Summary of Society for Maternal-Fetal Medicine (SMFM) Consult Series #52: Diagnosis and management of fetal growth restriction

Created in partnership with the Society for Maternal-Fetal Medicine. SMFM was established in 1977 to “give Maternal-Fetal Medicine (MFM) physicians and scientists a place to share knowledge, research and clinical best practices in order to improve care for moms and babies.”

Introduction

Fetal growth restriction (FGR) can result from a variety of maternal, fetal, and placental conditions. It occurs in up to 10% of pregnancies and is second to premature birth as the most common cause of infant morbidity and mortality.^1-3

Terminology & diagnostic criteria

FGR is commonly defined as an ultrasonographic estimated fetal weight (EFW) below the 10th percentile for gestational age. Small for gestational age (SGA) describes a newborn whose birth weight is less than the 10th percentile for gestational age. A challenge in the prenatal management of FGR is differentiating the constitutionally small fetus with a normal neonatal outcome from one who is pathologically growth restricted and at risk for postnatal complications.

There is significant variation in the diagnostic criteria used for FGR ^4-6. However, evidence supports the use of abdominal circumference (AC) as a diagnostic criterion for FGR.^7-9 We recommend that FGR be defined as an ultrasonographic EFW or AC below the 10th percentile for gestational age. (GRADE 1B)

Ultrasonographic estimation of fetal weight

The most widely used method for estimating fetal weight and calculating weight percentile in the United States is based on the Hadlock formula.¹⁰ Use of new standards, such as INTERGROWTH-21, National Institute of Child Health and Human Development (NICHD), and World Health Organization (WHO) standards, has not been shown to improve the detection and outcome of FGR.^11-13 We recommend the use of population-based fetal growth references (such as Hadlock) in determining fetal weight percentiles. (GRADE 1B)

Classification of FGR

Timing of diagnosis

Fetal growth restriction has been categorized as early- or late-onset based on gestational age at prenatal ultrasound diagnosis. Early-onset FGR is diagnosed before 32 weeks of gestation, is typically more severe, tends to follow an established Doppler pattern of fetal deterioration, shows more significant placental dysfunction than late-onset FGR, and is more commonly associated with maternal hypertensive disorders of pregnancy.

Fetuses with genetic abnormalities can also present with early-onset FGR, commonly in association with fetal and amniotic fluid abnormalities. Late-onset FGR is diagnosed at or after 32 weeks of gestation. Late-onset FGR represents approximately 70% to 80% of FGR cases and is typically milder in presentation.^14,15

Severity of FGR

The presence of abnormal umbilical artery Doppler indices has been found to predict adverse perinatal outcomes.¹⁶ An EFW below the 3rd percentile has also been associated with an increased risk of adverse perinatal outcome irrespective of umbilical and middle cerebral artery Doppler indices,¹⁷ and has therefore been found to represent a more severe form of FGR.

Symmetric & asymmetric FGR

FGR has been classified as symmetric or asymmetric based on the ratio between the head circumference and the abdominal circumference (HC/AC). Growth and developmental delay from birth to 4 years of age are similar in symmetric and asymmetric growth-restricted preterm newborns.¹⁸ Furthermore, HC/AC is not an independent predictor of adverse pregnancy outcomes.¹⁹

Management of FGR

General considerations

No preventive strategies or treatments, including nutritional and dietary supplements or bed rest, have been proven to be effective in preventing FGR or reducing the incidence of SGA births.^20-23 The American College of Obstetricians and Gynecologists recommends against low-dose aspirin for the sole indication of FGR prevention.²⁴ We recommend against the use of low-molecular-weight heparin for the sole indication of prevention of recurrent FGR. (GRADE 1B) We also recommend against sildenafil or activity restriction for in-utero treatment of FGR. (GRADE 1B)

Management of FGR is based on early diagnosis, optimal fetal surveillance, and timely delivery. In pregnancies with FGR, delivery decisions require balancing the risk of prematurity against that of stillbirth. Accumulating evidence suggests a benefit to the use of umbilical artery Doppler in the surveillance of FGR. The presence of a standardized protocol for diagnosis and management appears to be associated with more favorable outcomes.²⁵ The single most important prognostic factor in preterm fetuses with growth restriction is the gestational age at delivery.

