Early childhood respiratory tract infections according to parental subfertility and conception by assisted reproductive technologies.

study questionAre children conceived by ART or born to subfertile parents more susceptible to upper or lower respiratory tract infections (URTI, LRTI)? SUMMARY ANSWER: ART-conceived children had a higher frequency of and risk of hospitalization for respiratory infections up to age 3, which was only partly explained by parental subfertility. WHAT IS KNOWN ALREADY: Some studies report increased risks of infections in children conceived by ART. Results for URTIs and LRTIs are inconclusive, and the contribution of underlying parental subfertility remains unclear. STUDY DESIGN, SIZE, DURATION: We included 84 102 singletons of the Norwegian Mother, Father and Child Cohort Study (MoBa) born between 1999 and 2009. Mothers reported time-to-pregnancy at recruitment and child history of, frequency of and hospitalization for, respiratory infections when the child was 6, 18 and 36 months old by questionnaires. Subfertility was defined as having taken 12 or more months to conceive. The Medical Birth Registry of Norway (MBRN) provided information on ART. URTI included throat and ear infections, while LRTI included bronchitis, bronchiolitis, respiratory syncytial virus and pneumonia. PARTICIPANTS/MATERIALS, SETTING,

methodsWe used log-binomial regression to estimate risk ratios (RR) and 95% CI of any respiratory tract infection and hospitalization, and negative-binomial regression to calculate incidence rate ratios (IRR) and 95% CI for number of infections. We compared children conceived by ART, and naturally conceived children of subfertile parents, to children of fertile parents (<12 months to conceive) while adjusting for maternal age, education, BMI and smoking during pregnancy and previous livebirths. We accounted for dependency between children born to the same mother. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 7334 (8.7%) singletons were naturally conceived by subfertile parents and 1901 (2.3%) were conceived by ART. Between age 0 and 36 months, 41 609 (49.5%) of children experienced any URTI, 15 542 (18.5%) any LRTI and 4134 (4.9%) were hospitalized due to LRTI. Up to age 3, children conceived by ART had higher frequencies of URTI (adjusted IRR (aIRR) 1.16; 95% CI 1.05-1.28) and hospitalizations due to LRTI (adjusted RR (aRR) 1.25; 95% CI 1.02-1.53), which was not seen for children of subfertile parents. Children conceived by ART were not at higher risks of respiratory infections up to age 18 months; only at age 19-36 months, they had increased risk of any LRTI (aRR 1.16; 95% CI 1.01-1.33), increased frequency of LRTIs (IRR 1.22; 95% CI 1.02-1.47) and a higher risk of hospitalization for LRTI (aRR 1.35; 95% CI 1.01-1.80). They also had an increased frequency of URTIs (aIRR; 1.19; 95% CI 1.07-1.33). Children of subfertile parents only had a higher risk of LRTIs (aRR 1.09; 95% CI 1.01-1.17) at age 19-36 months. LIMITATIONS, REASONS FOR CAUTION: Self-reported time-to-pregnancy and respiratory tract infections by parents could lead to misclassification. Both the initial participation rate and loss to follow up in the MoBa limits generalizability to the general Norwegian population. WIDER IMPLICATIONS OF THE

findingsART-conceived children might be more susceptible to respiratory tract infections in early childhood. This appears to be only partly explained by underlying parental subfertility. Exactly what aspects related to the ART procedure might be reflected in these associations need to be further investigated. STUDY FUNDING/COMPETING INTEREST(S): Funding was received from the Swiss National Science Foundation (P2BEP3_191798), the Research Council of Norway (no. 262700), and the European Research Council (no. 947684). All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.