Interleukin-1 receptor antagonist, mode of analgesia and risk of Caesarean delivery after onset of labour: a Mendelian randomisation analysis

Last updated:

19 November 2025

Author(s):

Gareth L. Ackland, Stefan Van Duijvenboden, Tom E.F. Abbott, Ana Gutierrez del Arroyo, Matthew J. Wilson, Anna L. David, the EPIFEVER-2 investigators, Amaan Ali, Matt Wikner, James Noblett, Nusrat Usman, Sarah Wray, Holly Blake, Ana G. del Arroyo, Tom E.F. Abbott, Valentin Weber, Constantinos Papoutsos, Rebecca Black, Kara Bruce-Hickman, Parvesh Verma, Chris Sadler, Alice Barrett, Laura Fulton, Tim Martin, Tabitha Tanqueray, Rebecca Longbottom, Lisa Cancili, India Nokes, Rachel Frowd, Natasha Kennedy, Matt Wilson, Vicki Wilson, Anna L. David, Sarah Weist, Olivia Newth, Morenike Folorunsho, Jihana Ali, Yaa Achaempong, Miriam Bourke, Derek Brunnen, Jennifer Kim, Kei Mak, Pete Odor, Laura Sarmiento, Sarah Ciechanowicz

Publish date:

19 November 2021

Journal:

British Journal of Anaesthesia

PubMed ID:

34802694

DOI:

10.1016/j.bja.2021.09.039

Abstract

BACKGROUND: Lower circulating levels of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra) are associated with intrapartum inflammation and epidural analgesia-related maternal fever, both of which increase the rate of obstetric interventions. We hypothesised that genetic variants determining IL-1ra levels would be associated with Caesarean delivery rates after the onset of labour.

METHODS: We performed Mendelian randomisation analyses in parous women ≥16 yr old who received either non-neuraxial or neuraxial analgesia for their first two labours (UK Biobank). We used an established genetic score (calculated as 0-4, determined by the presence/absence of rs6743376 and rs1542176 alleles), in which the complete absence of both alleles causes the lowest IL-1ra levels. The primary outcome was Caesarean delivery after the onset of labour (odds ratio [OR]: 95% confidence intervals).

RESULTS: There were 7731 women (mean [standard deviation] age at first birth: 25 [5] yr) who had complete genetic scores and delivery data. For women who received non-neuraxial analgesia, Caesarean delivery rates were different across allele scores (χ²=12.4; P=0.015): 104/596 (17.4%) women with zero allele score underwent Caesarean delivery, compared with 654/5015 (13.0%) with allele score ≥1 (OR 1.41; 1.12-1.77). For women who had neuraxial analgesia, Caesarean delivery was not different across allele scores, ranging from 18.1% to 20.8% (χ²=0.29; P=0.99). Caesarean delivery was independent of type of analgesia for 818/7731 (10.6%) women with zero allele scores (OR 0.93; 0.63-1.39), but was higher in women receiving neuraxial analgesia with allele scores ≥1 (OR 1.55; 1.35-1.79; P<0.001).

CONCLUSIONS: Mendelian randomisation analysis suggests that higher IL-1ra levels are associated with reduced Caesarean delivery rate. Neuraxial analgesia appears to disrupt this link.

CLINICAL TRIAL REGISTRATION: UK Biobank study 62745.