Perinatal & Pediatric
Association of polygenic score of birthweight-reducing maternal variants with fetal growth and the influence of parity: a study in two multi-ancestral pregnancy cohorts Prabhavi Wijesiriwardhana* Prabhavi Wijesiriwardhana Tesfa Dejenie Habtewold Guisong Wang Jessica L. Gleason Ronald Wapner Katherine L. Grantz Fasil Tekola-Ayele
Association of polygenic score of birthweight-reducing maternal variants with fetal growth and the influence of parity: a study in two multi-ancestral pregnancy cohorts
Prabhavi Wijesiriwardhana1, Tesfa Dejenie Habtewold1, Guisong Wang2, Jessica L. Gleason1, Ronald Wapner3, Katherine L. Grantz1, Fasil Tekola-Ayele1
1Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
2The Prospective Group (TPG), contractor to Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
3Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA
Background: Maternal genetic factors and reproductive history such as nulliparity have been associated with lower birthweight. However, it is unknown when the maternal genome begins to influence fetal growth and whether the effect varies by parity. This study aims to i) determine the gestational week in which maternal birthweight-reducing genetic variants influence fetal growth, and ii) assess whether the associations vary by parity.
Methods: Discovery analyses for weekly fetal growth measures (at 10-40 weeks gestation) were performed using a multi-ancestral cohort of pregnant women recruited through the NICHD Fetal Growth Studies-Singletons (n=1944; nulliparous n=885). Replication analyses for estimated fetal weight were performed using the nuMoM2b multi-ancestral cohort of nulliparous women (n=6058). Genetic risk score (GRS) was derived from 32 and 33 previously identified birthweight-reducing maternal variants, in the discover and replication cohorts, respectively. Parity was categorized as nulliparous and multiparous (i.e., ≥1 previous delivery ≥20 weeks’ gestation). Associations of GRS with fetal growth measures were tested using linear regression adjusted for fetal sex and top 10 genetic principal components.
Results: GRS was significantly associated with lower fetal weight from gestational week 31 onwards (β at week 31=-8.59, 95%CI= -16.99, -0.19 grams), shorter humoral and femur lengths, and smaller head circumference beginning at 21, 29, and 31 weeks, respectively. Among nulliparas, all associations began earlier, and effect sizes strengthened (e.g., week 20 onwards in the discovery cohort, week 23 onwards in the replication cohort for fetal weight), but none was significant among multiparas.
Conclusions: Birthweight-reducing maternal genetic factors exhibited the earliest association with fetal skeletal bones followed by head circumference and overall weight. The pronounced association among nulliparas suggests a larger influence on physiological adaptations at first pregnancy and warrant further study.