Professor, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora
Dr. Hobbins reports no financial relationships relevant to this field of study.
In 2012, a special feature was devoted to the management of intrauterine growth restriction (IUGR). Since then, enough enlightening information has surfaced to necessitate our covering the topic again — with a few new twists. Most obstetric clinicians deal with IUGR on an almost daily basis, and since it can end with serious consequences for the affected fetus/child, it needs to be managed in a comprehensive way. Fetuses who are under-grown are subject to higher rates of perinatal mortality,1 immediate neonatal morbidity,2 and increased risks of later cardiovascular disease3 and neurodevelopmental abnormalities.4
Diagnosing an SGA Fetus
Small for gestational age (SGA) is defined as a fetus whose estimated fetal weight (EFW) is less than the 10th percentile or abdominal circumference (AC) is below the fifth percentile. Among the many formulas in the literature, the most commonly used is the Hadlock formula, which incorporates the head circumference, biparietal diameter, femur length, and AC.5 Through the years, this has been a serviceable method to assess fetal weight, but it is fraught with some inaccuracies. The AC is easier to acquire, and it adds the dimension of fetal deprivation because growth-restricted fetuses have smaller livers and less subcutaneous fat. Three-dimensional (3D) formulas for EFW enhance the predictability, but these formulas can be cumbersome and most require the addition of 3D thigh volumes.6
Once an EFW is calculated, it is plotted into nomograms based on gestational age. Here, the choices expand. The usual fire-up nomogram in ultrasound machines is the Hadlock curve,7 based on 372 mostly Caucasians from Texas. Other curves include a National Institute of Child Health and Human Development nomogram,8 constructed from four ethnic populations in the United States; the INTERGROWTH-21st Fetal Growth Standards Curve, which was based on World Health Organization data from eight countries;9 or homegrown formulas based on local populations. In vogue are curves that are based on maternal height, weight, sex, parity, and ethnicity and are customized to fit individual fetuses.10 Customized formulas are better at predicting perinatal outcome, such as preterm birth, need for emergency cesarean delivery, and newborn special care admissions.11
Interestingly, some researchers have questioned the benefit of the newer growth standard approaches, such as the INTERGROWTH-21 formula, when compared with the standard Hadlock formula.12 Although customized formulas are better at predicting short-term outcome, my preference is to deal with a method that leans toward over-predicting EFW < 10th percentile, since the false positives may include some deprived fetuses in the lower quartile who, while avoiding immediate perinatal morbidity, may be destined for neonatal or childhood morbidity.13
Potential for Fetal Compromise
Once the fetus is determined to be SGA, the next step has been to sort out the “constitutionally” small fetus from the growth-restricted (IUGR) one. This has been done by various Doppler and biomechanical methods. Many consider a fetus whose EFW is below the third percentile or whose mother had an abnormal uterine artery waveform earlier in pregnancy to have IUGR. There are two types of IUGR. The “early” variant usually is associated with severe growth restriction, often in patients with histories of stillbirth, preeclampsia, hypertension, previous IUGR, and in smokers. In these pregnancies, fetal growth falls off as early as 20 weeks and femur length can be curtailed almost as much as the AC, the latter always the first to be affected by intrauterine deprivation. Late IUGR usually becomes apparent after the 32nd week of gestation. The AC may be the only biometric measurement affected significantly, and these fetuses may show no sign of compromise until after 34 to 35 weeks, when the first Doppler sign is brain sparing. These babies generally are not at risk for stillbirth or severe neonatal morbidity, but often they tolerate labor poorly14 and can develop neurodevelopmental abnormalities in childhood15 and cardiovascular disease that can extend into adulthood.16
Surveillance of IUGR
Once a fetus has EFW below the 10th percentile, a variety of Doppler waveform analyses have been used to assess fetal condition. Data from recent studies have allowed a more enlightened approach to their place and worth in a diagnostic panel.
Umbilical Artery (UA) Doppler. The UAs reflect the richness of the placental circulation and often are the first sign of compromise in early IUGR when resistance is encountered from inadequate villus development, especially the terminal villi, and/or infarction. Absent/reversed end-diastolic flow is a sign of severe placental insufficiency and often is preceded by a sequential decrease in end-diastolic flow, resulting in an upward trend in the systolic to diastolic (S/D) ratio or pulsatility index (PI). Alone, UA results are not an indicator for interruption of pregnancy, but an increase in PI will alert the clinician to a placental problem to which fetuses may or may not be able to adapt.
