Zhao Sizheng Steven, Woolf Benjamin, Rogne Tormod, Gill Dipender
Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
School of Psychological Science and MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Rheumatol Adv Pract. 2025 Aug 29;9(3):rkaf100. doi: 10.1093/rap/rkaf100. eCollection 2025.
Evidence on the safety of TNF inhibitors (TNFi) for pregnancy-related maternal and foetal outcomes remains limited. While some studies report increased rates of preterm delivery, others have suggested a possible protective role for gestational diabetes. We used population-level data to examine the effect of genetically proxied TNFi on these outcomes.
We proxied TNFi using rs1800693, a splicing variant within the gene, which is strongly associated with CRP in a genome-wide association study of 575 531 individuals of European ancestry. CRP was selected as the biomarker because TNFi is recognized to suppression CRP. Genetic association data for pregnancy-related outcomes were taken from FinnGen and UK Biobank, including the outcomes of spontaneous abortion, ectopic pregnancy, hyperemesis gravidarum, gestational diabetes, pre-eclampsia or eclampsia, preterm birth and offspring birthweight. Colocalization analysis was used to examine genetic confounding.
We found no strong association between genetically proxied TNFi and any adverse pregnancy-related outcome, including spontaneous abortion (odds ratio [OR] 1.07, 95% CI: 0.41, 2.81), preterm birth (OR 0.48, 95% CI 0.14, 1.60), hyperemesis gravidarum (OR 0.20, 95% CI 0.02, 2.57), pre-eclampsia or eclampsia (OR 0.59, 95% CI 0.13, 2.65). Genetically proxied TNFi was associated with lower risk of gestational diabetes (OR 0.16, 95% CI 0.05, 0.52). There was no statistical evidence to suggest genetic confounding through linkage disequilibrium.
This genetic investigation found no evidence linking TNFi to adverse pregnancy-related outcomes. The suggestive association with a reduced risk of gestational diabetes warrants further research and may support its consideration for at-risk pregnant women.
关于肿瘤坏死因子抑制剂（TNFi）对妊娠相关母体和胎儿结局安全性的证据仍然有限。虽然一些研究报告早产率增加，但其他研究表明其对妊娠期糖尿病可能具有保护作用。我们使用人群水平数据来研究基因代理的TNFi对这些结局的影响。
我们使用rs1800693来代理TNFi，它是该基因内的一个剪接变体，在一项对575531名欧洲血统个体进行的全基因组关联研究中与CRP密切相关。选择CRP作为生物标志物是因为已知TNFi可抑制CRP。妊娠相关结局的遗传关联数据来自芬兰基因研究项目（FinnGen）和英国生物银行，包括自然流产、异位妊娠、妊娠剧吐、妊娠期糖尿病、先兆子痫或子痫、早产和子代出生体重等结局。采用共定位分析来检验基因混杂情况。
我们发现基因代理的TNFi与任何不良妊娠相关结局之间均无强关联，包括自然流产（比值比[OR]为1.07，95%置信区间：0.41，2.81）、早产（OR为0.48，95%置信区间0.14，1.60）、妊娠剧吐（OR为0.20，95%置信区间0.02，2.57）、先兆子痫或子痫（OR为0.59，95%置信区间0.13，2.65）。基因代理的TNFi与妊娠期糖尿病风险较低相关（OR为0.16，95%置信区间0.05，0.52）。没有统计学证据表明存在通过连锁不平衡导致的基因混杂。
这项基因研究未发现TNFi与不良妊娠相关结局之间存在关联的证据。与妊娠期糖尿病风险降低的提示性关联值得进一步研究，可能支持对高危孕妇考虑使用TNFi。
