Generally, fertility treatment cannot be said to increase the cancer risk in women and their children.
The current review includes studies from the period 2006–2017, owing to the fact that a number of new studies have been published since the last literature review (38). Treatment has also changed over time and, by restricting the time frame, we hoped to include studies with more homogeneous treatment exposure. Nevertheless, the studies proved to be relatively different in terms of methodology. Some studies took into account age, infertility diagnoses and the number of children borne by the women after treatment or whether they remained nulliparous. Other studies did not include such information. In addition, it is very important to control for overweight in connection with uterine cancer, which most studies did not.
A strength of the Nordic studies is that they used data from population-based registries, and also analysed the data at an individual level. A weakness of the Norwegian dataset is that there is no national, cycle-based registry of fertility treatment. Such a registry should be established. The Cancer Registry of Norway has been shown to have completeness of almost 100 % (39). However, quality and completeness are not as good in all countries (40). In the Israeli study (23), the authors included only those cancer cases diagnosed at the one centre from which the study population was recruited, a clear weakness of the study.
The Nordic cohort studies compared cancer risk in women who have undergone fertility treatment with the risk in the general population. Several of the non-Nordic studies obtained data from fertility clinics, which then enabled them to compare the risk of cancer in women who have had fertility treatment with the risk in untreated infertile women. In order to examine the effect of fertility treatment alone, the latter approach should ideally be used. However, this is difficult in practice, as the selection of women for treatment means that these two groups will differ. In addition, infertile or nulliparous women are a heterogeneous group, and various infertility diagnoses may themselves be associated with increased cancer risk. For example, endometriosis may be associated with increased risk of ovarian and uterine cancer (41, 42).
Other key challenges relate to study size and follow-up time. Many of the studies have few cancer cases in the exposed group, and several of the studies have short follow-up times. This is particularly relevant in the case of uterine cancer, which mainly affects older women (60–70 years of age).