LAUSR

Recently, the report of an increased risk of childhood cancers after assisted reproductive techniques (in vitro fertilization/ intracytoplasmic sperm injection (IVF/ICSI)) has generated considerable concerns [1]. However, is this accurate information? In recent years, in Italy and in parts of America of the restoration creationism [2], particularly when the issues involve contraception, hormonal therapies, and assisted reproduction techniques, debates generated by false or incorrect news are increasing. In fact, many of the associations between risk factors and diseases published by observational clinical research are often inaccurate, while the weight of a correlation is often exaggerated. This problem has many causes, including the inability of authors, reviewers, and editors (even of highly prestigious journals), to recognize the inherent limitations of these studies. This is particularly true for associations, defined as relative risks (RR) or odds ratios (OR), less than 4 times the probability that the event will occur in the absence of the condition under investigation. Such relationships are often attributed to bias or mere randomness rather than to a real cause-effect relationship. In general, only cohort studies with RR greater than 2 or 3 and case-control studies with OR higher than 3 or 4 (or 2–4 times the incidence in the control population) should be regarded as credible. A recent example of inaccurate reporting is the Israeli study cited by many newspapers [1] that presented retrospective data on 242,187 children of which 2603 (1.1%) born through IVF, 1172 (0.7%) conceived with help of medications to induce ovulation but not IVF, and 237,863 (98.3%) conceived naturally. The first important observation is that the ages of the mothers in the three groups (IVF, use of fertility drugs and natural) were different. Furthermore, there were differences in number of pregnancies and gestational age, premature birth, delivery and birth weights, hypertension, pre-gestational diabetes, gestational diabetes, and pregnancy-induced hypertension among the groups. In the study period (0–18 years), 429 children (1.77%) were hospitalized with a diagnosis of malignancy, including 7/2603 = 0.26% from IVF, 7/1172 = 0.59% from the use of fertility drugs, and 415/237,863 = 0.174% from natural conceptions. Multivariate analysis, without considering many other confounding factors, showed a relative risk of 1.89 (OR 0.894.02) after IVF and 2.03 (OR 0.96–4.30) after ovulation induction, when compared to natural conceptions. The incidence of a malignancywas low in children conceived spontaneously and after IVF, although for some specific malignancies like acute lymphocytic leukemia (ALL), due to the presence of genetic mutations, there was an increase [3]. The authors concluded that it was difficult to determine if the adverse events were related to fertility treatments or to the condition of being infertile [2]. After extensive discussions and review of the current literature on the topic of ART and risk of childhood cancer (articles discussed are listed in Table 1), we decided to write this commentary to highlight what is known and unknown on this important topic. The main biological question is whether IVF and embryo development from the 2 to 150 cells (about 2 to 5 days) in the laboratory cause an increased risk for cancers in childhood and adolescence. The theme is extremely relevant, as one couple in six has reproductive difficulties or a diagnosis of infertility and between 1 and 8% of annual births in some countries are from ART [4, 5]. A meta-analysis published in 2005 [6] reported on 11 of 14 published data sets, containing pertinent, non-overlapping, and comparable data. The final cohort included 38,815 subjects, with 38.21 cases of cancer expected vs 47 observed, giving a standardized incidence ratio (SIR) of 1.23 (95% CI 0.93–1.37). The analysis restricted to eight studies indicated 36.22 expected cases of childhood cancer and 35 observed, giving an SIR of 0.97 (95% CI 0.69–1.10). * Paolo Emanuele Levi-Setti [email protected]