LB Jorde, MS Esplin, WS Watkins, TA Manuck, J Ilekis, H Huang, H Zhan, J Biggio, UM Reddy, S Parry, W Andrews, R Bukowski, Y Sadovsky, , MW Varner, M Yandell, G Saade
To compare maternal genotypes between women with and without significant prolongation of pregnancy in the setting of 17-alpha hydroxyprogesterone caproate (17-P) administration for the prevention of recurrent preterm birth (PTB).
Three tertiary-care centres across the USA.
Women (n = 99) with ≥ 1 prior singleton spontaneous PTB, receiving 17-P.
Women were classified as having successful prolongation of pregnancy during the 17-P treated pregnancy, in two ways: (1) Definition A: success/non-success based on difference in gestational age at delivery between 17-P-treated and untreated pregnancies (success: delivered ≥ 3 weeks later with 17-P) and (2) Definition B: success/non-success based on reaching term (success: delivered at term with 17-P).
Main outcome measures
To assess genetic variation, all women underwent whole exome sequencing. Between-group sequence variation was analysed with the Variant Annotation, Analysis, and Search Tool (VAAST). Genes scored by VAAST with P < 0.05 were then analysed with two online tools: (1) Protein ANalysis THrough Evolutionary Relationships (PANTHER) and (2) Database for Annotation, Visualization, and Integrated Discovery (DAVID).
Using Definition A, there were 70 women with successful prolongation and 29 without; 1375 genes scored by VAAST had P < 0.05. Using Definition B, 47 women had successful prolongation and 52 did not; 1039 genes scored by VAAST had P < 0.05. PANTHER revealed key differences in gene ontology pathways. Many genes from definition A were classified as prematurity genes (P = 0.026), and those from definition B as pharmacogenetic genes (P = 0.0018); (P, non-significant after Bonferroni correction).
A novel analytic approach revealed several genetic differences among women delivering early vs later with 17-P.
Several key genetic differences are present in women with recurrent preterm birth despite 17-P treatment.