Fetal Growth Restriction ACOG PB 204 February 2019

Fetal Growth Restriction ACOG PB 204, February 2019 (Replaces Practice Bulletin Number 134, Feb 2013) Greg Epstein, PGY 2 CORE 4/16/2020

Background • Terminology • Fetal Growth Restriction (FGR) = Fetus with EFW <10 th %ile • Small for Gestational Age (SGA) = Newborn weighing < 10 th %ile • Prevalence • Difficult to assess, given reporting based on inconsistent definitions and individualized growth potential • Formulas for individualized growth standards have been proposed, but have not shown to improve outcomes

Background • Etiology • Many underlying pathophysiologic mechanisms, which generally have same final common pathway: • Sub-optimal uterine-placental perfusion • Sub-optimal fetal nutrition

Background - Etiology • Maternal disorders • Chronic disorders associated with vascular disease • • • Hypertensive diseases Renal insufficiency Pregestational diabetes Cyanotic cardiac disease Autoimmune disesase • Systemic lupus erythematosus • Antiphospholipid syndrome: acquired immune mediated thrombophilia • Not consistently associated • Factor V Leiden, Prothrombin mutation, MTHFR mutations

Background - Etiology • Substance use / abuse • • • Modifiable factors Tobacco: associate with 3. 5 -fold increased risk of SGA Alcohol: risk of SGA increased with intake of only 1 -2 drinks/day Cocaine Narcotics

Background - Etiology • Maternal Nutrition • Longitudinal studies of women who became pregnant during famines • Association between SGA and maternal malnutrition • Extremely poor protein intake before 26 wks SGA • Severe caloric restriction (600 -900 kcal/day) modest reduction in birth weight • Multiple Gestation • Twin pregnancies (2 -3% of live births in US) • • 10 -15% adverse neonatal outcomes Increased frequency of preterm births and SGA births Risk of SGA reported as high as 25% (twins) and 60% (triplets / quads) Monochorionic twin pregnancies: risk of SGA 2/2 TTTS

Background - Etiology • Teratogen Exposoure • Medication effects dependent on: • • Inherent teratogenicity of the drug Timing and duration of exposure Dosage Individual genetic predisposition for the drug • Certain drugs are associate with increased risk of FGR • Antineoplastics (e. g. cyclophosphamide) • Antiepileptics (e. g. valproic acid) • Antithrombotics (e. g. warfarin)

Background - Etiology • Infectious Diseases • Estimated 10 -15% of FGR caused by intrauterine infections • Malaria accounts for most cases of FGR worldwide • Other infections: • CMV, Rubella, Toxoplasmosis, Varicella, Syphillis • Genetic / Structural disorders • Trisomies (13/18): 50% of affected fetuses have FGR • Confined placental mosaicism (dx by CVS) is associated with FGR • Congenital heart disease: increased risk of FGR • Gastroschisis: 25% affected fetuses have FGR

Background - Etiology • Placental Disorders and Umbilical Cord Abnormalities • Abnormal placentation leading to poor perfusion is MCC for FGR • Also associated with FGR • Placenta: abruption, infarction, circumvallate shape, hemangioma, chorioangioma • Cord: velamentous / marginal insertion • Not associated with FGR: Accreta or Previa

Background • Perinatal Morbidity and Mortality • Increased risk of stillbirth • <10 th %ile : 1. 5% (2 x normal fetus) • <5 th %ile : 2. 5% • Increased risk of M&M if AEDF/REDF noted on UAD • SGA predisposed: • hypoglycemia, hyperbilirubinemia, hypothermia • intraventricular hemorrhage, necrotizing enterocolitis, seizures, respiratory distress syndrome • Sepsis • Neonatal death

Background • Screening for Fetal Growth Restriction • Fundal height between 24 -38 WGA • Single FH @ 32 -34 WGA: 65 -85% sensitive, 96% specific for detecting IUGR • Accuracy may be limited by obesity and uterine fibroids • Ultrasound • Biometrics: BPD, HC, AC and FL • EFW may deviate up to 20% (in 95% of cases); >20% in the other 5% • If IUGR diagnosed, evaluate amniotic fluid level and umbilical artery Doppler flow • Fetal anatomic survey is also recommended, if not already performed • Rate of perinatal death reduced by up to 29% when UAD velocimetry is used • Ductus venosus flow assessment not shown to improve outcomes

