BRCA1/2 pathogenetic variant carriers and reproductive decisions: Gender differences and factors associated with the choice of preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PND)

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method [17, 18].

We conducted a comprehensive literature search in PubMed, Scopus, and Web of Science. We searched for studies published in the last 21 years (from 2000 to 2021), using the following keywords in combination: reproductive, BRCA, decision (reproductive AND BRCA AND decision). We performed also a manual search of reference lists in publications selected in order to identify all studies relevant for the present review.

Studies were included if they were written in the English language. We assessed the eligibility criteria according to the PICO(S) model [17]:

Regarding exclusion criteria, articles were not considered eligible if they were not written in English, were specific on other hereditary syndromes, were literature reviews, letters to the editor, books, unpublished articles, doctoral theses, commentaries, abstracts of conferences, congresses, and case reports and if they were studies not reporting outcomes in line with the aim of the current review.

To assess how the BRCA status influenced reproductive decisions of participants, including their attitudes towards preimplantation genetic diagnosis and prenatal diagnosis for the BRCA pathogenetic variant, 7 (44%) of the included articles used interviews or semi-structured interviews [8, 11, 19‐23], and 5 (32%) used ad hoc questionnaires [10, 24‐27]. Two studies (12%) used ad hoc questionnaires in combination with validated questionnaires [9, 28], in specific, the Cancer Risk Perception (CRP) [29, 30] to assess the perception of the risk of run into a cancer diagnosis; the Perceived Health Status (PHS) [31] to assess the general health status; the Decision Regret Scale (DRS) [32] to assess decision-making processes; and the Satisfaction With Decision (SWD) scale [33] to assess satisfaction resulting from an important decision. Finally, two studies (12%) used semi-structured interviews in combination with validated questionnaires [34, 35], in this case, the Impact of Event Scale (IES) [36] to assess the distress associated with a specific event; the Hospital Anxiety and Depression Scale (HADS) [37] to assess anxiety and depression symptoms; and the Physical and Mental Health Short Form (SF-12) [38] to assess general health.

A summary of studies characteristics with the main results of each research is presented in Table 1.

As for the first aim of the current review, namely the way carriers of a BRCA1/2 pathogenetic variant make their reproductive decisions, ten of the considered articles explored this theme [8, 11, 19‐21, 23, 24, 26, 28, 34]. Most of the included studies showed that the risk of passing on the pathogenetic variant may change the idea of starting a family or expanding the family [8, 11, 19, 20, 24, 28, 34]. In the study of Chan et al. [24], 17.2% of females decided not to have children because of the BRCA pathogenetic variant risk transmission to their offspring, and because of concerns that pregnancy might increase the risk of developing cancer. In the research of Dekeuwer et al. [11], the findings suggested that when carriers are planning to have a or another child, they are concerned by the risk of transmitting not only the pathogenetic variant but also painful experiences such as illness or cancer surveillance. Another study highlighted that couples wanted to protect the future child form the BRCA pathogenetic variant and this desire may influence the decision of expanding the family [8]. Donnelly et al. [19] underlined that carrier individuals were under pressure to have children as soon as possible, especially if preventive surgery was proposed, and this sense of urgency was particularly evident for females without children. According to this result, another study reported three major consequences of being a BRCA1/2 pathogenetic variant carrier: first, an acceleration of the respondents’ reproductive plans due to the possibility of risk-reducing salpingo-oophorectomy; second, the feeling of guilt about possible transmission of the gene pathogenetic variant to the present or future offspring; and third, the renunciation of the desire to have children [28].

In this scenario, the PGD and the PND are considered. PGD, compared to PND, is evaluated as more advantageous because it would prevent the transmission to future generations, but it produces more concerns due to the embryo selection [21]. For this reason, couples have expressed the need to be well informed about the procedures and techniques used in PGD and PND [22].

Hurley et al. [20] suggested that for some individuals, the stress of testing and communicating the pathogenetic variant temporarily interfered with information processing, making them not able to take a decision on family plans in a short time.

