Abstract and Introduction
Study Question: Is the risk of attention-deficit hyperactivity disorder (ADHD) increased in children born to mothers with infertility, or after receipt of fertility treatment, compared to mothers with unassisted conception?
Summary Answer: Infertility itself may be associated with ADHD in the offspring, which is not amplified by the use of fertility treatment.
What is Known Already: Infertility, and use of fertility treatment, is common. The long-term neurodevelopmental outcome of a child born to a mother with infertility, including the risk of ADHD, remains unclear.
Study Design, Size, Duration: This population-based cohort study comprised all singleton and multiple hospital births in Ontario, Canada, 2006–2014. Outcomes were assessed up to June 2020.
Participants/Materials, Setting, Methods: Linked administrative datasets were used to capture all hospital births in Ontario, maternal health and pregnancy measures, fertility treatment and child outcomes. Included were all children born at ≥24 weeks gestation between 2006 and 2014, and who were alive at age 4 years. The main exposure was mode of conception, namely (i) unassisted conception (reference group), (ii) infertility without fertility treatment (history of an infertility consultation with a physician within 2 years prior to conception but no fertility treatment), (iii) ovulation induction (OI) or intrauterine insemination (IUI) and (iv) IVF or intracytoplasmic sperm injection (ICSI). The main outcome was a diagnosis of ADHD after age 4 years and assessed up to June 2020. Hazard ratios (HRs) were adjusted for maternal age, income quintile, rurality, immigration status, smoking, obesity, parity, any drug or alcohol use, maternal history of mental illness including ADHD, pre-pregnancy diabetes mellitus or chronic hypertension and infant sex. In addition, we performed pre-planned stratified analyses by mode of delivery (vaginal or caesarean delivery), infant sex, multiplicity (singleton or multiple), timing of birth (term or preterm <37 weeks) and neonatal adverse morbidity (absent or present).
Main Results and the Role of Chance: The study included 925 488 children born to 663 144 mothers, of whom 805 748 (87%) were from an unassisted conception, 94 206 (10.2%) followed infertility but no fertility treatment, 11 777 (1.3%) followed OI/IUI and 13 757 (1.5%) followed IVF/ICSI. Starting at age 4 years, children were followed for a median (interquartile range) of 6 (4–8) years. ADHD occurred among 7.0% of offspring in the unassisted conception group, 7.5% in the infertility without fertility treatment group, 6.8% in the OI/IUI group and 6.3% in the IVF/ICSI group. The incidence rate (per 1000 person-years) of ADHD was 12.0 among children in the unassisted conception group, 12.8 in the infertility without fertility treatment group, 12.9 in the OI/IUI group and 12.2 in the IVF/ICSI group. Relative to the unassisted conception group, the adjusted HR for ADHD was 1.19 (95% CI 1.16–1.22) in the infertility without fertility treatment group, 1.09 (95% CI 1.01–1.17) in the OI/IUI group and 1.12 (95% CI 1.04–1.20) in the IVF/ICSI group. In the stratified analyses, these patterns of risk for ADHD were largely preserved. An exception was seen in the sex-stratified analyses, wherein females had lower absolute rates of ADHD but relatively higher HRs compared with that seen among males.
Limitations, Reasons for Caution: Some mothers in the isolated infertility group may have received undocumented OI oral therapy, thereby leading to possible misclassification of their exposure status. Parenting behaviour, schooling and paternal mental health measures were not known, leading to potential residual confounding.
Wider Implications of the Findings: Infertility, even without treatment, is a modest risk factor for the development of ADHD in childhood. The reason underlying this finding warrants further study.
Study Funding/Competing Interest(s): This study was made possible with funding from the Canadian Institutes of Health Research, Grant number PJT 165840. The authors report no conflict of interest.
Trial Registration Number: N/A.
There is currently limited research examining the long-term neurodevelopmental outcomes of children born to women with infertility and/or fertility treatment. Previous work has demonstrated a higher risk of impaired behavioural, emotional and cognitive development, as well as mental disorders after exposure to fertility treatment (Svahn et al., 2015). However studies supporting a link between fertility treatment and attention-deficit hyperactivity disorder (ADHD) have been inconsistent. There remains uncertainty about whether reported associations stem from the parental infertility aetiology, the fertility treatment or some other confounding factors.
Methodological limitations of previous studies include small sample sizes, limited response rates, single fertility centres and cross-sectional design (Wagenaar et al., 2009; Beydoun et al., 2010; Mains et al., 2010; Halliday et al., 2014). More robust data from population-based studies linking health administrative registries have reported a modest association between maternal receipt of IVF and pharmacologically treated ADHD in the exposed offspring (Källén et al., 2011). Another register-based study reported an increased risk of ADHD in children born after ovulation induction (OI) with or without intrauterine insemination (IUI), but not after IVF (Bay et al., 2013).
The influence of infertility without fertility treatment on risks of ADHD merits further study. For example, among mothers with infertility, their offspring have a reportedly higher risk of ADHD in adulthood (Svahn et al., 2015). However, in a prospective cohort study of children aged 5 years, infertility was not associated with ADHD (Bay et al., 2014). Infertility and fertility treatment are associated with adverse pregnancy outcomes that may predispose to ADHD, including caesarean section, multiple pregnancy and preterm birth (Halmøy et al., 2012; Velez et al., 2014; Curran et al., 2015; Elias et al., 2020; Lodge-Tulloch et al., 2021; Richmond et al., 2022). The role of these adverse pregnancy outcomes on any possible association between infertility, fertility treatment and ADHD also warrants clarification (Hart and Norman, 2013).
There is a current paucity in research with respect to the association between infertility, fertility treatment and offspring ADHD, relative to unassisted conception. This population-based cohort study was undertaken to address this knowledge gap.
Hum Reprod. 2022;37(9):2126-2134. © 2022 Oxford University Press