Highlights
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In a cohort of women with pathogenic BRCA1, BRCA2, MLH1 and MSH2 mutations, 55% were nulliparous at time of diagnosis.
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At least 31% of patients desire future fertility at time of their hereditary cancer syndrome diagnosis.
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Fertility desires are not being documented in approximately one-third of newly diagnosed patients.
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Reproductive endocrinology referral and assisted reproductive technology rates remain low and may represent a gap in counseling and referral.
Keywords: Hereditary Care Syndromes, Fertility, Genetics, BRCA, Risk-Reduction
Abstract
Objective
Limited data exist on pregnancy desires, outcomes, or referral rates in patients with gynecologic hereditary cancer syndromes. This study describes fertility desires and pregnancy outcomes in patients with newly diagnosed BRCA1, BRCA2, MLH1, and MSH2 mutations.
Methods
This was a multi-site, retrospective cohort study including women aged 21–45 years old diagnosed with a pathogenic variant in BRCA1, BRCA2, MLH1, or MSH2 between January 2018 and December 2021. Women with prior sterilization procedures, bilateral salpingectomy, hysterectomy, or prior diagnosis of breast or ovarian cancer were excluded. Clinical and demographic variables were extracted from the medical record. The primary outcome was assessment of pregnancy desires. Secondary outcomes included rate of pregnancy and live birth, referral to REI or use of assisted reproductive technology (ART).
Results
We identified 396 patients with positive genetic testing during the study period. BRCA2 (n = 200, 51%) and BRCA1 (n = 173, 44%) mutations were the most common. Median age at diagnosis was 31.5 (27–38) years old with most women being non-Hispanic white (53.2%) and nulliparous (n = 216, 55%). In the cohort, 38.1% of women desired future fertility at the time of diagnosis, 31.3% had completed childbearing, and fertility desires were not documented in 30.6%. There were 65 pregnancies. Parity and age 25–34 years was associated with achieving pregnancy. Even in patients desiring future fertility, rates of referral to REI (17%) and use of ART (8%) were low.
Conclusion
Our findings demonstrate possible gaps in counseling and underutilization of fertility services for young mutation carriers.
1. Introduction
Young women diagnosed with hereditary cancer syndromes must weigh the benefit of removal of their reproductive organs to mitigate cancer risks with the impacts on fertility, menopause, and long-term health. Pathogenic mutations in BRCA1 and BRCA2 are associated with a lifetime ovarian cancer risk of up to 46% and 17% respectively (Website: National Comprehensive Cancer Network, 2020). Similarly, pathogenic variants in MLH1 and MSH2, while most associated with uterine and colon cancer, carry a lifetime ovarian cancer risk of 8–15% (Bonadona et al., 2011). The gold standard for managing this tubal, ovarian, and primary peritoneal cancer risk is bilateral salpingo-oophorectomy which results in iatrogenic infertility. While completion of childbearing prior to surgery is preferred, risk-reducing surgery is recommended during a patient’s reproductive years (ages 35–45) (Website: National Comprehensive Cancer Network, 2020). This is particularly relevant as age at first delivery rises, with as many as 30% of all pregnancies occurring after 35 years of age (Bane et al., 2026, Ely and Hamilton, 2018).
The reproductive implications of hereditary cancer syndromes are not limited to the impact of surgical menopause. Some studies suggest increased risk of primary infertility and diminished ovarian reserve in women with BRCA pathogenic variants (Lin et al., 2013, Porcu et al., 2020). Additionally, future offspring have a 50% risk of receiving the affected BRCA allele and are at risk for recessive conditions like Fanconi Anemia and congenital mismatch repair deficiency for which prenatal partner carrier testing is advisable (Hays, 2014).
