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Infertility, infertility treatment, and congenital malformations: Danish national birth cohort

BMJ 2006; 333 doi: (Published 28 September 2006) Cite this as: BMJ 2006;333:679
  1. Jin Liang Zhu (zjl{at}, research fellow1,
  2. Olga Basso, research fellow2,
  3. Carsten Obel, medical doctor3,
  4. Camilla Bille, medical doctor4,
  5. Jørn Olsen, professor5
  1. 1 Danish Epidemiology Science Centre, Department of Epidemiology, Institute of Public Health, University of Aarhus, DK 8000 Aarhus C, Denmark,
  2. 2Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, MD A3-05, USA,
  3. 3Perinatal Epidemiological Research Unit, Department of Gynaecology and Obstetrics, Aarhus University Hospital, DK 8200 Aarhus N, Denmark,
  4. 4Center for the Prevention of Congenital Malformations, Institute of Public Health, University of Southern Denmark, DK 5000 Odense C, Denmark,
  5. 5Department of Epidemiology, School of Public Health, UCLA, Los Angeles, CA 90095-1772, USA
  1. Correspondence to: J L Zhu
  • Accepted 14 July 2006


Objectives To examine whether infertile couples (with a time to pregnancy of > 12 months), who conceive naturally or after treatment, give birth to children with an increased prevalence of congenital malformations.

Design Longitudinal study.

Setting Danish national birth cohort.

Participants Three groups of liveborn children and their mothers: 50 897 singletons and 1366 twins born of fertile couples (time to pregnancy ≤ 12 months), 5764 singletons and 100 twins born of infertile couples who conceived naturally (time to pregnancy > 12 months), and 4588 singletons and 1690 twins born after infertility treatment.

Main outcome measures Prevalence of congenital malformations determined from hospital discharge diagnoses.

Results Compared with singletons born of fertile couples, singletons born of infertile couples who conceived naturally or after treatment had a higher prevalence of congenital malformations—hazard ratios 1.20 (95% confidence interval 1.07 to 1.35) and 1.39 (1.23 to 1.57). The overall prevalence of congenital malformations increased with increasing time to pregnancy. When the analysis was restricted to singletons born of infertile couples, babies born after treatment had an increased prevalence of genital organ malformations (hazard ratio 2.32, 1.24 to 4.35) compared with babies conceived naturally. No significant differences existed in the overall prevalence of congenital malformations among twins.

Conclusions Hormonal treatment for infertility may be related to the occurrence of malformations of genital organs, but our results suggest that the reported increased prevalence of congenital malformations seen in singletons born after assisted reproductive technology is partly due to the underlying infertility or its determinants. The association between untreated infertility and congenital malformations warrants further examination.


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    We thank Dionne Law, Donna Baird, and Clarice Weinberg for their valuable comments on the manuscript and Anne Vingård Olesen for statistical advice.

  • Contributors JLZ, OB, CO, and JO contributed to the study design. CB did the congenital malformation questionnaire survey. JLZ analysed the data and drafted the manuscript. All authors contributed to the conception of the paper, interpretation of data, and subsequent revisions of the manuscript. JO is the guarantor.

  • Funding JLZ is supported by a grant from the Danish Medical Research Council (No 271-05-0115). This research was also supported in part by the intramural research programme of the NIH, National Institute of Environmental Health Sciences. The Danish National Research Foundation established the Danish Epidemiology Science Centre, which initiated and created the Danish national birth cohort. The cohort is furthermore a result of a major grant from this foundation. Additional support for the Danish national birth cohort comes from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation.

  • Competing interests None declared.

  • Ethical approval The Danish Data Protection Agency granted authorisation for the implementation of the project (No 2005-41-5488), and the Danish National Birth Cohort Steering Committee granted authorisation for the use of data from the cohort (No 2005-10).

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