Association of Mode of Delivery and Birth Order with Hyperinsulinemia in Neonatal Cord Blood

Importance: Cesarean delivery (CD) is associated with higher risk of obesity development from childhood and with type 2 diabetes mellitus (T2DM) later in life. Higher neonatal cord C-peptide (CP) levels were reported to be associated with increased risk of offspring metabolic disorders in childhood as well. Objective: To assess the association between mode of delivery as the primary exposure and 27 additional maternal/neonatal clinical factors and the risk of neonatal hyperinsulinemia. Design: Retrospective data analysis. Setting: Multinational, multi-ancestry observational population-based Hyperglycemia Advanced Pregnancy Outcome (HAPO) cohort study gene-environment interaction (GEI) substudy. Participants: A total of 4967 mother-neonate pairs from 4 major ancestry groups (Afro-Caribbean, European, Hispanic, Thai) were assessed. Exposure: Data on mode of delivery and 27 additional (18 maternal + 9 neonatal) variables were utilized from the NIH dbGaP database (accession phs000096.v4.p1). Main outcome and measures: The primary outcome was neonatal hyperinsulinemia herein defined as cord serum CP level of ancestry specific > 90th percentile. χ ² -test was used to assess the difference between CD and vaginal delivery groups and standardized multivariate logistic regression with Akaike information criterion-based model selection and interaction analyses were used to model the primary outcome. Missing data were addressed using Bayesian joint modeling approach. Results: Out of the total 4967 pregnancies assessed CD was performed in 1154 mothers (23.2%). Cord blood hyperinsulinemia occurred in 447 cases of which 178 in the CD (15.4%) and 269 in vaginal delivery (7.1%) group (OR crude, 2.4; 95% CI, 1.96 to 2.94). We identified novel factors individually associated with neonatal hyperinsulinemia: CD (OR in firstborns: 4.25; 95% CI, 2.66-6.78, OR in non-firstborns: 4.25; 95% CI, 2.59-6.99) and non-firstborn vaginal delivery (OR, 1.95; 95% CI, 1.34-2.88) when compared to vaginally delivered firstborns. Sensitivity analyses confirmed the stability of these results and subgroup analyses revealed the consistency of the two novel associations across different ancestries. Conclusion : To our best knowledge we first report that neonatal hyperinsulinemia risk is more than quadrupled in neonates born via cesarean delivery independently of birth order when compared to vaginally delivered firstborns. Non-firstborns are also at increased risk.