Reproductive Decision-Making and Pregnancy in Germline CDH1 Variant Carriers

Abstract

Background:

Diagnosis of a hereditary cancer syndrome may impact family planning, particularly in reproductive age individuals. Factors influencing reproductive decision-making are understudied in individuals with a germline CDH1 pathogenic or likely pathogenic (P/LP) variants.

Methods:

We characterized reproductive decision-making and perinatal outcomes in 121 individuals aged 18 to 49 with hereditary diffuse gastric and lobular breast cancer syndrome due to a germline CDH1 P/LP variant.

Results:

Half of individuals 50% (60/121) reported their CDH1 diagnosis impacted family planning. Psychosocial and economic barriers to reproduction were encountered by 47% (56/119) of patients. Additionally, 12% (15/121) of individuals delayed pregnancy to prioritize personal cancer risk management with either endoscopic surveillance, prophylactic total gastrectomy (PTG), or mastectomy. Women were more likely to experience guilt about passing their CDH1 variant to offspring compared to men. Perinatal and fetal outcomes were investigated in six women who gave birth at a median time of 24 months (IQR 20-44) after PTG. Maternal micronutrient deficiencies were not uncommon in pregnant women after PTG despite compliance with a bariatric, prenatal multivitamin. Majority of women who became pregnant after PTG reported worsening post-gastrectomy syndromes. Most infants (90%, 9/10) born after PTG were full-term and no fetal complications were reported.

Conclusion:

Reproductive decision-making is complex in individuals with a germline CDH1 variants, who often encounter psychosocial and physical challenges during family planning and pregnancy. However, successful pregnancy is possible after PTG with the guidance of a multidisciplinary team including maternal fetal medicine specialists and a registered dietitian.

Introduction

Increased access to genetic testing has resulted in earlier diagnosis of deleterious germline variants, often in individuals within their reproductive period.¹ Individuals are presented with a variety of strategies for cancer prevention such as risk-reducing surgery, surveillance, and chemoprevention, for which effects on fertility are understudied. Germline loss-of-function variants in CDH1 are causally linked to hereditary diffuse gastric cancer and lobular breast cancer syndrome.² This autosomal dominant syndrome is characterized by early-onset diffuse gastric cancer, lobular breast cancer, and cleft lip/palate.^2,3 Recent estimates demonstrate a lifetime advanced gastric cancer risk of 7–42% and breast cancer risk of 37–55% in individuals with a CDH1 pathogenic or likely pathogenic (P/LP) variant.^4,5 International Gastric Cancer Linkage Consortium guidelines recommend breast cancer surveillance or prophylactic bilateral mastectomy at age 30 years and prophylactic total gastrectomy (PTG) at age 20–30 years for individuals with signet ring cell lesions detected on upper endoscopy and a family history of gastric cancer.⁶ Individuals who prefer to maximize advanced gastric cancer prevention are also recommended to undergo PTG, after consultation with a multidisciplinary team.⁷ However, PTG imparts life-altering sequelae and its impact on reproductive potential is unknown, making the decision to undergo gastrectomy particularly difficult for individuals of reproductive age considering starting or expanding one’s family.⁸

Previous literature has focused on reproductive decision-making challenges faced by individuals with BRCA1 and BRCA2 variants at risk of hereditary breast and ovarian cancer.^9,10 Cancer prevention strategies such as risk-reducing bilateral mastectomy and risk-reducing bilateral salpingo-oophorectomy have obvious repercussions on family planning, forcing individuals to weigh timing of surgery against childbearing and breastfeeding. Haddad and colleagues demonstrated BRCA1 and BRCA2 variant carriers experience urgency regarding romantic partnering, guilt over transmitting pathogenic variants to offspring, and feel underinformed about reproductive options.⁹ Similarly, individuals with Lynch syndrome also reported fear of transmitting pathogenic variants to offspring.¹¹ In a cohort of 370 individuals with hereditary breast and ovarian cancer, Lynch syndrome, Familial Adenomatous Polyposis, or Multiple Endocrine Neoplasia Type 1 or 2, only 28% of participants reported their genetic diagnosis impacted family planning, but most (72%) stated that preimplantation genetic testing (PGT) should be offered to at-risk individuals.¹²

