery of FGR instead of using CTG short-term variation (STV) [60]. The primary outcome measure was survival without neurodevelopmental impairment at two years of age. Pregnancies were randomly assigned to one of three monitoring approaches: CTG with delivery based on reduced STV, DV monitoring with delivery for early DV changes (pulsatility index [PI] >95^th percentile), or DV monitoring with delivery for late DV changes (a-wave indicating absent or reversed flow). The proportion of infants surviving without neurodevelopmental impairment was 77 to 85 percent, with no significant differences among the three groups. Delaying delivery until the development of late DV changes resulted in an improvement in survival without neurodevelopmental impairment (95 percent versus 91 percent for survivors in the early DV changes group and 85 percent for survivors in the reduced STV group). However, this benefit came at the cost of a small increase in unexpected fetal demise (0 of 166 in the STV group, 3 of 167 in the early ductal changes group, and 4 of 170 in the late ductal changes group). There were no differences in immediate neonatal composite morbidity or mortality across the groups.

In a post hoc analysis of their data, the TRUFFLE group concluded that both DV and computerized CTG evaluations are warranted since the majority of infants in the DV groups were delivered due to reduced STV or spontaneous decelerations in fetal heart rate, rather than early or late changes in the DV [61].

Our approach — Delivery should not be delayed beyond 39+0 weeks of gestation because the risk of fetal demise significantly increases at term, particularly as the severity of FGR increases, without clinically significant neonatal benefit from further maturation in utero. As an example, in a retrospective cohort study, the risk of fetal death at 39 weeks was estimated as 32 per 10,000 ongoing pregnancies for fetal weight <3^rd percentile, 23 per 10,000 ongoing pregnancies for fetal weight <5^th percentile, 13 per 10,000 ongoing pregnancies for fetal weight <10^th percentile, and 2 per 10,000 ongoing pregnancies for fetal weight ≥10^th percentile [62].

The following approach is consistent with major guidelines and is commonly used in the United States. However, it is important to emphasize that the BPP is not universally used and any fetal testing should be interpreted in the specific clinical context [2,3,8,63].

●Patients with a reactive NST and BPP score 8/8, 10/10 or 8/10 with normal amniotic fluid volume:

•UA reversed diastolic flow – Deliver between 30+0 and 32+0 weeks of gestation or at diagnosis if diagnosed at >32+0 weeks.

•UA absent diastolic flow – Deliver between 33+0 and 34+0 weeks of gestation or at diagnosis if diagnosed at >34+0 weeks.

•UA PI abnormal (PI >95^th percentile) – Deliver at 37+0 weeks or at diagnosis if diagnosed at >37+0 weeks.

•UA PI normal (PI ≤95^th percentile):

-EFW <3^rd percentile and no comorbidities – Deliver between 37+0 and 37.6 weeks or at the time of diagnosis if diagnosis occurs later.

-EFW ≥3^rd and <10^th percentile and no comorbidities – Deliver between 38+0 and 39+0 weeks of gestation or at diagnosis if diagnosed at >39+0 weeks.

-EFW ≥3^rd and <10^th percentile with oligohydramnios or comorbidities (eg, preeclampsia, chronic hypertension) – Timing should be individualized, but most patients should be delivered between 34+0 and 37+6 weeks of gestation.

The use of 30 to 34 weeks as the upper threshold for delivery of the most complicated FGR pregnancies is based on limited data, which suggest that when the UA has absent diastolic flow, the risk of fetal death exceeds neonatal morbidity and mortality rates in pregnancies that are at least 33 to 34 weeks of gestation. Likewise, when the UA has reversed diastolic flow, the risk of fetal death exceeds neonatal morbidity and mortality rates in pregnancies that are at least 30 weeks [64].

The use of 37+0 weeks as the upper threshold for delivery of the least complicated FGR pregnancies is based on very limited data and expert opinion [63]. The increased risk associated with advancing gestational age is supported by a study of over 57,000 pregnancies with estimated fetal weight (EFW) <10^th percentile in which the risk of stillbirth in the 37^th week was 28 in 10,000 and the cumulative risk increased with each advancing week of gestation (38^th week: 41 in 10,000, 39^th week: 77 in 10,000, 40^th week: 194 in 10,000) [65]. This study did not consider the impact of associated factors (eg, amniotic fluid volume, Doppler findings).

