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Malformation risk in subfertile couples

Reproductive BioMedicine Online, 3, 25, pages 225 - 226

As long ago as 1991 data were published showing that the risk of major malformation is directly correlated with the ‘time to pregnancy’ after assisted reproduction therapy was initiated: the longer it took to conceive, the higher was the risk of major malformations ( Ghazi et al., 1991 ). It has taken nearly 20 years to have new and more robust data coming from a recent registry-based study published in theNew England Journal of Medicine( Davies et al., 2012 ).

This Australian study is based on more than 308,974 pregnancies, and includes data not only on live births but also on late spontaneous pregnancy losses (after 20 weeks of gestation or fetuses weighing more than 400g), as well as from pregnancy terminations. The data from this database were linked with the national malformation registry. Of these pregnancies, 6163 (2%) came from assisted reproduction therapy (ART) cycles. The rate of major malformation recorded after ART cycles was in the range of 6–8%. This rate is quite high, higher than the usually reported 2–3%, and such a high rate is only described in cases when strict criteria for major malformation registration have been used.

The most interesting point in the study is not the finding that the risk of major malformations is increased in pregnancies conceived after use of assisted reproductive technologies: this is well known from other studies. The main and most important finding is that the risk was increased significantly in pregnancies from couples with subfertility, independently of whether they have conceived by use of assisted reproduction or spontaneously.

There is now a large body of evidence in the literature that the risk of major malformation in children born after conventional IVF and intracytoplasmic sperm injection (ICSI) is increased as compared with fertile couples who conceived spontaneously (Hansen et al, 2004 and Wen et al, 2012). These meta-analyses have also shown that the risk of major malformation is not different in children born after conventional IVF compared with births after ICSI. Why the authors of the present study found an elevated risk after ICSI but not after IVF (in the adjusted data) cannot be explained. The authors themselves state that this difference may be due to other unknown factors, which could not be used for their data adjustment. However, it may also be that the severity of subfertility increases the risk of major malformations and that more severely subfertile couples are treated by ICSI than by conventional IVF.

The factor ‘subfertility’per se, could not be evaluated well in the studies published in recent years and analysed in the published meta-analysis. However, several years ago we speculated on a possible role for the risk factor ‘subfertility’ (Edwards and Ludwig, 2003 and Ludwig, 2005). In 2008 the first large-scale evaluation with reliable data was published inThe Lancet, showing that subfertility has an influence on pregnancy and perinatal outcome ( Romundstad et al., 2008 ). Now, with the study from Davies and colleagues, we have additional reliable data that subfertilityper sealso influences the risk of major malformation – and it may be that different characteristics or grades of subfertility have a greater or lesser influence on this outcome.

Is this good or bad news? There are still many concerns in the population regarding assisted reproductive technologies. A lot of patients still worry about the safety regarding the children born after IVF or ICSI. The present study can reassure them at least that the observed increase in major malformations is not due to the procedures used to achieve a pregnancy, but to other factors inherent in the subfertile status of the couple. The study, however, does not clarify the exact nature of these risk factors and thus does not help to identify useful diagnostic indicators for them. We and others have speculated on imprinting errors, other gene defects, or organic factors. Since the spectrum of causes for subfertility is broad, there may be a hetergenous group of factors underlying the risks of pregnancy course, perinatal outcome and major malformations.

What is good news is that with several million procedures of IVF and ICSI worldwide, no harm was done to the children born. However, it would be helpful to both us and to our patients to know the exact cause(s) of major malformations, as well as other risks in pregnancies of subfertile couples, in order to at least be able to advise the at-risk patients and perhaps to reduce the risk for them.


  • Davies et al., 2012 M.J. Davies, V.M. Moore, K.J. Willson, E.P. Van, K. Priest, H. Scott, E.A. Haan, A. Chan. Reproductive technologies and the risk of birth defects. N. Engl. J. Med.. 2012;366:1803-1813 Crossref
  • Edwards and Ludwig, 2003 R.G. Edwards, M. Ludwig. Are major defects in children conceived in vitro due to innate problems in patients or to induced genetic damage?. Reprod. Biomed. Online. 2003;7:131-138 Crossref
  • Ghazi et al., 1991 H.A. Ghazi, C. Spielberger, B. Kallen. Delivery outcome after infertility – a registry study. Fertil. Steril.. 1991;55:726-732
  • Hansen et al., 2004 M. Hansen, C. Bower, E. Milne, N. de Klerk, J. Kurinczuk. Assisted reproductive technologies and the risk of birth defects – a systematic review. Hum. Reprod.. 2004;20:328-388
  • Ludwig, 2005 M. Ludwig. Is there an increased risk of malformations after assisted reproductive technologies?. Reprod. Biomed. Online. 2005;10:83-89 Crossref
  • Romundstad et al., 2008 L.B. Romundstad, P.R. Romundstad, A. Sunde, V. von Düring, R. Skjaerven, D. Gunnell, L.J. Vatten. Effects of technology or maternal factors on perinatal outcome after assisted fertilisation: a population-based cohort study. Lancet. 2008;372:737-743 Crossref
  • Wen et al., 2012 J. Wen, J. Jiang, C. Ding, J. Dai, Y. Liu, Y. Xia, J. Liu, Z. Hu. Birth defects in children conceived by in vitro fertilization and intracytoplasmic sperm injection: a meta-analysis. Fertil. Steril.. 2012;97:1331-1337