In the only longitudinal study considered in the current review, the authors highlighted that 2 years after genetic test confirming BRCA pathogenetic variant, females altered their family plan showing lower intentions to have additional children respect to not-carrier females. This difference was not significant between male carriers and not-carriers [34]. In fact, female pathogenetic variant carriers reported a reduction in fertility intentions [34]. In the study of Werner-Lin et al. [23], participants discussed how in the process of natural reproduction the genetic heritage is combined to produce something of unique and for this reason, individuals, even with the pathogenetic variant, took the risk of transmitting it to their children and were more inclined to biological reproduction.

In a study with only men, Quinn et al. [26] reported that some carriers strongly opposed to assisted reproductive technology, especially to PGD, because if it had been available to their parents, they would not have been born and for this reason, some carriers expressed doubts about moral justness of the decision they had to take [8], because, according to them, hereditary cancer syndrome was not a condition for which pregnancy termination was justified [21].

Consistent with the review aims, some factors associated with family planning and acceptance or regret of techniques to prevent gene inheritance, in specific PGD and PND, were analyzed. More specifically, 12 articles analyzed this issue [8‐11, 20, 21, 24‐28, 35]. Chan et al. [24] reported that females with a personal history of cancer were more likely to report that having the BRCA1/2 pathogenetic variant impacted their decision to have child than females without a cancer diagnosis, while women who were partnered were less likely to report that the BRCA status impacted their decision with respect to women without partners. Regarding PGD and PND, in this research, partner status and personal history of cancer were associated with the decision to have biological children but women who already had biological children were less likely to pursue fertility treatments.

In the research of Fortuny et al. [35], the authors reported that the diagnosis of cancer was positively associated with considering PGD. Also, Derks-Smeets et al. [8], Gietel-Habets et al. [10], and Ormondoryd et al. [21] underlined that the most important factor taken into account when couples make reproductive decision was the personal and familial experience with cancer. In contrast, in the research of Dekeuwer et al. [11], the risk of transmitting the pathogenetic variant was no less acceptable to females who had had breast or ovarian cancer than to those who had not.

In general, women who already had biological children were less likely to turn to assisted reproductive technology [24], because of the necessity of in vitro fertilization and low chance of pregnancy by IVF or PGD [8].

Derks-Smeets et al. [8] crafted a list of factors associated with both PGD acceptance and its regret. Among the most widely reported psychological motives to choose PGD, there were avoidance of feelings of guilt towards the child, preservation of control regarding pregnancy, faith in future medical developments, the BRCA1/2 pathogenetic variant elimination in family line, and avoidance of future pregnancy termination [8]. Among common psychological motives to refrain from PGD, there were loss of romance in couples, uncertainties during the assisted reproductive technology treatment, and high percentage of unsuccessful [8].

In other research, older age was the only variable significantly associated with considering PND [35]. All participants in this research reported that religious orientation did not influence their decision-making [35]. Also, in Mor et al. [9], the younger age and the religious beliefs were not associated to PGD, and a story of previous infertility was the only significant predictor of PGD. In contrast with these results, Menon et al. [25] highlighted that females who opted for PGD tended to be younger, less religious, more likely to have had breast cancer, and more concerned to transmit the gene pathogenetic variant to the offspring.

In general, it seemed that PGD was more acceptable than PND [28]. Julian-Reynier et al. [28] reported that PND acceptability was positively associated with lower educational levels and with male gender. Regarding the PGD, the decision did not depend on gender or age but was more present in those having no future childbearing plans and those having relatives with cancer [28]. In a wide research, the PGD acceptance was significantly associated with religion, the desire to have more children, and with previous prenatal genetic test [27].

Only three studies investigated gender differences [20, 28, 34]. They found that PND acceptability was observed among males, but not among females, and that PGD was more acceptable than PND among women but not among men [28]. Male carriers were more predisposed towards reproduction techniques than female carriers, maybe because they do not face the number or degree of personal risks that female carriers face and their attitudes towards PGD may be shaped by the fact that they would not directly undergo the IVF procedure [20]. Smith and colleagues [34] reported that pathogenetic variant carriers were significantly less likely to report a desire for future children than not-carriers among females but not among males. Furthermore, a significantly lower interest in having additional children was reported only among female pathogenetic variant carriers but not among male carriers.