Fertility therapies: at what risks?

Infertility strikes 10-20% of couples in the Western countries.¹ An increasing number of couples resort to medically assisted procreation techniques (intrauterine insemination, pharmacological induction of ovulation, in vitro fertilization with embryo transfer and intracytoplasmic sperm injection). To date, the number of children conceived by means of assisted procreation represents 1-4% of births in the developed countries.² If from one side it is necessary to monitor the safety of these procedures, for risk evaluation it is also important to consider the complexity of the context. A previous issue (Focus 2013;Sept:4-5) reported the results of two studies about the risk of developing psychiatric disorders and cancer in the children born thanks to fertilization procedures.^3,4 This column will deepen the subject.
The majority of assisted procreation procedures require the uterine transfer of several embryos, with consequent increase in the rate of multiple gestations. Higher risks for the health of both mothers (i.e. caesarian section) and newborns (for example preterm birth, low birth-weight, infant mortality, high risk of malformations, disability) are associated with this condition. One risk of assisted procreation, in vitro fertilization included, seems to be low birth-weight. Some evidences also associate low birth-weight to diabetes-type2, hypertension and cardiovascular pathologies.⁵ Besides, data from literature show that the risk of congenital malformations in children born with assisted procreation procedures is 15-40% higher than in newborns spontaneously conceived.^6,7 The mechanism possibly responsible of these effects are numerous and include: the type of technique, the effects of ovarian stimulation on the quality of oocytes and endometrium, the effects of in vitro embryos culture in a very delicate development phase, the endometrial receptivity, embryos cryopreservation and parents’ infertility.⁶ In regards to the techniques, for example, a recent meta-analysis of 46 studies showed increased risk of malformations in children conceived by means of in vitro fertilization or intracytoplasmic sperm injection in comparison to newborns spontaneously conceived (relative risk 1.37, 95% confidence interval 1.26-1.49).⁷
Besides, ovarian stimulation (for example with clomifene, aromatase inhibitors, gonadotropins) can alter the endocrinology profile increasing the amount of corpora lutea influencing implantation and beginning of foetal and placental development.⁶ Artificial selection of spermatozoa for fecundation can be a critical factor, especially in case of intracytoplasmic sperm injection, where a single spermatozoon is injected in the oocyte.
The use of different culture methods can modify the offspring’s phenotype by altering physical and chemical parameters such as birth weight, blood pressure, fasting glycaemia, pubertal gonadotropins levels and growth factors.⁸ Besides, ooctyes and embryos culture medium can cause epigenetic alterations at DNA methylation level within the regions that control gene expression, with a possible increased risk of developing diseases by genomic imprinting defects (i.e. Beckwith-Wiedemann, Angelman, Prader-Willi and Silver-Russel syndromes).⁹
Embryonic implantation can be affected by the amount of transferred embryos and by the abortion of one or more embryos.⁵ Infertility can influence perinatal outcomes too, including the risk of congenital anomalies. This effect might be due to causes underlying infertility (such as cervix pathologies, anovulation, polycystic ovarian syndrome, low-quality sperm).⁵ Therefore the impact on mothers and children’ safety caused by infertility can be hard to distinguish from the effects due to assisted procreation techniques. Anyway, the chances that other causes than pharmacological ones, often procedural, could be behind the arisen of the adverse events, particularly complicates both spontaneous reporting and the evaluation of the aggregated data of the spontaneous report itself. From these considerations, it is quite clear the need for new studies in order to understand the mechanisms at the base of congenital anomalies in children conceived by means of assisted procreation. Besides, for the safety evaluation of these techniques and the development of appropriate prevention strategies, it could be useful to establish national registers for type of procedure, parent characteristics, foetal congenital anomalies, pregnancy outcomes.