●Patients with a nonreactive NST or BPP <8/10 – Management depends on the specific findings and gestational age. In all cases in which delivery for nonreassuring fetal testing is generally indicated but would result in the birth of an extremely preterm neonate, patients should receive comprehensive counseling on neonatal morbidity and mortality by a team including the primary obstetric provider, maternal-fetal medicine, and neonatology services as part of shared decision-making about delivery timing, route of delivery, and neonatal resuscitation.

•Repetitive late decelerations – Prompt delivery is indicated.

•BPP score (BPP includes NST):

-0 or 2/10: This is a very abnormal score with a high risk of fetal death without intervention (perinatal mortality within one week: 600 and 125 in 1000, respectively [8]). These pregnancies should be delivered.

-4/10: This is an abnormal score (perinatal mortality within one week: 91 in 1000 [8]). The BPP generally should be repeated in one hour. If still 4/10, then delivery is often indicated.

-6/10 with oligohydramnios (maximum vertical pocket <2 cm): This is also an abnormal score (perinatal mortality within one week: 89 in 1000 [8]). The test should be repeated within 24 hours. The decision to deliver is often individualized based on the results of additional testing (eg, repeat BPP, NST), maternal status, gestational age, and severity of Doppler findings (UA, DV).

-6/10 without oligohydramnios or 8/10 with oligohydramnios (maximum vertical pocket <2 cm): These are equivocal scores (perinatal mortality within one week: variable and 89 in 1000, respectively [8]). The decision to deliver is individualized based on the results of additional testing (eg, NST, repeated BPP), maternal status, gestational age, and severity of Doppler findings (UA, DV).

Other approaches

●The ISUOG practice guideline on FGR support delivery following 26 weeks of gestation in the presence of DV a-wave at or below baseline [11]. It also recommends delivery between 26+0 and 28+6 weeks if STV is <2.6ms, and between 29+0 and 31+6 weeks if STV is <3.0ms.

In the United States, computerized CTG (cCTG) is not commonly utilized, and DV reversed flow is not considered an indication for delivery by SMFM, ACOG, and AIUM. Before 30 weeks of gestation, BPP and NST are the tests used for timing delivery based on fetal indication. Following 30 weeks, the UA Doppler is added to the BPP and NST for timing delivery.  

●The RCOG guideline states that in a term small fetus with normal UA Doppler, an abnormal MCA Doppler (PI <5^th percentile) has moderate predictive value for acidosis at birth and should be used to time delivery [12]. This is not an indication for delivery in the United States.  

Route of birth — Cesarean birth is performed for standard obstetric indications; otherwise a trial of labor is acceptable. An unfavorable cervix is not a reason to avoid induction [66]. However, when the indication for delivery is reversed flow of the UA, we give patients the option of a scheduled cesarean birth, especially when the cervix is unfavorable, because many of these fetuses will not tolerate labor and it is prudent to avoid adding an acute insult on a chronically hypoxic fetus.

We prefer a mechanical ripening method (insertion of a balloon catheter or hygroscopic dilator), which may be safer than prostaglandins in this setting [67]. If the Bishop score is >6, we administer oxytocin without mechanical ripening.

●In a meta-analysis of observational studies of labor induction with misoprostol, dinoprostone, or mechanical methods in FGR, mechanical methods appeared to be associated with a lower occurrence of adverse intrapartum outcomes, but a direct comparison among methods could not be performed [68].

●In a secondary analysis of data from the DIGITAT and HYPITAT trials (pregnancies complicated by FGR and hypertension), induction of labor at term in patients with median Bishop scores of 3 (range 1 to 6) was not associated with a higher rate of cesarean birth than expectant management, and approximately 85 percent of patients in both groups achieved a vaginal birth [69]. Prostaglandins or a balloon catheter was used for cervical ripening.

