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.

  • msamplaski

    These are compelling data for our patients who ask about offspring conceived to sub fertile couples. The numbers speak for themselves. It is interesting to note that these do not fall into a specific syndrome pattern (VACTRL). The next step would be to assess for known gene abnormalities associated with some of these conditions in the offspring and in the parental DNA. In addition, it would be interesting to know if DNA fragmentation or aneuploidy was correlated with any of these.

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