Perinatal and Infant Health Birthweight, gestational age and familial confounding in sex differences in infant mortality: a matched co-twin control study of Brazilian male-female twin pairs identified by population data linkage Lucas Calais-Ferreira , 1,2 * Marcos E Barreto, 3,4 Everton Mendonc¸a, 3 Gillian S Dite , 1,5 Martha Hickey , 6,7 Paulo H Ferreira, 8 Katrina J Scurrah 1 and John L Hopper 1 1 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia, 2 Centre for Adolescent Health, Murdoch Children’s Research Institute, Melbourne, VIC, Australia, 3 AtyImoLab, Computer Science Department, Federal University of Bahia, Salvador, Brazil, 4 Department of Statistics, London School of Economics and Political Science, London, UK, 5 Genetic Technologies Ltd., Melbourne, VIC, Australia, 6 Royal Women’s Hospital, Melbourne, VIC, Australia, 7 Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, VIC, Australia, and 8 Charles Perkins Centre Musculoskeletal Hub, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia *Corresponding author. Level 3, 207 Bouverie St, Carlton, VIC, 3010, Australia. E-mail: lucas.cf@unimelb.edu.au Received 2 June 2021; Editorial decision 12 October 2021; Accepted 3 November 2021 Abstract Background: In infancy, males are at higher risk of dying than females. Birthweight and gestational age are potential confounders or mediators but are also familial and corre- lated, posing epidemiological challenges that can be addressed by studying male-female twin pairs. Methods: We studied 28 558 male-female twin pairs born in Brazil between 2012 and 2016, by linking their birth and death records. Using a co-twin control study matched for gestational age and familial factors, we applied logistic regression with random effects (to account for paired data) to study the association between male sex and in- fant death, adjusting for: birthweight, within- and between-pair effects of birthweight, birth order and gestational age, including interactions. The main outcome was infant mortality (0–365 days) stratified by neonatal (early and late) and postneonatal deaths. Results: Males were 100 g heavier and more at risk of infant death than their female co- twins before [odds ratio (OR) ¼ 1.28, 95% confidence interval (CI): 1.11–1.49, P ¼ 0.001] and after (OR ¼ 1.60, 95% CI: 1.39–1.83, P <0.001) adjusting for birthweight and birth or- der. When adjusting for birthweight within-pair difference and mean separately, the OR attenuated to 1.40 (95% CI: 1.21–1.61, P <0.001), with evidence of familial confounding VC The Author(s) 2021. Published by Oxford University Press on behalf of the International Epidemiological Association. 1502 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unre- stricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. IEA International Epidemiological Association International Journal of Epidemiology, 2022, 1502–1510 https://doi.org/10.1093/ije/dyab242 Advance Access Publication Date: 29 November 2021 Original article Downloaded from https://academic.oup.com/ije/article/51/5/1502/6446132 by guest on 10 June 2023