Clinical Considerations and Recommendations How should pregnancies be screened for IUGR, and how is screening accomplished? • Start with Medical and Obstetric History • Fundal height measurements after 24 weeks gestational age • Proposed discrepancy between WGA and FH > 3 to identify possible IUGR • Limited by maternal obesity, multiple pregnancies, uterine fibroids • Ultrasound may be used for screening if fundus cannot be palpated • No evidence for using other screening methods to improve outcomes • Universal 3 TM US, UAD velocimetry, analyte measurements (PAPP-A)

Clinical Considerations and Recommendations How should women with prior history of SGA newborns be evaluated? • Risk of recurrence is ~ 20% • Review medical / OB history to identify modifiable factors • Serial US for growth assessment – reasonable, but no established regimen • History alone is not an indication for antenatal testing (NST, BPP, UAD) • Insufficient evidence for: • Screening and treatment for antiphospholipid syndrome • Maternal testing for inherited thrombophilias (e. g. factor V Leiden, etc)

Clinical Considerations and Recommendations Can fetal growth restriction be prevented? • No nutritional or dietary supplemental strategies have been found to be effective, or are recommended by ACOG • No consistent evidence that either inpatient of outpatient bed rest prevents IUGR, or incidence of SGA births • Insufficient evidence for use of aspirin to prevent placental insufficiency in women with history of SGA birth

Clinical Considerations and Recommendations When should genetic counseling and prenatal diagnostic testing be offered in the case of fetal growth restriction? • Combination of IUGR and structural defect should prompt patient counseling on type of anomaly, and consideration of diagnostic tests • IUGR detected earlier in gestation is more likely associated with aneuploidy • 2 nd TM onset of IUGR is an indication for genetic counseling and prenatal diagnostic testing

Clinical Considerations and Recommendations How should a pregnancy complicated by fetal growth restriction be evaluated and managed? • Ultrasound is the best method to evaluate IUGR • Serial measurements of fetal biometry and amniotic fluid volume • Should not start Antenatal testing (NST/BPP) or UA Dopplers before gestational age when delivery is considered for perinatal benefit • No optimal regimen has been established • Fetal growth can be adequately evaluated with serial US, every 3 -4 weeks • Not more frequently than every 2 weeks, because of error associate with ultrasound measurements

Clinical Considerations and Recommendations What is the role of Doppler velocimetry in evaluating pregnancy complicated by fetal growth restriction? • UAD is important for managing pregnancy c/b IUGR • Use in conjunction with ANT (NST/BPP) to improve outcomes • May reveal etiology of IUGR: increased umbilical artery impedance (increasing S/D ratio) is suggestive of placental insufficiency • Absent or reversed end diastolic flow (AEDF/REDF) are associated with increased risk of perinatal mortality • TRUFFLE study findings – uncertain role use of ductus venosus Doppler • Delivery based on late changes in the ductus venosus Doppler were associated with less neurodevelopmental deficiency at 2 yrs, compared to using FHT to decide; • But this strategy is associated with higher perinatal/infant mortality

Clinical Considerations and Recommendations When should a growth-restricted fetus be delivered? • Depends on etiology, gestational age and other findings (ANT/UAD) • Early delivery may not improve outcome for aneuploidy or congenital defects • If intervention for perinatal benefit is preferred, ANT may guide mgmt • Two timing strategies: • 1) Delivery between 38/0 – 39/6, if isolated IUGR • 2) Delivery between 32/0 – 37/6, if IUGR with additional risk factors* • When delivery for IUGR is anticipated <34 wks, ACS are recommended • ACS recommended between 34/0 – 36/6 if • Delivery expected w/in 7 days, AND • Patient has not already received previous course of ACS

Summary of Recommendations and Conclusions Level A • UAD in conjunction with standard ANT (NST/BPP) is associated with improved outcomes in fetuses with IUGR • ACS are recommended if delivery is anticipated before 34/0 because of improved preterm neonatal outcomes. • ACS are recommended between 34/0 – 36/6 in women at risk of delivery w/in 7 days, and who have not already received previous course of ACS. • For cases in which delivery occurs before 32 wks, Mg. SO 4 should be considered for fetal/neonatal neuroprotection • Nutritional and dietary strategies for prevention of IUGR are not effective and are not recommended

Summary of Recommendations and Conclusions Level C • Fetal growth restriction alone is not an indication for cesarean delivery • The optimal timing of delivery of IUGR fetus depends on underlying etiology of IUGR, estimated gestational age, and other findings such as antenatal fetal surveillance.