Children born after in vitro fertilization (IVF) or other fertility treatments appear to be at modestly elevated risk of cancer, although causality still isn’t clear, a meta-analysis showed.

The risk of any childhood cancer was 33% higher after medically-assisted reproduction compared with spontaneously conceived controls, Susanne Krüger Kjaer, MD, DMSc, of the Danish Cancer Society Research Center in Copenhagen, and colleagues found.

The association also was significant for leukemias, neuroblastomas, and retinoblastomas specifically, the group reported online in Fertility and Sterility.

But the absolute risk was low, they noted. For Denmark, where 9% of all babies are born with the assistance of fertility treatments, one excess childhood cancer would be expected for every 4,236 women treated, assuming the link is causal.

“However, our results do not rule out that factors related to underlying subfertility, rather than the procedure itself, are the most important predisposing factors for childhood cancer,” they cautioned.

Only two of the studies that went into the meta-analysis were designed to adequately control for underlying fertility problems.

A causal link is plausible, though, Kjaer and colleagues noted.

“Potential mechanisms whereby fertility treatment might cause childhood cancers include epigenetic changes induced by repeated hormone exposure, semen preparation, freezing of embryos and gametes, use of culture media, growth conditions for embryos, and delayed insemination,” they explained.

And unintended consequences aren’t unheard of in obstetrics.

“Of possible note is the fact that diethylstilbestrol, which was prescribed to pregnant women between 1940 and 1971 to prevent complications of pregnancy and was associated with the subsequent development of cancer in children, is structurally similar to the anti-estrogens used for ovulation stimulation,” the group pointed out.

On the other hand, though, “infertile couples may already have an increased number of epigenetic defects in their gametes, which come to light through the treatment process,” they acknowledged.

The group’s meta-analysis included 25 case-control and cohort studies from 12 countries.

The pooled cancer risk appeared roughly similar whether looking just at assisted reproductive technology or if hormone treatments were included as well.

For assisted reproductive technology only, such as IVF and intracytoplasmic sperm injection, the relative risk of any childhood cancer was 1.40 (95% confidence interval 1.12 to 1.74).

For overall medically assisted reproduction—which includes ovulation induction, controlled ovarian stimulation, ovulation triggering, and direct insemination along with assisted reproductive technology—the relative risk of any childhood cancer was 1.33 (95% CI 1.08 to 1.63).

“The results for both neuroblastomas and retinoblastomas should be interpreted with caution because of the small number of studies,” Kjaer’s group noted.

The risk estimates for CNS and neural cancers as well as other solid cancer appeared higher with assisted reproductive technology than with all the techniques combined, but these results were also based on small numbers and had a large degree of heterogeneity.

The meta-analysis didn’t turn up evidence for publication bias, but recall bias from the case-control studies couldn’t be excluded.

“Consequently, future large cohort studies with sufficient follow-up time and an adequate control population (i.e., children of couples with fertility problems conceived without fertility treatment) are needed,” they concluded.

The study was supported by Savværksejer Jeppe Juhl og Hustru Ovita Juhls Foundation.

Kjaer reported having no conflicts of interest to disclose.

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Primary source: Fertility and Sterility
Source reference: Hargreave M, et al “Fertility treatment and childhood cancer risk: a systematic meta-analysis” Fertil Steril
2013; DOI: 10.1016/j.fertnstert.2013.03.017.