Intrapartum management

●Magnesium sulfate for neuroprotection – Magnesium sulfate is administered for neuroprotection in pregnancies <32 weeks. When studied specifically in pregnancies with growth-restricted fetuses, a decrease in significant neurodevelopmental impairment and death was observed [70]. Dosing and evidence of efficacy are reviewed separately. (See "Neuroprotective effects of in utero exposure to magnesium sulfate".)

●Intrapartum fetal monitoring – Continuous fetal heart rate monitoring is indicated, given the increased potential for fetal hypoxemia during labor. (See "Intrapartum fetal heart rate monitoring: Overview" and "Intrapartum category I, II, and III fetal heart rate tracings: Management".)

OUTCOME/PROGNOSIS — 

The outcome/prognosis of FGR newborns with congenital or genetic abnormalities or congenital infection depends on the specific abnormality. (See separate topic reviews on specific disorders).

The outcome/prognosis in other cases is discussed below.

Pediatric

●Short-term morbidity and mortality – Fetal demise, neonatal death, and neonatal morbidity are more common in FGR than in neonates with birth weights that are appropriate for gestational age [71]. The prognosis worsens with early-onset FGR, increasing severity of FGR, and absent or reversed end-diastolic flow on umbilical artery (UA) Doppler [72]. In a systematic review of studies of FGR diagnosed before 32 weeks of gestation (2895 pregnancies delivered after 2000), the frequencies of fetal and neonatal death were 12 and 8 percent, respectively [73]. The most common neonatal morbidities were respiratory distress syndrome (34 percent), retinopathy of prematurity (13 percent), and sepsis (30 percent). The quality of evidence was generally rated as very low to moderate, except for three large, well-designed, randomized trials. Newborn complications are reviewed in depth separately. (See "Fetal growth restriction (FGR) and small for gestational age (SGA) newborns".)

●Long-term morbidity – FGR may predispose to hypertension, type-2 diabetes mellitus, coronary heart disease, and chronic kidney disease in adulthood, which has been attributed to partial resetting of fetal metabolic homeostasis and endocrine systems in response to in utero nutritional deprivation. (See "Fetal growth restriction (FGR) and small for gestational age (SGA) newborns", section on 'Impact on health status in adulthood'.)

The combination of preterm birth and severe FGR increases the risk for long-term neurodevelopmental abnormalities and impaired cognitive performance. In the systematic review of studies of FGR diagnosed before 32 weeks of gestation, 476 children underwent neurodevelopmental assessment and 12 percent were diagnosed with cognitive impairment and/or cerebral palsy [73]. These findings should be interpreted cautiously given the small proportion of children with follow-up and differences in patient and pregnancy characteristics among the studies.

Maternal

Risk for cardiovascular disease — It has been hypothesized that FGR may be a marker for prepregnancy subclinical maternal cardiovascular impairment. This would explain why the birth of a newborn with FGR unrelated to anatomic or genetic abnormalities appears to be predictive of an increased long-term maternal risk for cardiovascular disease (coronary artery disease, myocardial infarction, coronary revascularization, peripheral arterial disease, transient ischemic attack, stroke). A systematic review of 10 cohort studies found a weak but consistent trend of an increased risk of cardiovascular disease-related morbidity and mortality in patients with a history of birth of a small for gestational age (SGA) newborn compared with those with no such history (odds ratios ranged from 1.09 to 3.50) [74]. Pooling was not performed because of variations in the exposure definition among studies.

Whether risk-reduction interventions should be recommended because of a history of FGR is unclear, but healthy lifestyle changes in patients with traditional risk factors for cardiovascular disease (eg, smoking, overweight and obesity, unhealthy diet, physical inactivity) are beneficial. (See "Overview of primary prevention of cardiovascular disease in adults".)

Future pregnancies

Recurrence risk — There is a tendency to repeat SGA births in successive pregnancies [75,76]. As an example, a prospective national cohort study from the Netherlands reported that the risk of a nonanomalous SGA birth (<5^th percentile) in the second pregnancy of patients whose first birth was SGA versus not SGA was 23 and 3 percent, respectively [75]. The odds of recurrence increase markedly as the number of previous SGA births increases [77].

