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Question
Question: Are children conceived after fertility treatment at increased risk of mental health disorders compared with spontaneously conceived children?
People: 33 139 children conceived after fertility treatment and 555 828 spontaneously conceived children (age 8 –17 years). This represented all children born in Denmark during the study years of interest (1995–2003) identified through the Danish Medical Birth Register (excluding children born to mothers aged less than 20 years).
Setting: Denmark; birth cohort, 1995–2003, follow-up in 2012
Risk factors: Fertility treatment, either with in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) or with hormone treatments to induce ovulation, with or without intrauterine insemination (IUI). IVF/ICSI exposure was identified through the Danish IVF Register, which collects information of each woman on cause of infertility, treatments given, pregnancy outcomes and identification of any children born. Exposure to hormone treatments (based on a drug list prespecified by the authors) was identified through the Danish National Prescription Register. Women were considered to have received hormone treatment for induced ovulation (OI) if they received a prescription up to 12 weeks before and 4 weeks after the date of their last menstrual period (women in the IVF register with the same date of last menstrual period were excluded).
Outcomes: Any mental disorder of childhood or adolescence (ICD-10) as recorded in the Danish Psychiatric Central Research Register, which contains individual data on all admissions, outpatient visits, diagnoses and dates. Risk of mental disorder according to the method of conception was assessed using standard Cox regression analyses, with adjustment for covariates of maternal age, parity, smoking in pregnancy, educational level, psychiatric history and child multiplicity, sex, APGAR (appearance pulse grimace activity respiration) score and year of birth.
Methods
Design: Prospective cohort study.
Follow-up period: 8–17 years.
Main results
Four percent of all children in the birth cohort (n=23 278) had received a diagnosis of one or more mental disorders. Prevalence according to the method of conception was 3.9% for children spontaneously conceived, 3.5% for IVF/ICSI children and 4.1% for children conceived after OI or IUI. Mental disorders were more prevalent among boys than girls (5.8% vs 2.1%, p<0.001). In adjusted analyses, OI/IUI was associated with increased risk of any mental disorder as compared to spontaneous conception (HR 1.20, 95% CI 1.11 to 1.31). IVF/ICSI was not associated with risk of any mental disorder (HR 1.04, 95% CI 0.94 to 1.15). By individual disorder OI/IUI was associated with increased risk of autistic spectrum disorder (HR 1.20, 95% CI 1.05 to 1.37), hyperkinetic disorder (HR 1.23, 95% CI 1.08 to1.40), conduct/emotional/social disorders (HR 1.21, 95% CI 1.02 to 1.45) and tic disorder (HR 1.51, 95% CI 1.16 to 1.96). IVF/ICSI was not associated with any disorder of psychological development, or any behavioural or emotional disorder, with the exception of tic disorder (adjusted HR 1.40, 95% CI 1.01 to 1.95). Neither IVF/ICSI nor OI/IUI was associated with any severity of mental retardation. No individual hormone treatment was associated with risk of any individual mental disorder, neither was cause of infertility associated with risk.
Conclusions
Conception after OI, with or without IUI, is associated with a small increased risk of any mental disorder in childhood or adolescence. With the exception of tic disorder, fertility treatment with IVF/ICSI was not associated with increased risk.
Abstracted from
Commentary
Bay and colleagues report that while individuals born after assisted reproductive technologies (ART) - such as in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) - are not at increased risk of mental disorders in childhood or adolescence compared to spontaneously conceived children, those born after ovulation induction (OI) or artificial insemination (AI) are more likely to have adverse outcomes.
Utilising high-quality national registers, the authors constructed a cohort of all children born in Denmark between 1995 and 2003. They linked to IVF and ICSI data as well as prescriptions for drugs used in OI and AI to define their ‘exposed’ groups. Data were drawn from the Danish Psychiatric Central Register to assess a range of outcomes and presented as HRs. Children born after IVF and ICSI were not found to be at increased risk. Children born after OI and AI were about 20% more likely than spontaneously conceived children to be diagnosed with any mental disorder, specifically autism, hyperkinetic, conduct or tic disorders, although the absolute risk remained low. The results, based on a large population-based cohort and adjusted for important potential confounding factors, appear robust. However, the outcome includes only severe cases, meaning that subtle effects may have been missed. Furthermore, it was not possible to explore differences in parenting behaviours that may impact on mental health in ART families.
Evidence on the differing effects of types of ART on neurodevelopmental outcomes is limited. Another recent publication reported on the risk of autism and mental retardation in children after IVF/ICSI1 and, in contrast to Bay et al.1, found an adverse effect of ICSI. Questions remain unanswered about the long-term effects of OI. The underlying mechanism that would explain any increase in risk among the children of ICSI or OI patients is still unclear. This study is unlikely to alter clinical practice in the short term, but offers additional evidence on the safety of IVF and ICSI to reassure infertile couples.
Reference
Footnotes
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Sources of funding Aarhus University and The Augustinus Foundation, Denmark.
Footnotes
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Competing interests None.