Clear guidelines exist regarding fertility counseling and referral among patients with hereditary cancer syndromes. A joint statement by Society of Gynecology Oncology and the American Society for Reproductive Medicine was published in 2019 specifically guiding care in patients at risk for hereditary gynecologic cancer. They strongly encourage early (late 20′s − early 30 s) referral of women with BRCA1 and BRCA2 to reproductive endocrinology & infertility (REI) specialists for review of fertility preservation and family building strategies. The guidelines also highlight that these patients should have genetic counseling and be offered both pre-implantation genetic testing (PGT) and early diagnostic testing (chorionic villus sampling or amniocentesis) as choosing unaffected embryos can allow assurances that offspring will not share the same risk as their affected parent (Chen et al., 2019). Though not all patients with hereditary cancer syndromes will desire PGT, the majority believe these options should be discussed with mutation carriers in a standardized way and some report that if testing had been available to them, they would have made different reproductive choices (D'Alonzo et al., 2026).
Despite these recommendations, limited data exist on referral rate, pregnancy desires, or outcomes in this population. Our study objective was to generate this baseline data from a large cohort of patients with newly diagnosed BRCA1, BRCA2, MLH1, and MSH2 mutations.
2. Methods
This study was a retrospective cohort study examining assessment of fertility desires and pregnancy outcomes in women with hereditary cancer syndromes in Kaiser Permanente Northern California (KPNC). KPNC covers roughly 25% of the population of Northern California with patient demographics representative of the underlying population in the region (Davis et al., 2023). The health system has a long-standing and robust electronic medical record inclusive of primary and sub-specialty care allowing review of longitudinal pregnancy data in addition to details of genetic diagnosis, counseling, and infertility care. The project was approved by the Institutional Review Board prior to data extraction.
Female patients ages 21–45 who had been diagnosed with a mutation in BRCA1, BRCA2, MLH1, or MSH2 between January 2018 and December 2021 were identified via a genetic registry with diagnosis date and location confirmed by manual chart review. The study excluded those who had prior sterilization procedures, bilateral salpingectomy, or hysterectomy as well as those with prior diagnosis of breast or ovarian cancer (Fig. 1).
Fig. 1.
CONSORT Inclusion Diagram.
Demographic characteristics were extracted from the electronic health record (EHR) and included women’s age and patient self-reported race/ethnicity (non-Hispanic White, Asian/Pacific Islander, Black, Hispanic, Other/unknown). Age was calculated using the diagnosis date of the hereditary cancer syndrome as the index date. Neighborhood Deprivation Index (NDI), an indicator of neighborhood-level socioeconomic position that integrates census variables on education, housing, and income/poverty, were reported by quartile, with Q1 representing the “least deprived” and Q4 representing the “most deprived” (Messer et al., 2006). Parity was collected via clinician chart review and represents the patient’s parity status (parous/nulliparous) at the time of their hereditary cancer syndrome diagnosis. ICD-10 codes were used to electronically extract pre-existing diagnoses of polycystic ovarian syndrome (E28.2), hypertension (I10-I16), and infertility (N97) using a lookback period of one year prior to the index date. Pre-existing diabetes diagnosis was defined by patient inclusion on the diabetes registry before the index date.
The primary outcome was fertility desire which was divided into three groups: completed childbearing, desiring future fertility, and not discussed. Completed childbearing was assigned for patients who indicated they did not desire future fertility, regardless of previous pregnancy history. Not discussed was assigned for patients when no conversations regarding family planning or fertility were found documented on manual clinician chart review. Chart review included review of all genetics, gynecology, and gynecology-oncology notes as well as a global chart search for key words including “fertility” and “childbearing.” Secondary outcomes were also collected via clinician chart review and included rate of pregnancy and live birth, referral to REI or use of assisted reproductive technology (ART). Use of ART included in-vitro fertilization (IVF), intrauterine insemination (IUI), and cryopreservation.
Frequencies and percentages were used to describe sociodemographic (age, race/ethnicity, NDI) and clinical covariates [parity, preexisting diagnoses of polycystic ovary syndrome (PCOS), hypertension, diabetes, infertility]. Chi-square and Fisher’s exact tests were used to compare categorical socio-demographic and clinical covariates by primary and secondary fertility outcomes (fertility desire, pregnancy, REI referral, and use of ART). Chi-square test was also used to assess differences between secondary fertility outcomes by fertility desire. A p-value of < 0.05 was considered to be statistically significant. All data management and statistical analyses were performed in SAS 9.4.
