Researchers Dissect Link Between Fertility Treatment and Childhood Cancer

Medscape Ob/Gyn 

Peter Kovacs, MD, PhD

DisclosuresOct 02, 2013

Fertility Treatment and Childhood Cancer Risk: A Systematic Meta-analysis

Hargreave M, Jensen A, Toender A, Andersen KK, Kjaer SK
Fertil Steril. 2013;100:150-161

Background

Controlled ovarian stimulation has been available since the 1960s and in vitro fertilization (IVF) since the late 1970s. It is estimated that 4-5 million children have been born following IVF. In developed countries, up to 5% of children born are conceived through IVF.

Since assisted reproductive technology (ART) was introduced, its safety has been questioned and tested. There are immediate risks that are associated with the intervention itself, such as ovarian hyperstimulation; bladder, bowel, and blood vessel injury during retrieval; infections related to the vaginal procedures; and an increased risk for thrombosis.

Numerous studies have evaluated the long-term risks associated with hormone use itself. Most have been reassuring and have found no additional adverse effects with the use of hormones, though infertility itself is a known risk factor for certain gynecologic cancers.

The risk for birth defects following assisted reproduction has also been studied by several groups. While an overall increased risk was seen in ART pregnancies, it is believed that this excess is associated with infertility and the underlying problems rather than the treatment itself.^[2]

Risk for cancer in the offspring conceived through ART is much less studied. In 2005, a meta-analysis found no increased risk for childhood cancer in children conceived via IVF.^[3]

This study is another analysis based on the results of reports published before and after 2005.

Study Summary

Twenty-five studies were included in the analysis. They are all cohort or case-control studies that assessed the association between medically assisted reproduction (stimulation only, insemination, or IVF) and childhood cancer risk. Overall, an increased risk for cancer was seen among those exposed to ART (relative risk [RR], 1.33; 95% confidence interval [CI], 1.08-1.63). When cancer subtypes were evaluated separately, an increased risk was found for hematologic cancers (RR, 1.59; 95% CI, 1.232-1.91) and central nervous system cancers (RR, 1.88; 95% CI, 1.02-3.46). The risk for neuroblastoma, retinoblastoma, and other solid cancers was also higher among those exposed to ART, though the association was based on a small number of cancers.

In their concluding remarks, the authors discussed that while the relative risks show an increased risk, the absolute number of additional cancers is very low. They also mentioned that at this point it is unknown whether the increased risk is associated with infertility or with the technology used to treat it.

Viewpoint

Cancer is the leading cause of death by disease among children under the age of 15 years. Every year, cancer is diagnosed in 1-2 of every 10,000 children. The most common cancers are leukemias, brain tumors, and central nervous system tumors.

While diagnostic and treatment options constantly are improving, cancer is still associated with significant morbidity and mortality. Long-term health may be affected by the treatments even in those who are successfully cured of the disease.

The etiology of childhood cancer is not known, though infectious agents, inherited genetic problems, and exposure to radiation or carcinogens have been all considered. It is also possible that the eggs, sperm, and embryos exposed to in vitro culture conditions are programmed in a way to be at risk for cancer. Epigenetic alterations may activate harmful genes or may suppress genes that are protective. Imprinting defects are believed to play a role in some really rare conditions following ART.^[5]

The possibility that the increased risk is associated with infertility itself, however, cannot be ruled out. In order to answer this, one would need to compare cancer risk in children born to infertile mothers exposed to or not exposed to ART. The authors did point out that only 2 out of 25 studies have taken subfertility into account. Neither of them found an elevated risk for cancer in the children exposed to fertility treatment.

Another study published in 2013 also found an increased relative risk for cancer among children conceived through ART. The 18% relative increase in the risk found by this group would mean 4 additional childhood cancers per 100,000 exposed children.^[8] The absolute risk is low, though, and the couples need to be counseled about both the relative and absolute risks. In addition, it is also important to study how the laboratory procedures may affect the gene expression in the embryos and what steps could be made to avoid these undesired effects. It is already known that the obstetric outcome after ART is not as good as after spontaneous conceptions. It is also known that malformation rates are relatively increased (small absolute increase) following fertility treatment. It is, however, not known to what degree (if at all) the technology is responsible for these findings. The role of infertility as the etiology of these adverse effects needs to be further explored.