Interleukin-1 receptor antagonist polymorphisms in women receiving epidural analgesia who develop maternal intrapartum fever: a prospective, multicentre Mendelian randomised study

Abstract

Background: Genetically predicted higher levels of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL1-Ra) might reduce the risk of developing epidural-related maternal fever, a phenomenon that occurs exclusively in women having epidural analgesia in labour. We hypothesised that in women having epidural analgesia, the absence of specific alleles that lower circulating levels of IL1-Ra would be associated with the development of epidural-related maternal fever, administration of intrapartum antibiotics, or both.

Methods: We prospectively enrolled women ≥18 yr of age receiving epidural analgesia during labour, excluding those with pre-existing fever, antibiotic therapy, or immunodeficiency. Allele scores were constructed from genotyping the C-allele frequency at variants rs6743376 and rs1542176; more copies of each allele independently raise IL-1Ra. The composite primary outcome was maternal intrapartum fever (>38°C) or administration of intrapartum antibiotics after epidural placement. The exposure of interest was the IL1-Ra allele score, comparing 0 (lowest genetically predicted IL-1Ra levels) with ≥1 allele scores. Maternal fever and antibiotic administration were compared in women with 0 or ≥1 allele scores.

Results: Of 624 women genotyped, 155 (24.8%) developed maternal fever or received antibiotics. Fever or antibiotic administration occurred in 19/74 (25.7%) labouring women with an IL-1Ra allele score of 0, compared with 136/550 (24.7%) women with IL-1Ra allele scores ≥1 (odds ratio 1.05, 95% confidence interval 0.60-1.83; P=0.89).

Conclusions: In women who receive epidural analgesia during labour, genetically predicted (higher) interleukin-1 receptor antagonist levels do not alter the incidence of maternal intrapartum fever or use of intrapartum antibiotics.

Clinical trial registration: ISRCTN99641204.

Keywords: Mendelian randomisation; epidural; fever; genetics; inflammation; interleukin-1 receptor antagonist; intrapartum.

Fig. 1

Study protocol. Summary of study procedures and data collection. IL1-Ra, interleukin 1 receptor antagonist; NICE, UK National Institute for Clinical Excellence; SNP, single-nucleotide polymorphism.

Fig. 2

Study flow chart.

Fig. 3

Primary outcome: composite of either intrapartum maternal fever or antibiotic treatment before birth. (a) In total, 19/74 (25.7%) women with an allele score of 0 either developed the co-primary endpoint of intrapartum maternal fever or received antibiotic treatment, compared with 136/550 (24.7%) women with allele scores ≥1 (odds ratio 1.05, 95% CI 0.60–1.83; P=0.89). (b) For intrapartum maternal fever alone, 7/74 (9.5%) women with an allele score of 0 developed intrapartum maternal fever, compared with 59/550 (10.7%) women with allele scores ≥1 (odds ratio 0.87, 95% CI 0.38–1.98; P=0.84).

Fig. 4

Secondary outcome: mode of birth. Mode of birth in women with 0 or ≥1 allele scores. Cat. 1 and Cat. 2–3 refer to the Caesarean delivery category. The number in each bar refers to the number per allele score grouping.