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:
- Columbia University
- Christiana Care Health System
- Saint Peters University Hospital
- New York Hospital, Queens
- Medical University of South Carolina
- University of Alabama
- Northwestern University
- University of California, Irvine
- Long Beach Memorial Medical Center
- Fountain Valley Hospital
- Women and Infants Hospital of Rhode Island
- 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.
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; (2) to create an individualized standard for fetal growth potential; and (3) 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 the use of rigorously trained sonographers resulting in measurements that were highly (>0.99) correlated with those of experts (Hediger et al. Journal Ultrasound Medicine 2016).
Fetal Growth-GDM Study: Designed within this cohort is a study of risk factors of of gestational diabetes (GDM) and a nested case control study focusing on the etiology and prediction of GDM and its implications for fetal growth. The role of genetic factors and longitudinal nutritional and cardio-metabolic biomarkers in the development of GDM are being investigated. Initial findings indicated potential important roles of insulin growth factor (IGF) pathway (Zhu et al. 2016 Diabetes) and iron metabolism (Rawal et al 2017 Diabetologia) during as early as the first trimester in the development of GDM. Moreover, a U-shaped association between sleep duration in pregnancy and gestational diabetes was observed. Furthermore, the association between short sleep duration and increased GDM risk was only significant among women who rarely or never napped, providing for the first time, suggestive evidence that daytime napping may compensate for the adverse effects of insufficient sleep on GDM risk. (Rawal et al. 2016 American Journal of Obstetrics and Gynecology). In addition, bi-directional associations of depression and GDM were identified, which highlights the role of psychosocial factors in the development of this common pregnancy complication (Hinkle et al. 2016 Diabetologia).
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: (i) identify genetic loci associated with various measures of fetal growth and related maternal cardiometabolic traits at different stages of gestation, (ii) determine the influence of interactions between genetic variants and maternal cardiometabolic and socio-demographic factors on fetal growth, and (iii) 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.
- Germaine M. Buck Louis, PhD, M.S.
- Katherine Laughon Grantz, M.D., M.S.
- Cuilin Zhang, M.D., Ph.D., M.P.H.
- Jagteshwar (Una) Grewal, Ph.D., M.P.H.
- Fasil Tekola Ayele, Ph.D.
- Stefanie Hinkle, Ph.D.
- Aiyi Liu, Ph.D.
- Danping Liu, Ph.D.
- Melissa Smarr, Ph.D.
- Rajeshwari Sundaram, Ph.D.
- Tsegaselassie Workalemahu, M.S.
- Mohammad Rahman, ScD, M.A., MBBS
- Buck Louis GM; Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies' Research Team, Grewal J. Clarification of estimating fetal weight between 10-14 weeks gestation, NICHD Fetal Growth Studies. American Journal of Obstetrics and Gynecology. 2017;217(1):96-101. PMID: 28389223
- Grobman WA, Wing DA, Albert P, Kim S, Grewal J, Guille C, Newman R, Chien EK, Owen J, D'Alton ME, Wapner R, Sciscione A, Grantz KL. Maternal depressive symptoms, perceived stress, and fetal growth. Journal of Ultrasound in Medicine. 2017;36(8):1639-1648. PMID: 28393386
- Pugh SJ, Albert PS, Kim S, Grobman W, Hinkle SN, Newman RB, Wing DA, Grantz KL. Patterns of gestational weight gain and birthweight outcomes in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons: a prospective study. American Journal of Obstetrics and Gynecology. 2017 May 11. PMID: 28502760
- Rawal S, Hinkle SN, Bao W, Zhu Y, Grewal J, Albert PS, Weir NL, Tsai MY, Zhang C. A longitudinal study of iron status during pregnancy and the risk of gestational diabetes: findings from a prospective, multiracial cohort. Diabetologia. 2017;60(2):249-257. PMID: 27830277
- Rawal S, Hinkle SN, Zhu Y, Albert PS, Zhang C. A longitudinal study of sleep duration in pregnancy and subsequent risk of gestational diabetes: findings from a prospective, multiracial cohort. American Journal of Obstetrics and Gynecology. 2017;216(4):399.e1-399.e8. PMID: 27939328
- Wing DA, Ortega-Villa AM, Grobman WA, Hediger ML, Grewal J, Pugh SJ, Kim S, Newman R, Chien E, Owen J, D'Alton ME, Wapner R, Sciscione A, Albert PS, Grantz KL. Maternal stress and neonatal anthropometry: the NICHD Fetal Growth Studies. American Journal of Obstetrics and Gynecology. 2017;217(1):82.e1-82.e7. PMCID: PMC5511704 [Available on 2018-07-01]. PMID: 28263750
- Grantz KL, Grewal J, Albert PS, Wapner R, D'Alton ME, Sciscione A, Grobman WA, Wing DA, Owen J, Newman RB, Chien EK, Gore-Langton RE, Kim S, Zhang C, Buck Louis GM, Hediger ML. Dichorionic twin trajectories: the NICHD Fetal Growth Studies.American Journal of Obstetrics and Gynecology.2016;215(2);221.e1–221.e16. PMCID: PMCID: PMC4967402 [Available on 2017-08-01]. PMID: 27143399
- Hediger ML, Fuchs KM, Grantz KL, Grewal J, Kim S, Gore-Langton RE, Buck Louis GM, D'Alton ME, Albert PS. Ultrasound quality assurance for singletons in the National Institute of Child Health and Human Development Fetal Growth Studies. Journal of Ultrasound Medicine. 2016;35(8):1725-1733. PMID: 27353072
- Hinkle SN, Buck Louis GM, Rawal S, Zhu Y, Albert PS, Zhang C. A longitudinal study of depression and gestational diabetes in pregnancy and the postpartum period. Diabetologia. 2016;59(12):2594-2602. PMCID: PMCID: PMC5101167 [Available on 2017-12-01]. PMID: 27640810
- Zhu Y, Mendola P, Albert PS, Bao W, Hinkle SN, Tsai MY, Zhang C. Insulin-Like Growth Factor Axis and Gestational Diabetes Mellitus: A Longitudinal Study in a Multiracial Cohort. Diabetes. 2016;65(11):3495-3504. PMCID: PMCID: PMC5079637 [Available on 2017-11-01]. PMID: 27468747
- Buck Louis GM, Grewal J, Albert PS, Sciscione A, Wing DA, Grobman WA, Newman RB, Wapner R, D'Alton ME, Skupski D, Nageotte MP, Ranzini AC, Owen J, Chien EK, Craigo S, Hediger ML, Kim S, Zhang C, Grantz KL. Racial/ethnic standards for fetal growth: the NICHD Fetal Growth Studies. American Journal of Obstetrics and Gynecology. 2015;213(4):449.e1–449.e41. PMCID: PMCID: PMC4584427. PMID: 26410205