Middle Cerebral Artery (MCA) Doppler. In contrast to the UA, the MCA reflects a fetal attempt to adapt to relative hypoxia caused by a supply line problem. “Brain sparing” occurs when increased flow is directed to the brain because of vasodilation in arteries like the MCA and is triggered by a drop in the fetal pO2. Doppler waveforms in the MCA usually show high resistance, but in IUGR the end-diastolic flow rises, resulting in a decrease in the S/D ratio and PI. In late IUGR, this may be the only sign of early fetal compromise and, even when isolated, has been associated with later neurodevelopmental problems.4
Cerebral placental ratio (CPR). This simply represents a ratio between the MCA and UA PIs. As fetal condition worsens, PIs move toward each other, and when the CPR approaches 1.0, there can be a cause for concern. CPRs below 1.08 or those plotted below the 10th percentile have been associated with higher rates of emergency cesarean delivery,17 combined neonatal morbidity,18 NICU admissions,19 and compromised neonatal acid-base status.20 Although this method appears to provide the best insight regarding fetal condition in IUGR, its value is enhanced when combined with the other tests described here.
Doppler of the Ductus Venosus (DV). The DV brings oxygenated blood from the umbilical vein to the right atrium and across the foramen ovale to the left atrium, the left ventricle, and then through the aorta to the brain. In the later stages of IUGR, the fetus attempts to adapt to hypoxia by shutting down the right lobe of the liver, thus directing more flow through the DV. Here, the oxygenated blood encounters more competition for entry into the right atrium from blood returning from the “spared” brain via the superior vena cava. What matters most is the ability of the fetal heart (which often is dysfunctional) to handle the increased preload. The waveform gradually will show a decrease in flow during atrial contraction (reflected by the a wave) when the fetus is severely compromised. When the a wave approaches zero, or dips below it, the fetus is in a pre-demise state. One study showed about a six-day average lag time between absent/reversed (A/R) flow during atrial contraction and fetal demise.21 Longitudinal studies showed that in early IUGR, the DV becomes abnormal before the standard non-stress test becomes nonreactive.22 The well-cited Trial of Randomized Umbilical and Fetal Flow in Europe (TRUFFLE) study involved longitudinal surveillance of severely growth-restricted fetuses between 26 and 32 weeks of gestation. Delivery prior to 32 weeks was based on either abnormal fetal heart rate patterns (by computerized cardiotocography), early DV changes, or A/R DV flow. Two-year follow-up of live births showed that waiting to interrupt pregnancy based only on the latter finding prior to 32 weeks resulted in the best outcome.23 In our experience, the DV never is affected in late IUGR.
Uterine Artery. Despite debate over the years, studies have shown uterine artery to be useful in predicting IUGR and preeclampsia, especially when combined in a screening strategy consisting of maternal historical factors and various biological markers. Since studies show a three- to nine-fold increased risk for IUGR with abnormal second trimester uterine artery wave forms,24 some authors have advocated their use for screening high-risk patients (for IUGR) to fashion a timeline for surveillance studies. However, no existing guidelines in the literature include serial testing.
Fetal Cardiac Function. Since IUGR fetuses are prone to later cardiovascular dysfunction in childhood3 and adulthood,16 investigators have begun to study cardiac function in this condition using newer screening tests and more sophisticated techniques to evaluate myocardial contractility. Epigenetic influences during the intrauterine life of some IUGR fetuses render their cardiomyocytes particularly vulnerable to increased afterload in early growth restriction or relative hypoxia in late pregnancy. This results in a remodeling process that adversely affects systolic and diastolic function. Unfortunately, this can last throughout the lifespan of that individual. One of the earliest signs of cardiac dysfunction is a ballooning of the lateral ventricular walls, resulting in a more globular-shaped heart and general cardiac enlargement. Researchers have found assessments of cardiac area and global sphericity index to be useful screening tests.25,26,27 Our group has found a majority of IUGR fetuses to have one or more parameters of cardiac dysfunction,28 and since there has been no correlation between these abnormalities and standard Doppler results, there is a strong suggestion that cardiac dysfunction occurs in parallel with Doppler changes. Ongoing studies should allow a better understanding of the role of cardiac function studies in the management of IUGR. However, the potential to identify vulnerable fetuses may allow cardiovascular problems to be averted through preemptive dietetic and other measures in early childhood.29,30
Suggestions for Managing IUGR
Management guidelines from official bodies often are slow to surface while the authors await the results of randomized trials to make sure that their recommendations are “evidence based.” The following suggestions/opinions from this clinician are based on currently available meta-analyses, randomized, clinical trials, observational studies, and 50 years’ worth of experience dealing with this vexing problem.