Furthermore, uteroplacental insufficiency may manifest in different ways in different pregnancies. Growth restriction, preterm birth, preeclampsia, abruption, and stillbirth can all be sequelae of impaired placental function. The association between an SGA birth in a first pregnancy and stillbirth in a subsequent pregnancy was illustrated by analysis of data from the Swedish Birth Register (table 3) [78]; subsequent studies from the United States and Australia reported similar findings [79,80]. The highest risk of stillbirth was in patients with a preterm SGA birth.

Risk reduction in subsequent pregnancies

●General principles – In subsequent pregnancies, any potentially treatable causes of suboptimal fetal growth should be addressed (eg, cessation of smoking and alcohol intake, chemoprophylaxis and mosquito avoidance in areas where malaria is prevalent, balanced energy/protein supplementation in patients with significant nutritional deficiencies). (Refer to individual topic reviews).

Avoiding a short interpregnancy interval may also be beneficial as intervals less than 6 to 12 months have been associated with an increased risk of SGA birth [81]. (See "Interpregnancy interval: Optimizing time between pregnancies", section on 'Why birth spacing may affect pregnancy outcome'.)

Dietary changes and use of supplements have been evaluated, but the studies generally showed no benefit or had serious design limitations [82-86].

●Selective role for low-dose aspirin – Low-dose aspirin may be effective when FGR is secondary to preeclampsia since aspirin appears to reduce the risk of developing preeclampsia in patients at moderate to high risk of developing the disorder. In a meta-analysis of 45 randomized trials of low-dose aspirin for prevention of preeclampsia and FGR in patients at high risk, aspirin prophylaxis markedly reduced the incidence of FGR (relative risk [RR] 0.56, 95% CI 0.44-0.70) compared with placebo/no treatment [87]. Low-dose aspirin is not recommended in the absence of risk factors for preeclampsia [88]. These data are reviewed in more detail separately. (See "Preeclampsia: Prevention", section on 'Low-dose aspirin'.)

The combination of low-dose aspirin and low-molecular-weight heparin (LMWH) was not more effective than aspirin alone in a randomized trial [89].

●No role for anticoagulation – Anticoagulation with unfractionated heparin or LMWH does not reduce the risk of recurrent placenta-mediated late-pregnancy complications, such as growth restriction. In a meta-analysis using individual patient data from randomized trials of LMWH therapy versus no LMWH for patients with any prior placenta-mediated pregnancy complications, the intervention did not significantly reduce the incidence of the primary composite outcome (early-onset or severe preeclampsia, SGA <5^th percentile, abruption, pregnancy loss ≥20 weeks of gestation: 62 of 444 [14 percent] versus 95 of 443 [22 percent], RR 0.64, 95% CI 0.36-1.11) [90]. These data support avoiding anticoagulation in patients with previous placenta-mediated disease, given the lack of clear benefit and potential risks of anticoagulation, cost, and inconvenience.

Selected patients with obstetric antiphospholipid syndrome are an exception. Management of these patients is discussed elsewhere. (See "Antiphospholipid syndrome: Obstetric implications and management in pregnancy".)

Management of subsequent pregnancies — Accurate dating by early ultrasonography is important to establish gestational age, with subsequent intermittent ultrasound examinations to monitor fetal growth. A committee opinion from the American College of Obstetricians and Gynecologists (ACOG) suggests antenatal fetal surveillance in pregnancies after a previous FGR that required a preterm birth [91], based on data that these pregnancies (even if the fetus is an appropriate size for dates) are at increased risk of stillbirth and the risk is inversely related to the gestational age at the first SGA birth [78,80,92].

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

●Fetal surveillance – The focus of fetal surveillance in pregnancies with fetal growth restriction (FGR) is to identify those fetuses who are at highest risk of perinatal demise and thus may benefit from early delivery. Antenatal surveillance should begin at a gestational age when delivery would be considered for perinatal benefit. The key fetal evaluations are:

•Growth – Serial estimation of estimated fetal weight (EFW) is performed at two- to four-week intervals. (See 'Fetal weight' above.)

