EB Research: NICHD Fetal Growth Study

Normal fetal growth is a critical component for a healthy pregnancy and for ensuring the health and well-being of infants throughout childhood and adolescence. Pivotal to understanding the dynamics of human fetal growth and to defining normal and abnormal fetal growth is the development of standards for fetal anthropometric parameters, measured longitudinally throughout gestation. Such measures can be used to develop interval velocity curves and customized to assess etiologic determinants such as genetic and physiological factors.

The NICHD Fetal Growth Studies is an ambitious observational epidemiologic study that recruited 2,334 low risk pregnant women from 12 U.S. clinical sites, 2009-2013:

  1. Columbia University
  2. Christiana Care Health System
  3. Saint Peters University Hospital
  4. New York Hospital, Queens
  5. Medical University of South Carolina
  6. University of Alabama
  7. Northwestern University
  8. University of California, Irvine
  9. Long Beach Memorial Medical Center
  10. Fountain Valley Hospital
  11. Women and Infants Hospital of Rhode Island
  12. Tufts University

The cohort comprises 614 Caucasian women, 611 African American women, 649 Hispanic women, and 460 Asian women. In addition, two other cohorts were recruited: 1) an obese cohort comprising 468 pregnant women, and 2) a twin cohort comprising 171 women with dichorionic twin pregnancies. Study participants underwent 5 ultrasounds (2D and 3D imaging) during pregnancy at a priori defined gestational ages. Nutritional and anthropometric assessments were performed during clinical visits followed by the collection of blood specimens.

Singleton Cohort

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 (i.e., biparietal diameter, head circumference, abdominal circumference, humerus length, and femur length) 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. These findings were strengthened by using rigorously trained sonographers, resulting in measurements that were highly (>0.99) correlated with those of experts (Hediger et al. Journal Ultrasound Medicine 2016). In addition, significant difference in fetal growth was observed between obese women and non-obese women. More specifically, as early as 32 weeks of gestation, fetuses of obese women had higher weights than fetuses of non-obese women (Zhang et al. JAMA Pediatrics 2018).

Fetal Growth-Gestational Diabetes Mellitus Study

Designed within this cohort is a prospective study of longitudinal risk factors of gestational diabetes mellitus (GDM) and a nested case control study of a comprehensive panel of biomarkers including metabolomics profiles focusing on the etiology and prediction of GDM and its implications for fetal growth. Initial findings indicated potential important roles of insulin growth factor (IGF) pathway (Zhu et al. Diabetes 2016), iron metabolism (Rawal et al Diabetologia 2017), lipids (Bao et al. Journal of Diabetes 2017), saturated fatty acids (Zhu et al. American Journal of Clinical Nutrition 2018), thyroid function markers (Rawal et al. Journal of Clinical Endocrinology and Metabolism 2018) and telomere length (Lin et al. Epidemiology 2018) during as early as the first trimester in the development of GDM.

For instance, it was discovered that thyroid function in pregnant women may be involved in the pathophysiology of GDM (Rawal et al. Journal of Clinical Endocrinology and Metabolism 2018). These findings, in conjunction with previous evidence of thyroid-related adverse pregnancy outcomes, support the potential benefits of thyroid screening among pregnant women. In addition, a significantly increased risk of GDM was observed in association with saturated fatty acid levels as early as the first trimester of pregnancy (Zhu et al. American Journal of Clinical Nutrition 2018), providing impetus for future investigations that target circulating saturated fatty acids in pregnant women to improve our understanding of their distinct nutritional, metabolic, and physiologic roles in cardiometabolic outcomes.

In 2018, new research also discovered that HbA1C levels potentially can help identify women at risk for GDM early in pregnancy, when lifestyle changes may be more effective in reducing their risk (Hinkle et al. Scientific Reports 2018). Furthermore, new research found that women’s adipokine levels (Hinkle et al. International Journal of Obesity 2018) and vitamin D status (Francis et al. Nutrients 2018) in pregnancy appear to be involved in regulating fetal growth. While more work is needed, the data offer insight into how maternal body fat composition may influence different aspects of fetal growth.

Dichorionic Twin Cohort

Twin gestations represented 3.4% of U.S. births in 2013, yet there was 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. The primary NICHD Fetal Growth Studies – Twins found that compared with singleton fetuses, the mean abdominal circumference and estimated fetal weight trajectories of dichorionic twin fetuses diverged significantly beginning at 32 weeks and continuing through pregnancy (Grantz KL et al. American Journal of Obstetrics and Gynecology 2016). The mean head circumference/abdominal circumference ratio was progressively larger for twins compared with singletons beginning at 33 weeks, indicating a comparatively asymmetric growth pattern that is consistent with the concept that the intrauterine environment becomes constrained in its ability to sustain growth in twin fetuses. Near term, approximately 40% of twins would be classified as small for gestational age based on a singleton growth standard. Future studies with long term follow up are needed to know whether small estimated fetal weight percentile based on a singleton standard in otherwise uncomplicated pregnancies is associated with increased morbidity.

Genetics of Fetal Growth in Diverse Ancestral Populations

Despite strong influence of genetics on fetal growth, the specific genetic loci involved at different stages of gestation are not clearly known. Furthermore, fetal growth displays significant differences among global regions and ethnic populations, but what underlies this remains puzzling because established maternal and fetal non-genetic determinants of fetal growth explained only a very small fraction of these disparities. Therefore, using genome-wide data from the entire NICHD Fetal Growth Studies cohort, we seek to identify genetic variants that influence fetal growth and related maternal traits among diverse ancestral populations (PI: Fasil Tekola-Ayele). Specifically, we aim to: 1) identify genetic loci associated with various measures of fetal growth and related maternal cardiometabolic traits at different stages of gestation, 2) determine the influence of interactions between genetic variants and maternal cardiometabolic and socio-demographic factors on fetal growth, and 3) determine the contribution of genetic ancestry to observed disparities in fetal growth among diverse ancestral groups. Knowledge gained from the project is anticipated to illuminate genetic mechanisms in longitudinal fetal growth variations and the role of genetic ancestry for observed disparities in fetal growth among diverse ancestral populations.

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