If a fetus has either an EFW < 10th percentile or an AC below the fifth percentile, a first visit encounter should include Doppler waveform analysis of: 1) UA; 2) MCA; 3) CPR; and 4) uterine artery, which can be helpful. If Doppler studies are normal, there are no maternal preconditions for IUGR, and the EFW above the third percentile, the patient can return in three to four weeks. Between visits, the patient may begin fetal kick counts. Those with any Doppler measurements outside the normal range or with an EFW below the third percentile should return in two weeks for 1) UA; 2) MCA; 3) CPR; 4) repeat the AC; and 5) non-stress test/biophysical profile. If more than one Doppler finding is abnormal or there is no increase in AC, the DV should be added to the regimen and the patient should be seen at weekly intervals for all the above evaluations. EFW should be added to the protocol every three weeks.
Suggestions for Delivery in IUGR
- Not before 28 weeks in early IUGR, even if Doppler studies (including absent or reverse flow in the DV) are abnormal, since studies have suggested that prematurity under these circumstances is worse for the fetus than hypoxia associated with abnormal Doppler or non-stress test findings. Nevertheless, there can be mitigating circumstances, and this becomes a judgment call.
- At 29 to 31 weeks if A/R flow in the DV.
- At 32 to 34 weeks if weekly abnormal CPRs drop by > 20%.
- At 34 to 36 weeks if any CPR value is abnormal (it is realized that this opinion is debatable).
- At 37 to 39 weeks if any variable is abnormal or EFW below the third percentile.
- At 39 weeks for all SGA fetuses.
- Caradeux J, Martinez-Portilla RJ, Basuki TR, et al. 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-S782.e21.
- Khalil AA, Morales-Rosello J, Elsadigg M, et al. The association between fetal Doppler and admission to neonatal unit at term. Am J Obstet Gynecol 2015;213:57.e1-7.
- Cruz-Lemini M, Crispi F, Valenzuela-Alcaraz B, et al. Fetal cardiovascular remodeling persists at 6 months in infants with intrauterine growth restriction. Ultrasound Obstet Gynecol 2016;48:349-356.
- Eixarch E, Meler E, Iraola A, et al. Neurodevelopmental outcome in 2-year-old infants who were small for gestational age term fetuses with cerebral blood flow redistribution. Ultrasound Obstet Gynecol 2008;32:894-899.
- Hadlock FP, Deter RL, Harrist RB, Park SK. Estimating fetal age: Computer-assisted analysis of multiple fetal growth parameters. Radiology 1984;152:497-501.
- Lee W, Balasubramanian M, Deter RL, et al. New fetal weight estimation models using fractional limb volume. Ultrasound Obstet Gynecol 2009;34:556-565.
- Hadlock FP, Harrist RB, Sharman RS, et al. Estimation of fetal weight with the use of head, body, and femur measurements — a prospective study. Am J Obstet Gynecol 1985;151:333-337.
- Buck Louis GM, Grewel J, Albert PS, et al. Racial/ethnic standards for fetal growth: The NICHD Fetal Growth Studies. Am J Obstet Gynecol 2015;213:449.e1-449.e41.
- Papageorghiou AT, Ohuma EO, Altman DG, et al. International standards for fetal growth based on serial ultrasound measurements: The Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project. Lancet 2014;384:869-879.
- Gardosi J, Francis A. A customized standard to assess fetal growth in a US population. Am J Obstet Gynecol 2009;201:25.e1-7.
- Chiossi G, Pedroza C, Constantine MM, et al. Customized vs population-based growth charts to identify neonates at risk of adverse outcomes: Systematic review and Bayesian meta-analysis of observational studies. Ultrasound Obstet Gynecol 2017;50:156-166.
