Projects per year
Abstract
Objectives: Evidence on the safety of TNF inhibitors (TNFi) for pregnancy-related maternal and fetal 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.
Methods: We proxied TNFi using rs1800693, a splicing variant within the TNFRSF1A gene, which is strongly associated with C-reactive protein (CRP) in a genome-wide association study of 575,531 individuals of European ancestry. CRP was selected as the biomarker because TNFi is recognised 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.
Results: We found no strong association between genetically proxied TNFi and any adverse pregnancy-related outcome, including spontaneous abortion (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.
Conclusions: 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.
Methods: We proxied TNFi using rs1800693, a splicing variant within the TNFRSF1A gene, which is strongly associated with C-reactive protein (CRP) in a genome-wide association study of 575,531 individuals of European ancestry. CRP was selected as the biomarker because TNFi is recognised 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.
Results: We found no strong association between genetically proxied TNFi and any adverse pregnancy-related outcome, including spontaneous abortion (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.
Conclusions: 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.
| Original language | English |
|---|---|
| Journal | Rheumatology Advances in Practice |
| Publication status | Accepted/In press - 5 Aug 2025 |
Keywords
- TNF inhibitor
- gestational diabetes
- preterm birth
- spontaneous abortion
- birthweight
- eclampsia
- ectopic pregnancy
- hyperemesis gravidarum
Fingerprint
Dive into the research topics of 'Genetically proxied TNF inhibition and pregnancy-related maternal and fetal outcomes in the general population: a Mendelian randomization study'. Together they form a unique fingerprint.Projects
- 2 Active
-
NIHR Manchester Biomedical Research Centre
Bruce, I. (PI), Lord, G. (CoI), Lennon, R. (CoI), Black, G. (CoI), Wedge, D. (CoI), Morris, A. (CoI), Hussell, T. (CoI), Sharrocks, A. (CoI), Stivaros, S. (CoI), Buch, M. (CoI), Gough, J. (CoI), Kostarelos, K. (CoI), Thistlethwaite, F. (CoI), Kadler, K. (CoI), Barton, A. (CoI), Hyrich, K. (CoI), Mcbeth, J. (CoI), O'Neill, T. (CoI), Vestbo, J. (CoI), Simpson, A. (CoI), Singh, S. (CoI), Smith, J. (CoI), Felton, T. (CoI), Murray, C. (CoI), Griffiths, C. (CoI), Cullum, N. (CoI), Rhodes, L. (CoI), Warren, R. (CoI), Paus, R. (CoI), Dumville, J. (CoI), Viros Usandizaga, A. (CoI), Keavney, B. (CoI), Tomaszewski, M. (CoI), Allan, S. (CoI), Body, R. (CoI), Cartwright, E. (CoI), Heagerty, A. (CoI), Kalra, P. (CoI), Miller, C. (CoI), Rutter, M. (CoI), Smith, C. (CoI), Trafford, A. (CoI), Evans, D. (CoI), Crosbie, E. (CoI), Crosbie, P. (CoI), Harvie, M. (CoI), Howell, S. (CoI), Renehan, A. (CoI), Dive, C. (CoI), Blackhall, F. (CoI), Landers, D. (CoI), Krebs, M. (CoI), Cook, N. (CoI), Clarke, R. (CoI), Taylor, S. (CoI), Jorgensen, C. (CoI), Lorigan, P. (CoI), Jayson, G. (CoI), Valle, J. (CoI), Mccabe, M. (CoI), Armstrong, A. (CoI), Freitas, A. (CoI), Illidge, T. (CoI), Choudhury, A. (CoI), Hoskin, P. (CoI), West, C. (CoI), Van Herk, M. (CoI), Faivre-Finn, C. (CoI), Bristow, R. (CoI), Kirkby, K. (CoI), Birtle, A. (CoI), Mackay, R. (CoI), Radford, J. (CoI), Linton, K. (CoI), Higham, C. (CoI), Munro, K. (CoI), Plack, C. (CoI), Arden Armitage, C. (CoI), Bruce, I. (CoI), Moore, D. (CoI), Saunders, G. (CoI), Stone, M. (CoI), Haddock, G. (CoI), Lewis, S. (CoI), Elliott, R. (CoI), Green, J. (CoI), Lovell, K. (CoI), Morrison, A. (CoI), Shaw, J. (CoI), Bucci, S. (CoI), Ainsworth, J. (CoI), Webb, R. (CoI), Newman, W. (CoI), Banka, S. (CoI), Clayton-Smith, J. (CoI), Payne, K. (CoI), Moldovan, R. (CoI), Wynn, R. (CoI) & Jones, S. (CoI)
1/12/22 → 30/11/27
Project: Research
-
Centre for Epidemiology Versus Arthritis.
Dixon, W. (PI), Bruce, I. (CoI), Felson, D. (CoI), Hyrich, K. (CoI), Lunt, M. (CoI), Mcbeth, J. (CoI), Mcdonagh, J. (CoI), O'Neill, T. (CoI), Sergeant, J. (CoI), Verstappen, S. (CoI) & Serafimova, I. (Support team)
1/08/18 → 31/01/26
Project: Research