The impact of in utero exposure to cancer treatments on foetal reproductive development and future fertility: a systematic review.

Study question: Does cancer treatment during pregnancy affect gonadal development in the exposed foetus?

Summary answer: Our systematic review revealed that exposure in utero to many cancer therapies does negatively impact gonadal development.

What is known already: It is well known that many cancer therapies can have a detrimental impact on the fertility of children and young people who have been treated for cancer. However, it is not yet known how much these agents impact the gonadal development and subsequent fertility of an in utero-exposed foetus.

Study design size duration: We conducted a systematic review, following PRISMA guidelines, to investigate the evidence for associations between in utero cancer therapy exposure and gonadal development in human tissues and animal models. A systematic search was conducted across PubMed, Web of Science, and Google Scholar for titles or abstracts containing terms relating to chemotherapy or hormonal therapy agents, in utero exposure, and reproductive outcomes. We searched all available published articles up to July 2024.

Participants/materials setting methods: Two independent reviewers performed title and abstract, then full-text screening, using inclusion/exclusion criteria decided a priori. We included clinical and laboratory studies on human foetal gonads and animal studies, in vivo and in vitro, where gonadal exposure occurred during the window that corresponded with human prenatal gonadal development. Data from the included studies were independently extracted and analysed by chemotherapy and hormonal drug class, focusing on reproductive outcome measures and results. Bias and quality assessments were performed with SciRAP in vivo or in vitro tool version 2.3.

Main results and the role of chance: 3360 titles and abstracts were screened for inclusion, following the removal of duplicates, with 57 undergoing full text review and 26 eligible studies identified for inclusion (human = 4, animal-model = 22). The collated results show clear evidence of significant germ cell loss and disruption to other gonadal cell types in male and female animal-model gonadal tissues exposed both in vivo and in vitro to various chemotherapy and hormone therapies, and human male foetal tissue exposed to chemotherapy in vitro.

Limitations reasons for caution: The evidence provided was limited by the small number of studies available reporting on reproductive outcomes following in utero exposure to cancer therapies, a lack of comparable outcome measures, and the use of single-drug exposures compared to the more clinically relevant multi-drug combinations.

Wider implications of the findings: This review provides evidence for the vulnerability of foetal gonads to cancer therapy agents and the potentially damaging effects of in utero exposure on gonadal development and reproductive health. We hope these findings help raise awareness for the need of long-term follow-up studies to explore whether fertility is impacted in people who were exposed to cancer agents in utero and to identify whether they may require fertility preservation strategies.

Study funding/competing interests: No specific funding was received for this study. R.T.M. is supported by a UK Research and Innovation (UKRI) Future Leaders Fellowship (Grant Reference: MR/Y011783/1). The authors declare that they have no conflicts of interest.

Registration number: Study protocol-PROSPERO (RD42021272882 and CRD42021271892).