Initial diagnosis

With the initial diagnosis of FGR and if not previously performed, we recommend that a detailed obstetrical ultrasound examination (CPT code 76811) be performed with early-onset FGR since up to 20% of cases are associated with fetal or chromosomal abnormalities. (GRADE 1B) We recommend that women be offered fetal diagnostic testing, including chromosomal microarray analysis (CMA), when FGR is detected and a fetal malformation, polyhydramnios, or both are also present, regardless of gestational age. (GRADE 1B) Recent studies evaluating the role of CMA in fetuses with early-onset growth restriction and no structural malformations have identified a 4% to 10% incremental yield of CMA over karyotype.^26-28 Therefore, we recommend that pregnant women be offered prenatal diagnostic testing with CMA when unexplained isolated FGR is diagnosed at less than 32 weeks of gestation. (GRADE 1C)

Regarding the association of maternal infections with FGR, a study that included 319 pregnancies found no cases of maternal or congenital infection with toxoplasma, rubella, or herpes. Six (1.8%) fetuses were diagnosed with congenital CMV; 2 (0.6%) of these fetuses had no ultrasonographic findings other than FGR.29 We recommend against screening for toxoplasmosis, rubella, or herpes in pregnancies with FGR in the absence of other risk factors and recommend PCR for CMV in women with unexplained FGR who elect diagnostic testing with amniocentesis. (GRADE 1C)

Umbilical artery Doppler

An abnormal umbilical artery Doppler waveform reflects the presence of placental insufficiency and can help differentiate the growth-restricted fetus from the fetus that is constitutionally small. Incorporation of umbilical artery Doppler evaluation in the management of high-risk pregnancies has been shown to significantly reduce the risk of perinatal death, induction of labor, and cesarean delivery. However, it does not reliably predict adverse pregnancy outcome in late-onset FGR.³⁰ 

An abnormal umbilical artery Doppler is defined as a pulsatility index (PI), resistance index (RI), or systolic/diastolic (S/D) ratio S/D ratio greater than the 95th percentile for gestational age or an absent or reversed end-diastolic velocity (AEDV or REDV).

Because no randomized trials with adequate sample size have been done regarding the optimal frequency of umbilical artery Doppler for FGR surveillance, protocols vary from weekly umbilical artery Doppler to a 2- to 4-week interval. We recommend that once FGR is diagnosed, serial umbilical artery Doppler assessment should be performed to assess for deterioration. (GRADE 1C) This assessment should initially occur every 1 to 2 weeks. If the umbilical artery Doppler remains normal after this initial assessment, a less frequent interval of umbilical artery Doppler testing (eg, every 2 to 4 weeks) may be considered.

With decreased end-diastolic velocity, ie, flow ratios greater than the 95th percentile, or in pregnancies with severe FGR (EFW less than the 3rd percentile), we suggest weekly umbilical artery Doppler evaluation. (GRADE 2C) We recommend Doppler assessment up to 2 to 3 times per week when umbilical artery AEDV is detected due to the potential for deterioration and development of REDV. (GRADE 1C) In the setting of REDV, we suggest hospitalization, administration of antenatal corticosteroids, heightened surveillance with cardiotocography (CTG) at least 1 to 2 times per day, and consideration of delivery depending on the entire clinical picture and results of additional evaluation of fetal well-being. (GRADE 2C) Hospital admission should be considered if fetal surveillance of more often than 3 times per week is deemed necessary.

Once FGR is diagnosed, assessment of fetal growth and weight should be performed at least every 3 to 4 weeks. Consideration can be given for a 2-week interval in cases of severe FGR or with abnormal umbilical artery Doppler.

Doppler assessment of other blood vessels

Clinical trials are needed to evaluate the use of ductus venosus Doppler and middle cerebral artery Doppler in guiding clinical management of early- to late-onset FGR. In addition, uterine artery Doppler has limited diagnostic accuracy and clinical utility in predicting FGR, SGA birth, and perinatal mortality. We suggest that Doppler assessment of the ductus venosus, middle cerebral artery, or uterine artery not be used for routine clinical management of early- or late-onset FGR. (GRADE 2B)

Cardiotocography

Despite the absence of large prospective studies on the role of CTG in the management of FGR, a normal CTG in pregnancies with FGR is more likely to be associated with a normal perinatal outcome, and the presence of spontaneous repetitive late decelerations is accepted as an indication for delivery in viable pregnancies with FGR, irrespective of Doppler findings. We suggest weekly CTG testing after viability for FGR without A/REDV and that the frequency be increased when FGR is complicated by A/REDV or other comorbidities or risk factors. (GRADE 2C)

Biophysical profile

Recent studies have questioned the value of BPP in fetal surveillance of high-risk pregnancies, including early-onset severe FGR, due to a high prevalence of false-positive and false-negative results. While fetal deterioration has been reported to be independently reflected by Doppler and BPP testing, further studies are required to prove the usefulness of BPP or of combining these testing modalities.

Amniotic fluid volume

Amniotic fluid volume abnormalities do not independently increase the risk for adverse outcomes in FGR.⁶ There is currently a paucity of data on the role of amniotic fluid volume measurement in FGR management and delivery. However, current guidelines on medically indicated late-preterm and early-term deliveries suggest delivery between 34 weeks 0 days and 37 weeks 6 days of gestation for FGR associated with oligohydramnios.³¹

Neonatal outcomes and delivery timing

The decision for delivery in FGR is driven by fetal and maternal factors. Fetal factors include EFW, gestational age, and findings on fetal surveillance. Maternal factors include the presence of comorbidities, such as hypertension.