3. Results
Our study population consisted of 396 patients followed for a median of 35.0 months (IQR: 23.0 – 46.0 months). BRCA1/2 mutations were the most common mutations (44% and 51% respectively). Three percent of patients had MLH1 mutations and 2.8% had MSH2 mutations. (Table 1). Thirty-eight percent of the patients had a documented desire for future fertility at the time of their hereditary cancer syndrome diagnosis. Fertility desires were not documented in nearly one-third (30.6%) of the patients while 31.3% reported having completed childbearing (Table 1). The mean age of women without documented fertility discussion [28.4 years, standard deviation (SD): 6.9] and those who desired future fertility (30.2 years, SD: 5.2) were younger compared to women who completed childbearing (37.1, SD: 5.8; p < 0.01). Women categorized as completed childbearing were more likely to have had a previous delivery than those who desired future fertility and those in whom fertility desires were not discussed (72.6% vs 34.4% vs 31.4% respectively, p < 0.01). Women who desired future fertility were more likely to have a pre-existing diagnosis of infertility compared to women who had completed childbearing or did not discuss fertility desires (4.6% vs 1.6% vs 0.0% respectively, p = 0.03). There were no other significant differences between cohorts (Table 1).
Table 1.
Demographic and Clinical Characteristics of Patients with Hereditary Cancer Syndromes by Fertility Desire, 2018–2021 (N = 396).
| Fertility Desire at Time of Diagnosis |
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|---|---|---|---|---|
| Patient Characteristic | Completed Childbearing n = 124 (31.3%) |
Desires Future Fertility n = 151 (38.1%) |
Not Addressed n = 121 (30.6%) |
Chi-square p-value |
| Age at Index, n (%) | ||||
| 21–24 | 4 (3.2%) | 18 (11.9%) | 38 (31.4%) | <0.01 |
| 25–34 | 36 (29.0%) | 104 (68.9%) | 58 (47.9%) | |
| 35+ | 84 (67.7%) | 29 (19.2%) | 25 (20.7%) | |
| Race/Ethnicity, n (%) | ||||
| Asian | 16 (12.9%) | 23 (15.2%) | 16 (13.2%) | 0.94 |
| Black | 5 (4.0%) | 10 (6.6%) | 8 (6.6%) | |
| Hispanic | 30 (24.2%) | 35 (23.2%) | 23 (19.0%) | |
| Other | 7 (5.7%) | 7 (4.6%) | 8 (6.6%) | |
| Non-Hispanic White | 66 (53.2%) | 76 (50.3%) | 66 (54.6%) | |
| Neighborhood Deprivation Index (NDI), n, % | ||||
| Q1 (least deprived) | 34 (27.4%) | 40 (26.9%) | 34 (28.8%) | 0.61 |
| Q2 | 42 (33.9%) | 42 (28.2%) | 44 (37.3%) | |
| Q3 | 23 (18.6%) | 35 (23.5%) | 18 (15.3%) | |
| Q4 (most deprived) | 25 (20.2%) | 32 (21.5%) | 22 (18.6%) | |
| Parity, n (%) | ||||
| Nulliparous | 34 (27.4%) | 99 (65.6%) | 83 (68.6%) | <0.01 |
| Parous | 90 (72.6%) | 52 (34.4%) | 38 (31.4%) | |
| Type of Genetic Mutation, n (%) | ||||
| BRCA1 | 54 (43.6%) | 72 (47.7%) | 47 (38.8%) | 0.45* |
| BRCA2 | 65 (52.4%) | 69 (45.7%) | 66 (54.6%) | |
| MLH1 | 2 (1.6%) | 7 (4.6%) | 3 (2.5%) | |
| MSH2 | 3 (2.4%) | 3 (2.0%) | 5 (4.1%) | |
| Preexisting Diagnosis of PCOS, n (%) | ||||
| Yes | 1 (0.8%) | 2 (1.3%) | 1 (0.8%) | 1.00* |
| No | 123 (99.2%) | 149 (98.7%) | 120 (99.2%) | |
| Preexisting Diagnosis of Hypertension, n (%) | ||||
| Yes | 5 (4.0%) | 3 (2.0%) | 1 (0.8%) | 0.27* |
| No | 119 (96.0%) | 148 (98.0%) | 120 (99.2%) | |
| Preexisting Diagnosis of Diabetes, n (%) | ||||
| Yes | 1 (0.8%) | 2 (1.3%) | 5 (4.1%) | 0.20* |
| No | 123 (99.2%) | 149 (98.7%) | 116 (95.9%) | |
| Preexisting Diagnosis of Infertility, n (%) | ||||
| Yes | 2 (1.6%) | 7 (4.6%) | 0 (0.0%) | 0.03* |
| No | 122 (98.4%) | 144 (95.4%) | 121 (100.0%) | |
Note: Five patients missing NDI; HCP = Hereditary Cancer Program; PCOS = Polycystic Ovary Syndrome, *Fisher’s Exact Test Used.
