Pharmacogenomics of 17-alpha hydroxyprogesterone caproate for recurrent preterm birth: a case-control study

BJOG. 2018 Feb;125(3):343-350. doi: 10.1111/1471-0528.14485. Epub 2017 Jan 31.

Abstract

Objective: 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).

Design: Case-control.

Setting: Three tertiary-care centres across the USA.

Population: Women (n = 99) with ≥ 1 prior singleton spontaneous PTB, receiving 17-P.

Methods: 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).

Results: 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).

Conclusion: A novel analytic approach revealed several genetic differences among women delivering early vs later with 17-P.

Tweetable abstract: Several key genetic differences are present in women with recurrent preterm birth despite 17-P treatment.

Keywords: 17-Alpha hydroxyprogesterone caproate; current preterm birth; pharmacogenomics; spontaneous prematurity.

MeSH terms

  • 17 alpha-Hydroxyprogesterone Caproate / therapeutic use*
  • Adult
  • Analysis of Variance
  • Case-Control Studies
  • Female
  • Gestational Age
  • Humans
  • Pharmacogenetics
  • Pregnancy
  • Pregnancy Outcome / epidemiology
  • Premature Birth* / epidemiology
  • Premature Birth* / genetics
  • Premature Birth* / prevention & control
  • Progestins / therapeutic use
  • Recurrence
  • United States / epidemiology
  • Whole Exome Sequencing / methods
  • Whole Exome Sequencing / statistics & numerical data

Substances

  • Progestins
  • 17 alpha-Hydroxyprogesterone Caproate