The evidence supporting the timing of delivery in pregnancies with FGR and abnormal umbilical artery Doppler but without AEDV/REDV is limited. We recommend delivery at 37 weeks of gestation in pregnancies with FGR and an umbilical artery Doppler waveform with decreased diastolic flow (S/D, RI, or PI greater than the 95th percentile) but without AEDV/REDV or with severe FGR with EFW less than the 3rd percentile. (GRADE 1B)

Neonatal morbidity and mortality rates associated with AEDV are higher than rates of complications of prematurity at 33 to 34 weeks of gestation.³² Therefore, we recommend delivery at 33 to 34 weeks of gestation for pregnancies with FGR and AEDV. (GRADE 1B) In the presence of REDV, neonatal morbidity and mortality rates are higher than complications of prematurity at 30 to 32 weeks of gestation.³² Therefore, we recommend delivery at 30 to 32 weeks of gestation for pregnancies with FGR and REDV. (GRADE 1B) We suggest delivery at 38 to 39 weeks of gestation with FGR when the EFW is between the 3rd and 10th percentile and the umbilical artery Doppler is normal. (GRADE 2C)

Growth-restricted fetuses, particularly those with AEDV/REDV, are at an increased risk for decelerations in labor, emergency cesarean delivery, and metabolic acidemia at delivery. We suggest that for pregnancies with FGR complicated by AEDV/REDV, cesarean delivery should be considered based on the entire clinical scenario. (GRADE 2C)

We recommend antenatal corticosteroids if delivery is anticipated before 33 weeks 6 days of gestation or for pregnancies between 34 weeks 1 days and 36 weeks 6 days of gestation in women without contraindications who are at risk of preterm delivery within 7 days and who have not received a prior course of antenatal corticosteroids. (GRADE 1A) We also recommend magnesium sulfate for fetal and neonatal neuroprotection for women with pregnancies that are less than 32 weeks of gestation. (GRADE 1A)

References

1.Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A. Morbidity and mortality among very-low-birth-weight neonates with intrauterine growth restriction. The Vermont Oxford Network. Am J Obstet Gynecol 2000;182:198-206.

2.Swanson AM, David AL. Animal models of fetal growth restriction: Considerations for translational medicine. Placenta 2015;36:623-30.

3.Unterscheider J, O'Donoghue K, Daly S, et al. Fetal growth restriction and the risk of perinatal mortality-case studies from the multicentre PORTO study. BMC Pregnancy Childbirth 2014;14:63.

4.Chauhan SP, Gupta LM, Hendrix NW, Berghella V. Intrauterine growth restriction: comparison of American College of Obstetricians and Gynecologists practice bulletin with other national guidelines. Am J Obstet Gynecol 2009;200:409.e1-6.

5.McCowan LM, Figueras F, Anderson NH. Evidence-based national guidelines for the management of suspected fetal growth restriction: comparison, consensus, and controversy. Am J Obstet Gynecol 2018;218:S855-s68.

6.Unterscheider J, Daly S, Geary MP, et al. Optimizing the definition of intrauterine growth restriction: the multicenter prospective PORTO Study. Am J Obstet Gynecol 2013;208:290.e1-6.

7.David C, Tagliavini G, Pilu G, Rudenholz A, Bovicelli L. Receiver-operator characteristic curves for the ultrasonographic prediction of small-for-gestational-age fetuses in low-risk pregnancies. Am J Obstet Gynecol 1996;174:1037-42.

8.Blue NR, Yordan JMP, Holbrook BD, Nirgudkar PA, Mozurkewich EL. Abdominal Circumference Alone versus Estimated Fetal Weight after 24 Weeks to Predict Small or Large for Gestational Age at Birth: A Meta-Analysis. Am J Perinatol 2017;34:1115-24.

9.Caradeux J, Martinez-Portilla RJ, Peguero A, Sotiriadis A, Figueras F. Diagnostic performance of third-trimester ultrasound for the prediction of late-onset fetal growth restriction: a systematic review and meta-analysis. Am J Obstet Gynecol 2019;220:449-59.e19.

10.Hadlock FP, Harrist RB, Martinez-Poyer J. In utero analysis of fetal growth: a sonographic weight standard. Radiology 1991;181:129-33.

11.Blue NR, Beddow ME, Savabi M, Katukuri VR, Chao CR. Comparing the Hadlock fetal growth standard to the Eunice Kennedy Shriver National Institute of Child Health and Human Development racial/ethnic standard for the prediction of neonatal morbidity and small for gestational age. Am J Obstet Gynecol 2018;219:474.e1-.e12.

