Does IVF cause cancer in offspring?

In over 40 years of IVF practice, likely no question has been investigated more thoroughly than this: Does IVF in any way adversely affects the lives of IVF offspring? The general answer of a large number of studies has usually been that, with very few exceptions, there are no adverse effects of significance. Studies have already extended into second generations as well, because of concerns about the so-called epigenetic effects that may be inherited into next generations and, therefore, only manifest in later generations.

Colleagues in The Netherlands have been a leading force in many of these investigations. Using a nationwide historical cohort study with median prospective follow-up of 21 years, they now reported on the long-term risk of developing cancer as an offspring conceived via IVF as one of 24 269 offspring followed. Reassuringly, they concluded that, overall, children conceived via IVF do not demonstrate increased cancer risks (Spaan et al., Hum Reprod 2019;34:740-750).

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In this conclusion, they reaffirmed a number of earlier studies, though, because of the size of the study and the relative cohesions of the study population, this Dutch study allowed for some additional comment: Despite the large number of IVF offspring followed, cancers were still quite rare and overall cancer cases, therefore, were still small. This forbade the authors to perform subgroup analyses for individual cancers. Moreover, even though mean follow-up was 21 years, cancer is mostly a disease of advanced ages, and here investigated IVF offspring, of course, were still children and young adults, in whom cancer rate are very low by definition. These studies, therefore, must continue, especially in children conceived with intracytoplasmic sperm injection (ICSI) and after embryo freezing where non-significant potential trends in increased overall cancer rates were, indeed, observed.

The findings, however, also point out many of the difficulties encountered in these kinds of studies in differentiating between causal contributions to IVF outcomes between underlying causes of infertility and the IVF process itself. For example, ICSI is mostly performed in couples with male-factor infertility, and in such IVF cycles increased urogenital birth defects occur in male offspring, not necessarily because of utilization of IVF/ICSI but because of the father’s genetic predispositions inherited by his offspring. Similarly, one could argue that women and men with cancer histories, of course, use more ICSI and egg/embryo freezing. Therefore, even if at some point in such populations an increased cancer risk is discovered, it could very well be inherited from their parents and have nothing to do with the IVF process itself. In earlier studies, cancers that have been reported mildly associated with IVF were leukemias and rare brain tumors, but the Dutch study, indeed, specifically ruled out an increase in leukemia risk.

All of this also warrants some evolutionary considerations: Infertility, after all, is nature’s way to interrupt procreation and, with it, transmission of harmful genes and polygenetic inheritance into next generations. For example, before insulin therapy became practical, diabetic women in principle never had children; they either never conceived or miscarried if they did conceive. With modern infertility treatments, diabetic women now have children at normal rates and these children, of course, inherit their mothers’ genetic predisposition toward diabetes. Through treatment successes in overcoming infertility, mankind, therefore, greatly increases continuous transmission of genetic risks into next generation, even if nature’s intent may have been to interrupt such transmission. Infertility treatments, in this sense, have major effects on human evolution.

This is a part of the July 2019 issue of the CHR VOICE.

Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned specialist in reproductive endocrinology, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.