During follow-up, 33.1% of women who desired fertility achieved pregnancy and 25.8% had a live birth (Table 2). In bivariate analysis, age 25–34 years, NDI in the most deprived quartile, and being parous at time of diagnosis were associated with achieving pregnancy over the study period. We found no difference in prevalence of polycystic ovarian syndrome (PCOS), hypertension, or diabetes between these three groups. Few patients were referred to REI or utilized ART. Only 16.7% of patients who desired future fertility were referred to REI with 8% of those using ART (Table 2). NDI was associated with the use of ART with patients living in less deprived neighborhoods being more likely to utilize ART (p = 0.03). Patients who were parous were more likely to receive an REI referral compared to those who were nulliparous (10.7% vs 2.2%, p < 0.01). Patients who had a documented history of infertility were more likely to receive both an REI referral (66.7% vs 5.4%; p < 0.01) and to use ART (44.4% vs 2.6%; p < 0.01).
Table 2.
Fertility Outcomes of Patients with Hereditary Cancer Syndromes by Fertility Desire 2018–2021 (N = 396).
| Fertility Desire at Time of Diagnosis |
||||
|---|---|---|---|---|
| Fertility Outcome | Completed Childbearing n = 124 (31.3%) |
Desires Future Fertility n = 151 (38.1%) |
Not Addressed n = 121 (30.6%) |
Chi-Square p-value |
| Pregnancy | 6 (4.8%) | 50 (33.1%) | 9 (7.4%) | <0.01 |
| Live Birth | 3 (2.4%) | 39 (25.8%) | 9 (7.4%) | <0.01 |
| REI Referral | 1 (0.8%) | 25 (16.7%) | 1 (0.8%) | <0.01 |
| Use of ART | 1 (0.8%) | 12 (8.0%) | 1 (0.8%) | <0.01 |
Notes: REI = Reproductive Endocrinology and Infertility; ART = Assisted Reproductive Technology. Median follow-up for the cohort was 35.0 months (IQR: 23.0–46.0 months).
4. Conclusions
In this study population, 54.6% of patients were nulliparous at time of diagnosis and at least 38.1% desired future fertility. Fertility desires were not documented in one-third of patients and only 16.7% of those who desired future fertility were referred to REI.
When reviewing the literature, data on fertility desires and pregnancy outcomes in this population is limited. However, the risk of affected offspring without genetic testing and need for additional genetic counseling and partner testing in BRCA2 patients to prevent rare genetic conditions like Fanconi anemia is clear (Lin et al., 2013, Porcu et al., 2020). The 2019 joint SGO/ASRM guidelines which encourage early REI referral were published during this study; however BRCA has been described as an indication for PGT since 2008 (Chen et al., 2019, The Practice Committee of the Society for Assisted Reproductive Technology, Practice Committee of the American Society for Reproductive Medicine, 2008).
Our finding of low referral rates is consistent with a prior cross-sectional data that found only 29% of providers referred patients worried about their offspring to genetic counseling (Brandt et al., 2010). Given that over 80% of patients with BRCA mutations believe PGT should be offered to all mutation carriers (D'Alonzo et al., 2026), and that many gynecology and gynecologic oncology providers feel counseling regarding PGT is not within their scope of practice (Brandt et al., 2010), the referral rate of 16.7% in our paper may highlight an opportunity to strengthen this area of care for our hereditary cancer patients.