12.Blue NR, Savabi M, Beddow ME, et al. The Hadlock Method Is Superior to Newer Methods for the Prediction of the Birth Weight Percentile. J Ultrasound Med 2019;38:587-96.

13.Monier I, Ego A, Benachi A, Ancel PY, Goffinet F, Zeitlin J. Comparison of the Hadlock and INTERGROWTH formulas for calculating estimated fetal weight in a preterm population in France. Am J Obstet Gynecol 2018;219:476.e1-.e12.

14.Figueras F, Caradeux J, Crispi F, Eixarch E, Peguero A, Gratacos E. Diagnosis and surveillance of late-onset fetal growth restriction. Am J Obstet Gynecol 2018;218:S790-S802.e1.

15.Dall'Asta A, Brunelli V, Prefumo F, Frusca T, Lees CC. Early onset fetal growth restriction. Matern Health Neonatol Perinatol 2017;3:2.

16.Unterscheider J, Daly S, Geary MP, et al. Predictable progressive Doppler deterioration in IUGR: does it really exist? Am J Obstet Gynecol 2013;209:539.e1-7.

17.Savchev S, Figueras F, Cruz-Martinez R, Illa M, Botet F, Gratacos E. Estimated weight centile as a predictor of perinatal outcome in small-for-gestational-age pregnancies with normal fetal and maternal Doppler indices. Ultrasound Obstet Gynecol 2012;39:299-303.

18.Bocca-Tjeertes I, Bos A, Kerstjens J, de Winter A, Reijneveld S. Symmetrical and asymmetrical growth restriction in preterm-born children. Pediatrics 2014;133:e650-6.

19.David C, Gabrielli S, Pilu G, Bovicelli L. The head-to-abdomen circumference ratio: a reappraisal. Ultrasound Obstet Gynecol 1995;5:256-9.

20.Gülmezoglu AM, Hofmeyr GJ. Bed rest in hospital for suspected impaired fetal growth. Cochrane Database Syst Rev 2000;1996:Cd000034.

21.Khoury J, Henriksen T, Christophersen B, Tonstad S. Effect of a cholesterol-lowering diet on maternal, cord, and neonatal lipids, and pregnancy outcome: a randomized clinical trial. Am J Obstet Gynecol 2005;193:1292-301.

22.Mori R, Ota E, Middleton P, Tobe-Gai R, Mahomed K, Bhutta ZA. Zinc supplementation for improving pregnancy and infant outcome. Cochrane Database Syst Rev 2012:Cd000230.

23.Peña-Rosas JP, De-Regil LM, Garcia-Casal MN, Dowswell T. Daily oral iron supplementation during pregnancy. Cochrane Database Syst Rev 2015:Cd004736.

24.American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 743: Low-Dose Aspirin Use During Pregnancy. Obstet Gynecol 2018;132:e44-e52.

25.Lees C, Marlow N, Arabin B, et al. Perinatal morbidity and mortality in early-onset fetal growth restriction: cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE). Ultrasound Obstet Gynecol 2013;42:400-8.

26.An G, Lin Y, Xu LP, et al. Application of chromosomal microarray to investigate genetic causes of isolated fetal growth restriction. Mol Cytogenet 2018;11:33.

27.Borrell A, Grande M, Meler E, et al. Genomic Microarray in Fetuses with Early Growth Restriction: A Multicenter Study. Fetal Diagn Ther 2017;42:174-80.

28.Borrell A, Grande M, Pauta M, Rodriguez-Revenga L, Figueras F. Chromosomal Microarray Analysis in Fetuses with Growth Restriction and Normal Karyotype: A Systematic Review and Meta-Analysis. Fetal Diagn Ther 2018;44:1-9.

29.Yamamoto R, Ishii K, Shimada M, et al. Significance of maternal screening for toxoplasmosis, rubella, cytomegalovirus and herpes simplex virus infection in cases of fetal growth restriction. J Obstet Gynaecol Res 2013;39:653-7.

30.Oros D, Figueras F, Cruz-Martinez R, Meler E, Munmany M, Gratacos E. Longitudinal changes in uterine, umbilical and fetal cerebral Doppler indices in late-onset small-for-gestational age fetuses. Ultrasound Obstet Gynecol 2011;37:191-5.

31.Spong CY, Mercer BM, D'Alton M, Kilpatrick S, Blackwell S, Saade G. Timing of indicated late-preterm and early-term birth. Obstet Gynecol 2011;118:323-33.

32.Caradeux J, Martinez-Portilla RJ, Basuki TR, Kiserud T, Figueras F. Risk of fetal death in growth-restricted fetuses with umbilical and/or ductus venosus absent or reversed end-diastolic velocities before 34 weeks of gestation: a systematic review and meta-analysis. Am J Obstet Gynecol 2018;218:S774-S82.e21.