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A Systematic Review and Meta-analysis

Dorte Hvidtjørn, MPH; Laura Schieve, PhD; Diana Schendel, PhD; Bo Jacobsson, PhD; Claus Sværke, MSc; Poul Thorsen, PhD

Arch Pediatr Adolesc Med. 2009;163(1):72-83.

Objective  To assess the existing evidence of associations between assisted conception and cerebral palsy (CP), autism spectrum disorders (ASD), and developmental delay.

Data Sources  Forty-one studies identified in a systematical PubMed and Excerpta Medica Database (EMBASE) search for articles published from January 1, 1996, to April 1, 2008.

Study Selection  Studies written in English comparing children born after assisted conception with children born after natural conception assessing CP, ASD, and developmental delay, based on original data with a follow-up of 1 year or more.

Main Exposures  In vitro fertilization (IVF) with or without intracytoplasmic sperm injection or ovulation induction with or without subsequent intrauterine insemination.

Main Outcome Measures  Cerebral palsy, ASD, and developmental delay.

Results  Nine CP studies showed that children born after IVF had an increased risk of CP associated with preterm delivery. In our meta-analysis including 19 462 children exposed to IVF, we estimated a crude odds ratio of 2.18 (95% confidence interval, 1.71-2.77). Eight ASD studies and 30 studies on developmental delay showed inconsistent results. No studies assessed the risk of CP, ASD, or developmental delay in children born after ovulation induction exclusively.

Conclusions  Methodological problems were revealed in the identified studies, and the gaps in our knowledge about the long-term outcomes of children born after assisted conception are considerable, including a lack of information on the long-term consequences of ovulation induction. Possible associations with ASD and developmental delay need assessment in larger studies. Studies on assisted conception and CP from countries outside of Scandinavia are needed, including detailed information on time to pregnancy, underlying cause of infertility, and type of IVF treatment.

Author Affiliations: North Atlantic Nuro Epidemiolgy Alliances, Institute of Public Health, Department of Epidemiology, University of Aarhus, Århus, Denmark (Ms Hvidtjørn, Drs Jacobsson and Thorsen, and Mr Sværke); Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, Atlanta, Georgia (Drs Schieve and Schendel); Perinatal Center, Department of Obstetrics and Gynecology, Institute for the Health of Women and Children, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden (Dr Jacobsson); Department of Obstetrics and Gynecology, Rikshospitalet, Oslo, Norway (Dr Jacobsson); Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia (Dr Thorsen).

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