- Nwabuobi C, Camisaca-Lopina, Leavitt, et al. INTERGROWTH-21st and Hadlock growth standards to predict neonatal small for gestational age and short-term neonatal outcomes. SMFM abstract. Am J Obstet Gynecol 2018; January supplement, S310.
- MacDonald TM, Hui L, Tong S, et al. Reduced growth velocity across the third trimester is associated with placental insufficiency in fetuses born at a normal birth weight: A prospective cohort study. BMC Med 2017;15:164.
- Cruz-Martinez R, Figueras F, Hernandez-Adrade E, et al. Brain Doppler to predict cesarean delivery for nonreassuring fetal status in term SGA fetuses. Obstet Gynecol 2011;117:618-626.
- Cruz-Martinez R, Figueras F, Oros D, et al. Cerebral blood perfusion and neurobehavioral performance in full-term small-for-gestational-age fetuses. Am J Obstet Gynecol 2009;201:474.e1-7.
- Barker DJP, Osmond C, Winter PD, et al. Weight in infancy and death from ischemic heart disease. Lancet 1989;2:577-580.
- Prior T, Mullins E, Bennett P, Kumar S. Prediction of fetal compromise in labor. Obstet Gynecol 2014;123:1263-1271.
- Bakalis S, Akolekar R, Gallo DM, et al. Umbilical and fetal middle cerebral artery Doppler at 30-34 weeks’ gestation in the prediction of adverse perinatal outcome. Ultrasound Obstet Gynecol 2015;45:409-420.
- Khalil AA, Morales-Rosello J, Morlando M, et al. Is fetal cerebroplacental ratio an independent predictor of intrapartum fetal compromise and neonatal unit admission? Am J Obstet Gynecol 2015;213:54.e1–10.
- Morales-Rosello J, Khalil A, Morlando M, et al. Poor neonatal acid-base status in term fetuses with low cerebroplacental ratio. Ultrasound Obstet Gynecol 2015;45:156-161.
- Lees CC, Marlow N, van Wassenaer-Leemhuis A, et al. 2 year neurodevelopmental and intermediate perinatal outcomes in infants with very preterm fetal growth restriction (TRUFFLE): A randomized trial. Lancet 2015;385:2162-2172.
- Turan OM, Turan S, Berg C, et al. duration of persistent abnormal ductus venosus flow and its impact on perinatal outcome and fetal growth restriction. Ultrasound Obstet Gynecol 2011;38:295-302.
- Ferrazzi E, Bozzo M, Rigano S, et al. Temporal sequence of abnormal Doppler changes in the peripheral and central circulatory system of the severely growth restricted fetus. Ultrasound Obstet Gynecol 2002;19:140-146.
- Cnossen JS, Morris RK, ter Riet G, et al. Use of uterine artery Doppler ultrasonography to predict pre-eclampsia and intrauterine growth restriction: A systematic review and bivariable meta-analysis. CMAJ 2008;178:701-711.
- Rodríguez-López M, Cruz-Lemini M, Valenzuela-Alcaraz B, et al. Descriptive analysis of different phenotypes of cardiac remodeling in fetal growth restriction. Ultrasound Obstet Gynecol 2017;50:207-214.
- DeVore GR, Satou G, Sklansky M. Abnormal fetal findings associated with a global sphericity index of the 4-chamber view below the 5th centile. J Ultrasound Med 2017;36:2309-2318.
- DeVore GR, Satou G, Sklansky M. Area of the fetal heart four-chamber view: A practical screening tool to improve detection of cardiac abnormalities in a low-risk population. Prenat Diagn 2017;37:151-155.
- Hobbins JC, et al. Measurements of cardiac shape and size in the four-chamber view of fetuses with intrauterine growth restriction: Correlation with Doppler waveforms from the umbilical and middle cerebral arteries. Manuscript submitted.
- Vickers MH, Gluckman PD, Coveny AH, et al. Neonatal leptin treatment reverses developmental programming. Endocrinology 2005;146:4211-4216.
- Rodriguez-Lopez M, Osorio L, Acosta-Rojas R, et al. Influence of breastfeeding and postnatal nutrition on cardiovascular remodeling induced by fetal growth restriction. Pediatr Res 2016;79:100-106.