What are the risks of assisted reproduction?

During the interviews and preliminary visits, couples who are about to embark on an assisted fertilization process are made aware of the type of treatment suitable for their problems. Costs, times, drugs and techniques used, and any problems that may arise are explained.

All of this including the risks and complications are listed in the informed consent document that couples must read and sign before starting treatment (the points governing the drafting of informed consent are contained in the Official Gazette General Series No. 40 of  17 -02-2017).

Going into detail for the topics we address in this article, the informed consent must list:

• unwanted or side effects related to treatments;
• the risks for the mother and for the unborn child , ascertained or possible, as evidenced by the scientific literature;
• the risks associated with heterologous PMA techniques and the measures taken to mitigate them, with particular reference to the clinical tests to which the donor was subjected, including the medical genetic examination, and the related tests used, representing that such tests cannot guarantee, absolutely, the absence of pathologies for the unborn child;
• the commitment to communicate to the center, in the event of access to heterologous MAP techniques, any pathologies that have arisen, even after some time, in the woman, in the unborn child or in the newborn, and whose presence it is reasonable to assume prior to the donation;
• the possible psychological effects for the individual applicants, for the couple and for the offspring, resulting from the application of ART techniques, with particular regard to the specificity of ART techniques of heterologous type.

The most discussed risks of assisted reproduction treatments

There are several theoretical risks related to PMA, here we focus only on 4 highly debated and discussed topics which are:

• Risk of Ovarian Hyperstimulation (OHSS)
• Risk of twin pregnancy
• Risk of birth defects in children born due to ART
• Risk of developing cancer after undergoing one or more IVF treatments.

The risk of ovarian hyperstimulation and the risk of twin pregnancies can be drastically reduced by applying protocols adapted to the patient’s problems and by transferring only one embryo per treatment.

Regarding the risk of birth defects in babies born with the help of IVF, it seems that IVF increases the risk , but more studies and insights are needed to fully understand the causes.

With regard to breast and ovarian cancer, it is difficult to say whether it is infertility, or the treatment, that determines an increased risk of cancer, if and when it exists.

The most recent reviews are reassuring and have pointed to infertility , rather than in vitro fertilization, as the causal factor.

However, the question of whether IVF can lead to higher rates of cancer is not fully resolved, and requires further study. Given the complexity of the answer, a definitive conclusion will probably never be reached.

As always, it is important to discuss each of these issues openly and in detail with the doctors of your centre, also in relation to your personal and family medical history.

The ovarian hyperstimulation syndrome

Most of the patients who undergo MAP treatment receive gonadotropins to stimulate the ovaries to produce a large number of follicles in which the oocytes mature, which will be collected at the time of the pick-up.

Women who have been “overstimulated” with gonadotropins can develop Ovarian Hyperstimulation Syndrome (OHSS). OHSS occurs in 1-10% of women on treatment, particularly younger women, or with PCOS or high AMH.

Twin pregnancies

Many couples would like to have two, or even three children, with just one treatment. This is because they are unaware of the risks involved in a twin pregnancy.

When more embryos are transferred, the risks of a multiple pregnancy increase from 1% up to 30%. This results in an increased risk for the mother and for the babies.

Twins are more likely to be born prematurely, and preterm birth is a serious condition.

Prematurity has also been associated by various studies with lower cognitive function.

Much of this risk can be canceled by transferring just one embryo. While the one-time transfer may increase the chances that the first treatment will fail (requiring an additional transfer, and thus additional cost), it does not reduce the chances that the treatment will result in having a baby in your arms.

Risks of birth defects in the unborn child

This is a difficult subject to study and understand. First, the very definition of “birth defects” varies according to the type and age of the offspring. Second, patients who undergo PMA often have fertility problems and are, by definition, different from the general population. Consequently, any difference in the rates of birth defects in the offspring could be due to the factors that caused the infertility itself, or to the treatment of PMA, or to another factor as well. It can therefore be difficult to trace the actual cause.

The currently available studies obtained by comparing PMA and natural conception pregnancies  show an increased risk of congenital birth defects in children born with PMA . In children born, congenital anomalies occur with a frequency increased by 36% compared to controls.

If in the general population the rate of congenital malformations is equal to 2.5% ( Eurocat data ) it is expected that in children born from in vitro fertilization this rate will increase up to 3.4-4.1%.

The same review did not note a significant difference in congenital malformations between children born with IVF or ICSI even if, comparing the two techniques with natural conception, IVF shows a lower risk than ICSI.

Are there strategies to decrease the risk of birth defects in an MAP treatment?

• Certainly transferring single embryos reduces the risk, given that children born from multiple pregnancies are more likely to face physical and cognitive challenges.
• Use ICSI as a fertilization technique only when absolutely necessary. As a large study in the New England Journal of Medicine demonstrates, the incidence of congenital malformations is lower when conventional insemination is practiced. Also in this case, however, the groups of patients who need ICSI (due to serious male factors) obviously have different characteristics than those who can resort to IVF.

Does PMA expose you to cancer risk?

This is a very frequent question among those who are about to undergo a treatment and there is often a lot of misinformation on the subject, even among the doctors themselves.

The studies mainly focus on verifying the risk of developing breast or ovarian cancer in women who undergo MAP. And the results currently seem reassuring (but obviously conditional is a must).

In any case, this is a difficult subject to deal with for two reasons. First, when trying to figure out whether PMA treatment is the cause of the cancer, researchers need to make sure the populations they’re comparing are the same. This way any difference in results can be attributed to PMA and not to another factor.

This is practically not possible as researchers have to compare populations that do not need ART (fertile populations) with those who do (infertile populations). As a result, it can be difficult to distinguish whether treatment, or different populations, is responsible for any differences in cancer rates. This is especially important because infertility per se has been shown to correlate with a higher susceptibility to developing cancer.

Second, cancer is a rare event and therefore requires monitoring large volumes of patients, over many decades, to detect any differences in disease rates. This often means relying on historical registries, which are less effective at revealing answers than a prospective randomized study.

Risk of breast and ovarian cancer

It’s not clear whether taking fertility drugs, especially gonadotropins, increases the risk of developing breast cancer.

One of the largest studies available was recently published in 2018, taking into consideration over 200,000 patients and a 10-year follow-up.

The researchers found no increased risk compared for breast cancer in general, but a slightly higher risk for breast cancer in situ (often located in the lactiferous ducts) and for borderline and invasive ovarian cancers.

Is this increased risk related to the fertility treatment or to the fact that the patients are infertile?

According to a 2016 Dutch study , among women who underwent fertility treatments in the Netherlands between 1980 and 1995, in vitro treatment compared with non-in vitro fertility treatment was not associated with an increased risk of breast cancer after a 21-year follow-up. The risk of breast cancer among women treated with IVF was also not significantly different from that in the general population. These results would therefore be consistent with the absence of a significant increase in the long-term risk of breast cancer among women who received PMA treatment.

There are some interesting observations on the subject of age. Some studies indicate that IVF at a young age is riskier, while others have shown that treatment at a later age is riskier.

As you can understand despite the studies currently available, there are no definitive conclusions.

What is certain is that PMA is indispensable for having a biologically proper child, for couples who have particular fertility problems (tubal factor, male factor, etc.). So is it worth taking any risks? The answer is not universal, everyone will make their own choice, the important thing is to make it consciously.