In young patients with gynecologic cancer, ART utilization is more likely in non-Hispanic white patients of high socioeconomic status (Jorgensen et al., 2023). This study identified a similar trend with patients living in less deprived neighborhoods being more likely to utilize ART. Disparities in ART are likely driven by cost and access to care. Insurance coverage for fertility preservation varies widely between states with policies ranging from full coverage of fertility services to no coverage. Even in states with benefits, patients using Medicaid or other publicly funded healthcare plans are often excluded (Weigel et al., 2020). When counseling, it is important to acknowledge how financial barriers may be influencing patient decisions and to advocate for equitable access to care.
Counseling of patients with hereditary cancer syndromes is complex. Discussions should include a review of cancer risk, screening, risk-reduction strategies, family disclosures, and future reproductive wishes. Conversations are further complicated by different overall cancer risk and options for management depending on patient age (Website: National Comprehensive Cancer Network, 2020). Recommendations also change overtime guided by scientific advances in cancer genomics and current guidelines do not recommend an optimal age for egg harvesting or fertility preservation. The gap in fertility discussions found in our data, demonstrate how a one-time consultation is not adequately addressing the complex needs of this population. Instead, counseling should focus on the most pertinent issues to the patient’s phase of life with a longitudinal and collaborative approach to care. This approach could offer the flexibility to counsel about age-appropriate issues at a time when patients can best engage with the information and decision making.
The strengths of our study include that it represents a large, socioeconomically, and ethnically diverse cross section of northern California. The integrated health system and EMR allowed our study team to confirm genetic testing results, pregnancy history, and pregnancy outcomes increasing the reliability of results. A limitation is that despite our integrated system, many patients access REI care via private clinics that do not have available records within our EMR. This may lead to our study underestimating REI consults and use of ART. Care provided at other large health centers was available for review via electronic health record sharing and infertility care is often captured at entry to prenatal care even if occurring with private practice providers minimizing this effect. Additionally, our report of pregnancy desires relies on provider documentation which may not fully reflect patient counseling and discussion. Providers may have been more likely to document counseling for patients who were interested in future fertility than for those who did not. This could partially account for the gap in counseling identified in this study. Finally, the amount of follow-up available to us only captures a small segment of patient’s reproductive years and may have missed longer term trends in fertility outcomes – particularly in patients diagnosed in their teens and early 20 s.
Despite these limitations, this study provides a novel baseline data set and identifies an unmet need in this group of patients. Moving forward, additional research is needed to understand the barriers to standard fertility counseling and pathways to REI referral & services. This becomes even more relevant in a landscape of changing financial access and coverage for fertility services.
As we are getting better at diagnosing hereditary cancer syndromes for more patients at younger ages, we need to ensure that all implications are addressed throughout their lifespan. Fertility desires may be of paramount concern to our young mutation carriers who may be overwhelmed by cancer fears, when reassurance about age level risks can be provided. Our study demonstrates a need for improved discussion and offering of services to the young hereditary cancer population.
Author contributions
Project design and conception was guided by C.G. who also served as the study’s principal investigator. E.C., C.L, and C.G. collectively performed all required data extraction and chart-review. C.C. and J.W. served as the project’s statistician performing data analysis, developing study tables, and drafting statistical methodology. The manuscript was written by E.C. and was subsequently reviewed and edited by all members of the research team.
CRediT authorship contribution statement
Elizabeth A. Connelly: Writing – review & editing, Writing – original draft, Data curation. Christina M. Lowry: Writing – review & editing, Data curation, Conceptualization. Chelsea Camara: Methodology, Formal analysis. Julia Wei: Writing – review & editing, Methodology, Formal analysis. Christine Garcia: Writing – review & editing, Writing – original draft, Supervision, Data curation, Conceptualization.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This research was financially supported by the 2023 Kaiser Community Benefit Grant.
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