Congenital anomalies in offspring of subfertile couples A registry based study in the northern Netherlands

This registry-based study suggests that the associations between IVF/ICSI and penoscrotal hypospadia and imprinting disorders reported in the literature are better explained by the underlying subfertility than by IVF/ICSI treatment.


Jorien Seggers, M.D., Hermien E.K. de Walle, Ph.D., Jorieke E.H. Bergman, M.D., Ph.D., Henk Groen, M.D., Ph.D., Mijna Hadders-Algra, M.D., Ph.D., Marly E. Bos, B.Sc., Annemieke Hoek, M.D., Ph.D., Maaike L. Haadsma, M.D., Ph.D.

Volume 103, Issue 4, Pages 1001-1010



To study whether specific congenital anomalies occur more often with a history of subfertility and/or the use of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI).


Case-only analyses.


Not applicable.


We included live births, stillbirths, and terminated pregnancies with congenital anomalies without a known cause that had a birth year between 1997 and 2010 (n = 4,525). A total of 4,185 malformed cases were born to fertile couples and 340 to subfertile couples, of whom 139 had conceived after IVF/ICSI and 201 had conceived naturally after >12 months.



Main Outcome Measure(s):

The contribution, expressed in odds ratios (ORs), of a history of subfertility and IVF/ICSI to each specific type of congenital anomaly, imprinting disorder, and syndromal disorder.


We found subfertility to be associated with an increase in abdominal wall defects (adjusted OR [aOR] 2.43, 95% CI 1.05–5.62), penoscrotal hypospadia (aOR 9.83, 95% CI 3.58–27.04), right ventricular outflow tract obstruction (aOR 1.77, 95% CI 1.06–2.97), and methylation defects causing imprinting disorders (aOR 13.49, 95% CI 2.93–62.06). In vitro fertilization/ICSI was associated with an increased risk of polydactyly (OR 4.83, 95% CI 1.39–16.77) and more specifically polydactyly of the hands (OR 5.02, 95% CI 1.43–17.65).


In our registry-based study, parental subfertility was associated with an increase in abdominal wall defects, penoscrotal hypospadia, right ventricular outflow tract obstruction, and methylation defects causing imprinting disorders. In vitro fertilization/ICSI was associated with an increase in polydactyly, mainly of the hands.

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