Fetal growth restriction, defined as estimated fetal weight less than the 10th percentile for gestational age, is a common pregnancy complication that is associated with increased perinatal morbidity and mortality.1,2 Most of the data on the association of growth restriction with these outcomes is based on growth restriction diagnosed in the late second or third trimester.2–4 Some studies have evaluated earlier onset growth restriction; however, these analyses are largely limited to those with growth restriction diagnosed after 24 weeks of gestation.5–7
Few data exist to guide counseling and management of women when growth restriction is diagnosed before 24 weeks of gestation in the absence of an identifiable cause. We therefore aimed to estimate the risk of adverse perinatal outcomes among women with isolated fetal growth restriction diagnosed at the time of ultrasonography to assess fetal anatomy.
MATERIALS AND METHODS
We conducted a retrospective cohort study of women undergoing routine ultrasonography to assess fetal anatomy at a single institution between January 1, 2010, and December 31, 2014. Patients were included if they had singleton, nonanomalous pregnancies and were between 17 0/7 and 22 6/7 weeks of gestation with an estimated fetal weight performed at the time of ultrasonography. Patients were excluded if they had fetal structural malformations, chromosomal abnormalities, identified infectious etiologies, or if the pregnancy did not continue past 20 weeks of gestation. They were also excluded if outcome data were missing or not available. Pregnancies with ultrasonographic soft markers for aneuploidy including echogenic intracardiac focus, single umbilical artery, and pyelectasis were included.8 Gestational age was determined based on last menstrual period if first-trimester ultrasonogram agreed with the estimated due date within 7 days or second-trimester ultrasonogram agreed with estimated due date within 14 days. If the due date differed by more than 7 days in the first trimester or 14 days in the second trimester, or if the last menstrual period was unknown, the estimated due date was changed to that calculated by the earliest available ultrasonogram. Any dating discrepancy was resolved after review of the medical record by an attending maternal-fetal medicine physician. For the purposes of this study, if the patient had more than one pregnancy during the study period, only the first pregnancy was included. The study was conducted after approval from the Washington University School of Medicine Human Research Protection Office.
Details regarding maternal and obstetric history, antepartum complications as well as obstetric and neonatal outcomes are obtained and entered into a database by dedicated perinatal research nurses in a prospective, ongoing manner for all women having ultrasonograms at our institution. Maternal demographic and pregnancy information is entered at the time of the ultrasonogram. Perinatal research nurses obtain information about antepartum complications and obstetric and neonatal outcomes using electronic medical records, records from referring health care providers, and telephone contact with the patient. This database was used to identify study participants.
We first calculated the incidence of fetal growth restriction at the time of ultrasonography to assess fetal anatomy in our cohort with 95% CIs based on the binomial exact method. Fetal growth restriction was defined as estimated fetal weight less than the 10th percentile using Warsof growth curves before 20 0/7 weeks of gestation and Hadlock growth curves from 20 0/7 weeks of gestation onward.9–12 Patients underwent standardized management of fetal growth restriction with serial growth ultrasonograms beginning at viability, antenatal surveillance including umbilical artery Dopplers, and timing of delivery based on the National Institute of Child Health and Human Development and Society for Maternal-Fetal Medicine recommendations.13
We compared maternal demographic information and outcomes between women with and without fetal growth restriction. The primary outcome for this analysis was small for gestational age (SGA) at birth, which was defined as less than the 10th percentile birth weight on the Alexander growth curves.14 Secondary outcomes included SGA based on the newer Oken and Fenton growth curves,15,16 birth weight, gestational age at delivery, indicated preterm birth, stillbirth, abruption, preeclampsia, neonatal death, neonatal intensive care unit admission, need for neonatal respiratory support, neonatal intraventricular hemorrhage, and necrotizing enterocolitis in the neonate. We performed a stratified analysis on estimated fetal weight less than the fifth percentile and from the fifth to 10th percentile for the primary outcome of SGA.
Baseline characteristics were compared between the two groups using the unpaired Student t test or the Wilcoxon rank-sum test as appropriate for continuous variables and the χ2 test or Fisher exact test as appropriate for categorical variables. We calculated rates and unadjusted odds ratios (ORs) and 95% CIs for the primary and secondary outcomes. Multivariable logistic regression was used to adjust for confounders and estimate the association between isolated growth restriction and adverse outcomes. Factors adjusted for were chosen based on results of bivariate analysis as well as biologically plausible risk factors associated with adverse outcomes. Model fit for the final model was assessed with the Hosmer-Lemeshow goodness-of-fit test.
No a priori sample size estimation was performed and all consecutive patients meeting inclusion criteria were included. All tests were two-tailed with a P value of >.05 considered significant. Statistical analysis was completed with STATA 12.
Of 12,783 eligible women, 355 (2.8%, 95% CI 2.5–3.1%) had growth restriction at the time of survey to assess fetal anatomy, of whom 131 (1.0%, 95% CI 0.9–1.2%) had estimated fetal weight less than the fifth percentile for gestational age and 224 (1.8%, 95% CI 1.5–2.0%) had estimated fetal weight between the fifth and 10th percentiles (Fig. 1). Women with fetal growth restriction had ultrasonography performed at a slightly later gestational age and were more likely to be African American and to smoke. Other baseline characteristics, including parity, chronic hypertension, body mass index, and diabetes, were similar between those with and without fetal growth restriction (Table 1).
