not-yet-known not-yet-known not-yet-known unknown Objective: Maternal genotypes may be useful to customize fetal growth assessment, but generalizability across diverse racial and ancestral groups remains uncertain. We assessed the generalizability of a genetic risk score for birth weight (GRS BW), derived from European ancestry participants, within a diverse U.S. cohort. Design: Secondary analysis of a prospective observational cohort of nulliparous patients. Setting: Eight U.S. recruitment centers. Population or Sample: Participants in the parent study with available maternal DNA. Methods: We used log-linear modeling to test the association of maternal GRS BW with fetal weight. We then assessed the robustness of the association by self-identified race and genetically predicted continental ancestry (GPA) groups. Main Outcome Measures: Association between GRS BW and fetal weight. Results: Among 8,147 eligible participants, GRS BW was associated with fetal weight (p<0.001). Across self-identified racial groups, the association was significant in White (p=0.007) and multiracial (p=0.03) groups but not in Black, Asian, or unknown race groups (p>0.09 for all). Among GPA groups, the association was significant among European (p=0.001) and American (p=0.02) ancestry groups but not African, East or South Asian, or unknown ancestry (p>0.05 for all). Conclusions: This GRS BW is not generalizable across races, highlighting the need for globally representative genetic discovery cohorts.

Objective: To derive and test the implications of a sex-specific fetal growth standard. Design: Secondary analysis of a prospective observational cohort. Setting: Eight U.S. centers. Population or Sample: Nulliparas followed longitudinally through pregnancy. A lower-risk subgroup (exclusions: chronic hypertension, pre-gestational diabetes, suspected aneuploidy, preterm delivery) was selected for fetal growth equation derivation. Methods: Fetal weights at 14-20 weeks, 22-29 weeks, and birth were used to derive a sex-specific fetal growth equation. We compared rates of SGA and LGA by sex using the sex-specific and sex-neutral (Hadlock) standards. Using the full unselected cohort, we assessed outcomes and clinical management according to SGA and LGA status. Main outcome measures: Proportion considered SGA and LGA; obstetric interventions relevant to SGA and LGA. Results: We derived a sex-specific equation using 7,280 infants. The sex-neutral standard diagnosed SGA more often in female and LGA more often in male newborns. The sex-specific standard resolved these disparities. Using the full unselected cohort (N=8,339), newborns reclassified from SGA to AGA by the sex-specific standard were more likely to be delivered for growth restriction with comparable risk of morbidity compared to newborns considered AGA by both methods. Newborns reclassified from AGA to LGA by the sex-specific standard had higher rates of cesarean for arrest of descent, cesarean for arrest of dilation, and shoulder dystocia than newborns considered AGA by both methods. Conclusions: The sex-neutral standard generates sex disparities in SGA and LGA at birth. A sex-specific standard resolves these disparities and may improve growth pathology risk stratification.