Abstract
Background: Within-sibship analyses show lower perinatal mortality after assisted reproductive technology (ART) compared with natural conception (NC), a finding that appears biologically unlikely. We investigated whether this may be attributed to bias from selective fertility and carryover effects. Methods: Using data from national registries in Denmark (1994–2014), Finland (1990–2014) and Norway and Sweden (1988–2015), we studied 5 722 826 singleton pregnancies, including 119 900 ART-conceived and 37 590 exposure-discordant sibships. Perinatal mortality at the population level and within sibships was compared using multilevel logistic regression with random and fixed intercepts, respectively. We estimated selective fertility as the proportion of primiparous women with and without perinatal loss who had a second delivery, and carryover effects through bidirectional and crosswise associations. Results: Population analysis showed higher perinatal mortality among ART conception compared with NC (odds ratio 1.21, 95% CI 1.13 to 1.30), whereas within-sibship analysis showed the opposite (OR 0.36, 95% CI 0.31 to 0.43). Primiparous women with perinatal loss were more likely to give birth again (selective fertility) and to use ART in this subsequent pregnancy (carryover effects), resulting in strong selection of double-discordant sibships with death of the naturally conceived and survival of the ART-conceived sibling. After controlling for conception method and outcome in the first pregnancy, ART was not consistently associated with perinatal mortality in the second pregnancy. Conclusions: Whereas population estimates may be biased by residual confounding, within-sibship estimates were biased by selective fertility and carryover effects. It remains unclear whether ART conception contributes to perinatal mortality.
Originalsprog | Engelsk |
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Tidsskrift | International Journal of Epidemiology |
Vol/bind | 52 |
Udgave nummer | 2 |
Sider (fra-til) | 403-413 |
Antal sider | 11 |
ISSN | 0300-5771 |
DOI | |
Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:This work was supported by the Nordic Trial Alliance (a pilot project jointly funded by the Nordic Council of Ministers and NordForsk, grant number 71450), the Central Norway Regional Health Authorities (grant number 46045000 to LBR), the Nordic Federation of Obstetrics and Gynaecology (grant numbers NF13041, NF15058, NF16026 and NF17043 to U.B.W. and A.T.), the Interreg Öresund-Kattegat-Skagerrak European Regional Development Fund (ReproUnion project) to A.P. and C.B., the Research Council of Norway’s Centre of Excellence funding scheme (grant number 262700 to S.E.H. and L.B.R.), the European Research Council (ART-HEALTH 101021566 ERC Advanced Grant to D.A.L.), Medical Research Council (MC_UU_00011/6 to D.A.L.), Bristol National Institute of Health (NIHR) Research Biomedical Research Centre to D.A.L., NIHR Senior Investigator award (NF-0616–10102 to D.A.L.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Publisher Copyright:
© The Author(s) 2023; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.