Fetal growth restriction at the early second trimester was associated with a more than fivefold increased risk of SGA at birth (36.9% compared with 9.1%, adjusted OR 5.5, 95% CI 4.3–7.0). This remained true using the Oken and Fenton growth curves (Table 2). When stratified by degree of growth restriction, those with estimated fetal weight less than 5% had a more than sevenfold increased risk of SGA compared with those with normally grown fetuses (46.6% compared with 9.1%, adjusted OR 7.9, 95% CI 5.5–11.4) and those with estimated fetal weight 5–10% had a more than fourfold increased risk of SGA (31.3% compared with 9.1%, OR 4.4, 95% CI 3.2–5.9).
Women with growth restriction were more likely to deliver at earlier gestational ages (37.2±3.4 weeks compared with 38.3±2.4 weeks of gestation, P<.001), deliver neonates with lower birth weights (2,725±763 g compared with 3,267±775 g, P<.001), and undergo indicated delivery before 37 weeks and 28 weeks of gestation (Table 2). Rates of abruption and preeclampsia were not significantly different between those with and without early second-trimester fetal growth restriction. Although rates of neonatal intensive care unit admission and intraventricular hemorrhage were not significantly different between groups, neonates born to those with fetal growth restriction were more likely to need respiratory support and to develop necrotizing enterocolitis (Table 2).
Rates of neonatal death (1.4% compared with 0.3%, OR 5.2, 95% CI 1.6–13.5) and stillbirth were significantly higher in those with fetal growth restriction (2.5% compared with 0.4%, OR 6.2, 95% CI 2.7–12.8). The gestational age at stillbirth was not significantly different between those with and without fetal growth restriction at the ultrasonogram to assess anatomy (25.1±5.2 weeks compared with 27.7±6.9 weeks of gestation, P=.29). Among those with fetal growth restriction, the rate of stillbirth was significantly higher among those with estimated fetal weight less than the fifth percentile than those with estimated fetal weight from the fifth to 10th percentile (6.1% compared with 0.5%, OR 14.5, 95% CI 1.9–646.3) (Appendix 1, available online at http://links.lww.com/AOG/A984).
Fetal growth restriction between 17 and 22 weeks of gestation, in the absence of those anomalies, aneuploidy, or infection, was significantly associated with SGA at birth. Although the rate of adverse perinatal outcomes among those with the diagnosis was low, it was still elevated and significantly associated with stillbirth, neonatal death, indicated preterm birth, neonatal need for respiratory support, and necrotizing enterocolitis. It was not associated with increased rates of abruption or preeclampsia.
Although it intuitively would seem that earlier diagnosis of fetal growth restriction would lead to worse consequences, estimated fetal weights are known to be less accurate at the lower and higher extremes of estimated fetal size.17 Additionally, at earlier gestational ages, small changes in measurements can result in large changes in growth percentiles.9 Given the relative lack of clinical data in this context, clinicians may wonder whether growth restriction at the time of ultrasonography to assess fetal anatomy without an identifiable cause represents true pathology or measurement imprecision.
Few studies have evaluated outcomes when growth restriction is diagnosed before 24 weeks of gestation. A large, population-based study conducted by Nakling and Backe18 found that lagging growth at the time of 18-weeks ultrasonography of fetal anatomy was associated with increased risks of preterm birth, perinatal death, low birth weight, and SGA. This study included fetuses with known anomalies, infections, and aneuploidy, which makes its results difficult to generalize their findings to fetuses without these conditions. A study by Fox et al compared outcomes between 252 patients with an estimated fetal weight less than the 25th percentile with unmatched women in a control group with normal growth between 18 and 24 weeks of gestation and found increased rates of stillbirth, neonatal death, indicated preterm birth, SGA, and admission to the neonatal intensive care unit.
Our findings are consistent with and build on these previous studies. We excluded patients with clear etiologies for growth restriction and used the commonly accepted definition of growth restriction of less than the 10th percentile. We used a large cohort of patients with detailed, prospectively collected data, which enabled us to examine a comprehensive set of outcomes. We had birth weight and outcome data available on 99.4% of those eligible for the study and used three growth curves to assess the diagnosis of SGA. We used both the traditional Alexander growth curve and the more modern Oken and Fenton growth curves. The Oken growth curve is based on U.S. birth certificate data from 1999 to 2000, whereas the Fenton growth curve may be more sensitive for use in preterm neonates. The use of three curves increases the generalizability and strength of our conclusions regarding SGA.
There are potential limitations of our study. Although the data were collected prospectively, the study design was retrospective in nature and therefore subject to selection bias, confounding, and errors in data collection. However, the database used has been validated in several previous studies.19,20 Although we controlled for multiple confounders, there is the potential for residual or unmeasured confounding. Additionally, some of the adverse outcomes, including abruption and intraventricular hemorrhage, occurred infrequently and thus we were likely underpowered to detect associations with these outcomes and fetal growth restriction. Finally, detailed information on postnatal diagnosis of anomalies or genetic disorders was not available in the database. This allows for the possibility of inclusion of patients in whom a cause for growth restriction was discovered postnatally, which could bias the results toward an association with adverse outcomes. However, our approach that included those with early second-trimester fetal growth restriction without an antenatally identifiable cause is consistent with the way growth restriction is diagnosed and managed in clinical practice.
In summary, although fetal growth restriction between 17 and 22 weeks of gestation occurred in less than 3% of our cohort and most of those with isolated growth restriction did not have adverse outcomes, it is a strong risk factor for SGA, stillbirth, neonatal death, and indicated preterm birth.
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