Genomic Differences Between Spontaneous Versus Indicated Extreme Preterm Birth

Background: Extremely preterm infants are at high risk of neonatal mortality and morbidity. Extreme preterm birth may result from spontaneous preterm labor or preterm premature rupture of membranes (PPROM), or may be indicated due to pre-eclampsia, eclampsia, hypertension or other causes. Methods: Our objective was to identify single nucleotide polymorphisms (SNPs) and biological pathways associated with spontaneous versus indicated extreme preterm birth using the neonatal genome. We evaluated 523 spontaneous births and 134 indicated births weighing 401-1000 g at birth from the Eunice Kennedy Shriver NICHD Neonatal Research Network (NRN)'s Genomics dataset by GWAS and pathway analysis. The TOLSURF cohort was used to replicate the results. Results: In the NRN GWAS, no statistically significant results were found, although the Manhattan plot showed one almost significant peak (rs60854043 on chromosome 14 at p=1.03E-07) along with many other modest peaks at p=1-9E-06, for a total of 15 suggestive associations at this locus. In the NRN pathway analysis, multiple pathways were identified, with the most significant being "GO_mf:go_low_density_lipoprotein_particle_receptor_activity"at p=1.14E-06. However, these results could not be replicated in the TOLSURF cohort. Conclusion: Genomic differences are seen between infants born by spontaneous versus indicated extreme preterm birth. Due to the limited sample size, there is a need for larger studies.