In a recent study published in Human Reproduction, researchers evaluated the risk of attention-deficit hyperactivity disorder (ADHD) in offspring of infertile mothers or those receiving infertility treatment compared to offspring of mothers with unaided conception.
Studies investigating the long-term neurodevelopmental outcomes in offspring of mothers with infertility and/or receiving infertility treatment are limited. Previous studies have shown increased risks of behavioral, cognitive, and emotional impairments post-exposure to infertility treatment. However, studies evaluating the association between infertility treatment and ADHD have shown inconsistent results, and the causes of such associations are unclear.
About the study
In the present study, researchers investigated whether the risk of ADHD was higher among offspring born to mothers with infertility and/or receiving infertility treatment than mothers who conceived without such assistance.
The study was conducted between 2006 and 2014 in the Ontario province of Canada and comprised single and multiple hospital live births at 24 weeks gestation by mothers aged between 18 and 55 years at the time of delivery with a valid Ontario health insurance program (OHIP) number.
Data on infertility treatment, hospital births, maternal health, pregnancy measures, and outcomes in the offspring were obtained from the inpatient and outpatient records of the institute for clinical evaluative sciences (ICES) datasets. Data were obtained on pregnancy characteristics such as the type of conception from the better outcomes registry & network (BORN) database and its associated Niday legacy datasets.
The team excluded the offspring of surrogate mothers from the analysis due to the gestational and biological complexities of surrogacy. Pregnancies resulting in abortions or death of the offspring before four years of age or those with inadequate data records were also excluded.
The prime exposure was the conception mode as follows: (i) unaided conception group (for reference), (ii) infertility with no corresponding treatment, diagnosed within two years before conception (international classification of diseases, ninth revision (ICD-9) code 628); (iii) ovulation induction (OI)/ intrauterine insemination (IUI) and (iv) in vitro fertilization (IVF)/intracytoplasmic sperm injections (ICSI).
The prime outcome was ADHD diagnosis in the offspring after the age of four years, described as two outpatient diagnoses (ICD-9 codes 312-14) by either a psychiatrist or pediatrician and/or one diagnosis during hospitalization (ICD-10 F90,91). The outcome was assessed till June 2020.
The team calculated hazard ratios (HRs) after data adjustments for the mother’s age, rural residency, income, the status of immigration, parity, smoking habits, obesity, use of alcohol and/or drugs, and mother’s medical history, including mental illnesses (such as ADHD), chronic hypertension, non-gestational diabetes, and sex of the child. Additionally, stratified analyses were performed by delivery mode (cesarean or vaginal delivery), sex of the infant, multiplicity (single or multiple), and the infant birth timing (preterm or term).
A total of 925,488 infants of 663,144 women were included in the analysis. Of these, 87% were born after unaided conception, 10% were born following infertility without infertility treatment, 1% were born following infertility OI/IUI, and 1.5% were born following IVF/ICSI. Follow-up assessments were performed for children aged four to eight years (median six years).
ADHD was diagnosed in seven percent of children born by unaided conception, eight percent in children born to the mothers with infertility without infertility treatment, seven percent in children born following OI/IUI, and six percent in those born following IVF/ICSI. The ADHD incidence rates (per 1000 individuals-years) were 12, 12.8, 12.9, and 12.2 among children of mothers belonging to the unaided conception group, infertility without infertility treatment group, OI/IUI group, and the IVF/ICSI group, respectively.
In relation to the unaided conception group, the adjusted HRs for ADHD diagnosis were 1.2, 1,1, and 1.1 among infertility with no infertility treatment, OI/IUI, and IVF/ICSI groups, respectively. In the stratified analyses, the patterns of ADHD risks were preserved to a large extent, with an exception in stratified analyses by sex, in which the absolute rates of ADHD were lower for females, but the HRs were relatively higher than for males.
In the sensitivity analysis limited to the infertile group, in relation to infertility without infertility treatment group, the adjusted HR was 0.9 and 0.9 for children born following OI/IUI and following IVF/ICSI, respectively. On adding a birth year to the analysis, considering ADHD diagnosis at two years of age, or limiting the analysis to children with maternal body mass index (BMI) availability(n=293,123), the results were similar to those of the main analysis.
Overall, the study findings showed that infertility, even without infertility treatment, could be modestly associated with the risk of development of ADHD in the child. The risk is not increased by treatment for infertility. However, further research must be conducted to explore the factors associated with maternal infertility contributing to ADHD in the child.