•Monitoring – The general approach to Doppler and fetal behavioral monitoring is shown in the algorithm (algorithm 1).

-Doppler – The umbilical artery (UA) Doppler is the key Doppler parameter that is monitored. The frequency of testing depends on the findings. Although not all centers in the United States use middle cerebral artery (MCA) and ductus venosus (DV) Doppler in fetal surveillance of FGR because of its low predictive value for adverse perinatal outcome, the author of this topic monitors UA and MCA Doppler starting at 26 weeks of gestation or if the EFW is greater than 500 grams. If one of the two is abnormal, the frequency of fetal monitoring is increased to twice a week: a biophysical profile (BPP) and Doppler on one day (eg, Monday) and a nonstress test (NST) on a second day (eg, Thursday). The author also monitors DV Doppler in patients with absent or reversed UA Doppler (these patients are usually admitted to the hospital) to assess the severity of the condition but not to determine delivery. (See 'Doppler ultrasonography, nonstress test/cardiotocography, and biophysical profile' above.)

-Fetal behavior (nonstress test [NST]/cardiotocography [CTG] and biophysical profile [BPP]) – NST/CTG/BPP frequency is based on Doppler results and presence of oligohydramnios or other comorbidities. (See 'Doppler ultrasonography, nonstress test/cardiotocography, and biophysical profile' above.)

●Timing of delivery – The timing of delivery for fetal indication is based on a combination of factors, including UA Doppler findings, BPP score, NST/CTG results, gestational age, and fetal weight. A course of antenatal betamethasone (or dexamethasone) is administered to pregnancies at less than 34+0 weeks of gestation when preterm birth is anticipated in the next seven days. (See 'General approach to timing' above and 'Antenatal corticosteroids' above.)

●Delivery route – Cesarean birth is performed for standard obstetric indications. If a trial of labor is planned, an unfavorable cervix is not a reason to avoid induction. However, when the indication for delivery is reversed flow of the UA, we give patients the option of a scheduled cesarean birth, especially when the cervix is unfavorable, because many of these fetuses will not tolerate labor and we wish to avoid adding more stress on a chronic hypoxic fetus. (See 'Route of birth' above.)

●Pediatric outcome/prognosis – The outcome/prognosis of newborns with anatomic or genetic abnormalities or congenital infection depends on the specific abnormality and are discussed elsewhere. (See separate topic reviews on specific disorders).

Fetal demise, neonatal death, and neonatal morbidity are more common in FGR than in neonates with birth weights that are appropriate for gestational age. The prognosis worsens with early-onset FGR, increasing severity of growth restriction, and absent or reversed end-diastolic flow on UA Doppler. Long-term risks include growth abnormalities, impaired neurodevelopment, and increased risk for hypertension, type-2 diabetes mellitus, coronary heart disease, and chronic kidney disease in adulthood. (See 'Pediatric' above.)

●Maternal outcome/prognosis

•There is a tendency to repeat small for gestational age (SGA) births in successive pregnancies. Furthermore, uteroplacental insufficiency may manifest in different ways in different pregnancies. Growth restriction, preterm birth, preeclampsia, abruption, and stillbirth can all be sequelae of impaired placental function (table 3). (See 'Future pregnancies' above.).

Low-dose aspirin may be effective when FGR is secondary to preeclampsia (see "Preeclampsia: Prevention", section on 'Low-dose aspirin'). Anticoagulation with unfractionated heparin or low-molecular-weight heparin (LMWH) does not reduce the risk of recurrent placenta-mediated late-pregnancy complications, such as growth restriction. (See 'Risk reduction in subsequent pregnancies' above.)

•The birth of a newborn with FGR may be predictive of an increased long-term maternal risk for cardiovascular disease. Whether risk-reduction interventions should be recommended because of a history of FGR is unclear, but healthy lifestyle changes in patients with traditional risk factors for cardiovascular disease (eg, smoking, overweight and obesity, unhealthy diet, physical inactivity) are beneficial. (See 'Risk for cardiovascular disease' above and "Overview of primary prevention of cardiovascular disease in adults".)

ACKNOWLEDGMENT — 

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