A total of 599
126 children were born alive in Denmark from 1 January 1995 to 31 December 2003. We excluded 10
159 children born to mothers aged under 20, leaving 588
967 children in the study. Of these, 555
828 were born after spontaneous conception and 33
139 were conceived after any type of fertility treatment (14
991 born after IVF/ICSI and 18
148 after induced ovulation/intrauterine insemination).
Tables 1 and 2 show baseline characteristics of children and mothers according to conception methods.
At the end of follow-up the age of the children ranged from 8.1 to 17.1 (mean 12.7, SD 2.6), and 23
278 children (4%) has received a diagnosis of one or more of the included mental disorders. The absolute risk was 3.9% among children born after spontaneous conception, 3.5% in IVF/ICSI children, and 4.1% in children born after induced ovulation/intrauterine insemination. The proportion of children with a diagnosis of any mental disorder was significantly higher among boys (5.8%) than among girls (2.1%) (P<0.001). The mean age at the time of any diagnosis was 9.3 (SD 3.4, range 8 days-17 years).
Table 1 Characteristics of children conceived after in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) and ovulation induction/intrauterine insemination (OI/IUI) or spontaneous conception in Denmark, 1995-2003. Figures are numbers (percentage) (more ...)
Table 2 Maternal characteristics according to conception after vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) and ovulation induction/intrauterine insemination (OI/IUI) or spontaneous conception in Denmark, 1995-2003. Figures are numbers (more ...)
Hazards associated with conception methods
Compared with children born after spontaneous conception, children born after IVF or ICSI had a higher hazard of tic disorders (hazard ratio 1.41, 95% confidence interval 1.05 to 1.87; absolute risk 0.3%) (table 3). This difference remained significant after adjustment for potential confounding variables (1.40, 1.01 to 1.95) and after restriction of analyses to infant survivors (1.40, 1.01 to 1.94). When we stratified analyses for multiplicity or sex of the child, the hazard ratio for tic disorders was not significantly increased. There were no other significant crude or adjusted hazard ratios of mental disorder in children or adolescents born after IVF/ICSI and spontaneously conceived controls.
Table 3 Hazard ratios and 95% confidence intervals for mental disorders* in 14 991children aged 0-17 born after in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) compared with 558 828 spontaneously conceived children
Children conceived after induced ovulation/intrauterine insemination had significantly increased hazard ratio for any mental disorder in both crude (hazard ratio 1.15, 95% confidence interval 1.07 to 1.24) and adjusted analyses (1.20, 1.11 to 1.31; absolute risk 4.1%; table 4). The increased hazards were significant for both singletons, multiples, boys, girls, and infant survivors. When we examined categories of mental disorders, induced ovulation/intrauterine insemination was not associated with an increased hazard ratio for mental retardation or unspecified mental disorders but was systematically related to disorders of psychological development (1.17, 1.05 to 1.31; 2.2%) as well as behavioural and emotional disorders (1.22, 1.11 to 1.35; 2.8%). Within these categories the increased hazard ratio was primarily confined to autism spectrum disorders, hyperkinetic disorder, tic disorders and conduct, and emotional or social disorders. After stratification, we found that the increased hazard ratios for mental disorders within these categories were more consistent in boys than in girls, in whom they fell short of significance for hyperkinetic disorder, tic disorders, and conduct, emotional, or social disorders. Stratification for sex of the child did not show any significant differences in estimates between boys and girls, and thus no effect modification was present.
Table 4 Hazard ratios and 95% confidence intervals for mental disorders* in 18 148 children aged 0-17 born after ovulation induction with or without intrauterine insemination (OI/IUI) compared with 558 828 spontaneously conceived children
In general, the hazard estimates were systematically increased when we adjusted for maternal age, educational level, smoking in pregnancy, or psychiatric history. This increase in estimates ranged from 3% (developmental disorders) to a maximum of 24% (conduct, emotional, or social disorders) (detailed analyses available from the authors). Adjustment for all other variables reduced or did not change the estimates.
Hazards associated with type of treatment and cause of infertility
Apart from conception after induced ovulation/intrauterine insemination there were no systematic associations with type of treatment nor when we looked at children conceived after IVF and ICSI as separate groups (table 5). Similarly, there were no associations with the reported cause of infertility (available only for IVF/ICSI group).
Table 5 Hazard rates and 95% confidence intervals for mental disorders*† in children aged 0-17 according to type of infertility treatment, hormones, gametes, and aetiology of infertility compared with spontaneously conceived children
Hazards associated with type of specific hormones and type of gamete or embryo
Information on type of hormonal treatment was available for all mothers in the induced ovulation/intrauterine insemination group and 51% of the mothers in the IVF/ICSI group. Some 8335 mothers were treated with a single type of hormonal drug. We found no association between treatment with clomiphene citrate, human chorionic gonadotrophin (hCG), or gonadotrophin releasing hormone (GnRH) and the hazard of any mental disorders, but there was an increased hazard ratio for any mental disorder after treatment with follicle stimulating hormone, although this was not significant within any category of mental disorders.
Information on type of embryo (fresh, frozen or donor egg, donor sperm) used for the conception was available for IVF/ICSI treatments. We found an increased hazard ratio for any mental disorder after IVF conception with donor sperm and hazard ratio of behavioural and emotional disorders after conception with donor oocyte but no significantly increased hazards associated with fresh or cryopreserved embryos.