Associations with spontaneous and indicated preterm birth in a densely phenotyped EHR cohort

Preterm birth (PTB) is the leading cause of infant mortality and follows multiple biological pathways, many of which are poorly understood. Some PTBs result from medically indicated labor following complications from hypertension and/or diabetes, while many others are spontaneous with unknown causes. Previously, investigation of potential risk factors has been limited by lack of data on maternal medical history and the difficulty of classifying PTBs as indicated or spontaneous. Here, we leverage electronic health record (EHR) data (patient health information including demographics, diagnoses, and medications) and a supplemental curated pregnancy database to overcome these limitations. Novel associations may provide new insight into the pathophysiology of PTB as well as help identify individuals who would be at risk of PTB.

We quantified associations between maternal diagnoses and preterm birth using logistic regression controlling for maternal age and socioeconomic factors within a University of California, San Francisco (UCSF), EHR cohort with 10,643 births ( nterm = 9692, nspontaneous_preterm = 449, nindicated_preterm = 418) and maternal pre-conception diagnosis phenotypes derived from International Classification of Diseases (ICD) 9 and 10 codes.

Eighteen conditions significantly and robustly (False Discovery Rate (FDR)<0.05) associated with PTBs compared to term. We discovered known (hypertension, diabetes, and chronic kidney disease) and less established (blood, cardiac, gynecological, and liver conditions) associations. Type 1 diabetes was the most significant overall association (adjusted p = 1.6×10 ^-14 , adjusted OR = 7 (95% CI 5, 12)), and the odds ratios for the significant phenotypes ranged from 3 to 13. We further carried out analysis stratified by spontaneous vs. indicated PTB. No phenotypes significantly associated with spontaneous PTB; however, the results for indicated PTB largely recapitulated the phenotype associations with all PTBs.

Our study underscores the limitations of approaches that combine indicated and spontaneous births together. When combined, significant associations were almost entirely driven by indicated PTBs, although our spontaneous and indicated groups were of a similar size. Investigating the spontaneous population has the potential to reveal new pathways and understanding of the heterogeneity of PTB.