NICHD Fetal Growth Studies

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

Investigators

Linked publications, trials & patents

Abstract

Overview The primary goal of this study was to establish a standard for normal fetal growth (velocity) and size for gestational age in the U.S. population. Additional goals were to create an individualized standard for fetal growth potential and to improve accuracy of fetal weight estimation. The primary NICHD Fetal Growth Studies Singletons found significant differences in fetal growth and individual fetal dimensions by self-reported maternal race/ethnicity with some differences occurring earlier than others but remaining throughout gestation (Buck Louis et al. American Journal of Obstetrics and Gynecology 2015). These findings suggest that assessment of fetal growth by ultrasound needs to be evaluated clinically using racial/ethnic-specific standards for early identification of potential abnormalities and to minimize misdiagnosis of intrauterine growth restriction and unnecessary clinical interventions. Two online calculators, an EFW calculator, https://www.nichd.nih.gov/fetalgrowthcalculator, and an EFW Fetal Growth velocity calculator, https://www.nichd.nih.gov/fetalvelocitycalculator, provide more accurate estimates compared to conventional growth charts. Given the recognition that inclusion of self-reported race/ethnicity in clinical algorithms may create unintended consequences for diagnosis and intervention, our team followed up this original work and created a unified, multi-ethnic fetal growth and fetal growth velocity standards, weighted using 2011 U.S. births. (Grantz KL et al. American Journal of Obstetrics and Gynecology, 2021 and Grantz KL et al. American Journal of Obstetrics and Gynecology, 2022) Screening for gestational diabetes is often recommended during 24-28 weeks of gestation. Emerging evidence suggest that the impact of maternal glycemia on fetal health may start earlier than the regular screening time. The NICHD Fetal Growth Study was used to assess the association between gestational diabetes and early measures of glucose and longitudinal fetal growth trajectories across gestation (Li et al. Lancet Diabetes Endocrinol 2020). An association between gestational diabetes and larger estimated fetal weight started to emerge at gestational week 20 and became significant at week 28; the association persisted through term despite standard clinical treatment. We also observed transitory deviations in estimated fetal weight between weeks 10 and 17 related to gestational diabetes with a family history of diabetes. The study also provides the first evidence that, irrespective of gestational diabetes status, higher glucose concentrations measured as early as weeks 10 to 14 were related to a larger estimated fetal weight in the second half of pregnancy. These findings suggest that efforts to mitigate fetal overgrowth related to gestational diabetes may be initiated earlier than 24-28 gestational weeks, when gestational diabetes is typically screened for in the US, and early screening for hyperglycemia may be beneficial. (Zhang & Catalano, JAMA, 2021) Obese Cohort Obesity is common among women of reproductive age and is known to increase the risk for maternal and fetal pregnancy complications. The NICHD Fetal Growth Studies enrolled 468 obese women with singleton pregnancies with the goal of comparing fetal growth patterns between women with obesity and non-obese women. Furthermore, because pregnancy complications such as GDM and preeclampsia are more common in women with obesity, this additional cohort offers the opportunity to examine how fetal growth is impacted by such complications. The researchers found that as early as 32 weeks' gestation, fetuses of obese women had higher weights than fetuses of nonobese women (Zhang et al. JAMA Pediatrics 2018). The team followed up the work and further investigated whether maternal obesity status may modify the effect of maternal glycemia status on fetal growth (Li et al. Lancet Diabetes Endocrinology 2020). In addition, in the past year, laboratory measurement of persistent organic pollutants (POPs) in the obese cohort completed. The team is in the process of evaluating the influences of POPs on longitudinal fetal growth trajectories. Dichorionic Twin Cohort Twin gestations represented 3.4% of U.S. births in 2013, yet there is limited contemporary data on the estimation of fetal growth trajectories in twins. The NICHD Fetal Growth Studies enrolled 171 dichorionic twin pregnancies. The primary objective was to empirically define the trajectory of fetal growth in dichorionic twins using longitudinal two-dimensional ultrasonography and to compare the fetal growth trajectories for dichorionic twins with those based on a growth standard developed by our group for singletons. (Grantz et al. AJOG 2016) Compared with singleton fetuses, the mean abdominal circumference and estimated fetal weight trajectories of dichorionic twin fetuses diverged significantly beginning at 32 weeks. The team followed up this work and found that dichorionic inter-twin estimated weight differences increased across gestation, with a larger percentage of pregnancies exceeding a fixed percent discordance cut-off as gestation advanced, suggesting that a percentile cut-point (e.g., 90th) may be more clinically useful than a fixed cut-point for defining discordance. (Amyx et al AJOG 2020) These findings suggest some part of this increase in twin discordance across pregnancy may be physiologic, and the current definition of twin discordance may need to be reconsidered for clinical practice. Biomedical Markers and Modifiable Risk Factors in Relation to Gestational Diabetes and Fetal Growth The NICHD Fetal Growth Studies is the basis for studying risk factors and the pathogenesis of gestational diabetes (GDM) and fetal growth and to identify factors that can inform the understanding of the etiology of GDM and improve early prediction of GDM. This work is grounded within an evolving body of research suggestive of important roles of maternal metabolism and nutrition in the development of GDM and in fetal growth. Pathway specific biomedical markers, and non-targeted metabolomics and lipidomics were measured longitudinally in 107 GDM cases and 214 non-GDM controls in the NICHD Fetal Growth Studies-Singleton Cohort (c.f. Gestational Diabetes Mellitus: Epidemiology, Etiology, and Health Consequences). Notably, based on these data, it was discovered that thyroid function in pregnant women as early as first trimester may be involved in the pathophysiology of gestational diabetes and that HbA1c levels can potentially help identify women at risk for gestational diabetes early in pregnancy, when lifestyle changes may be more effective in reducing their risk. Further, multiple advances have been made to our understanding of the pathogenesis of GDM. Research on plasma fatty acids provides novel evidence for distinct associations of individual and subclasses of saturated fatty acids (SFAs) and poly-unsaturated fatty acids (PUFAs) varying by chain length, in relation to subsequent risk of GDM). Several plasma acylcarnitine species are differentially associated with GDM risk by chain length (Lin Y, Clinical Nutrition, 2021). In addition, based on non-targeted lipidomics profile of 420 metabolites, we observed that plasma lipid metabolites in early pregnancy both individually and interactively in distinct netwo