There is a paucity of data related to reproductive decision-making in individuals with a germline CDH1 P/LP variant who are at elevated risk of gastric and breast cancer. As in other inherited cancer syndromes, individuals with CDH1 have reported the desire to avoid passing pathogenic variants to children; however, the cost of PGT is a major barrier.¹³ Although PGT is recommended for pathogenic variants that cause significant genetic susceptibility to severe diseases, which includes CDH1 and other hereditary cancer-related genes, PGT typically involves testing relatives with the PV for haplotyping, creating an additional barrier to availability for patients with a de novo variant.¹⁴ A recent small study demonstrated that 42% (5/12) of CDH1 variant carriers intended to conceive via reproductive technologies, especially those who experienced post-gastrectomy complications.¹⁵ Some referred to PTG as a “parental responsibility” to eliminate the risk of premature loss of a parent, but also described post-PTG recovery as diminishing parental abilities.¹⁵ Other individuals with a CDH1 P/LP variant delayed PTG due to fertility-related concerns.¹⁶ To date, only a single case report and case series demonstrate successful pregnancy after TG with anemia as the most common complication attributed to pregnancy post-TG.^17,18 In this study, we explored the complex reproductive decision-making process in a large cohort of individuals with germline CDH1 P/LP variants of reproductive age, including the impact of CDH1 diagnosis on family planning, timing of risk-reducing surgeries, reproductive barriers encountered, and resources utilized. We also investigated fertility, methods of contraception, conception, and perinatal outcomes after gastrectomy.

Material and Methods

Study cohort

Individuals with germline CDH1 P/LP variants who were prospectively enrolled in a natural history study of hereditary gastric cancer (NCT03030404) from October 2017 to November 2024 were identified. The study was approved by the National Institutes of Health Institutional Review Board (IRB). Inclusion criteria included individuals ages 18 to 49 years and proficiency in the English language. We excluded individuals with CDH1 variants of uncertain significance and CTNNA1 variants. A standardized reproductive decision-making survey (Supplemental material 1) developed by co-authors was administered electronically via email to individuals who provided written consent. Participants could access and complete the survey on a web browser at any time during the study period. Demographic data collected included age, sex, race, family history of gastric and/or breast cancer, partner status, and childbearing status. All participants were asked about previous risk-reducing operations (i.e., total gastrectomy and bilateral mastectomy). Reproduction decision-making surveys included seven sections: family planning, conception/contraception methods, relationships and extended family, individuals who have conceived biological children, women with pregnancies before and after total gastrectomy, women with pregnancies before and after mastectomy, and future research areas. Factors impacting family planning, reproductive decision-making, and methods of conception and contraception were analyzed. Feelings of guilt and concerns about passing on the CDH1 variant to offspring, delay of pregnancy to prioritize personal gastric and breast cancer risk, barriers to family planning, and resources utilized were queried. Five-point Likert scales (strongly disagree, disagree, neither disagree nor agree, agree, and strongly agree) were utilized to assess opinions, such as “I am concerned about passing the CDH1 variant to my child/children.” Pregnancy outcomes after PTG, including peripartum micronutrient deficiencies, gestational weight gain, and prevalence of post-gastrectomy syndromes were analyzed. Rates of live birth, miscarriage, and fetal outcomes were examined. The survey was developed to skip and avoid inappropriate questions based on participant selections; for example, questions about post-gastrectomy syndromes were omitted in individuals who had not undergone PTG. Categorical variables were expressed as a total with proportion and compared using Fisher’s exact tests, and continuous variables were expressed as a median with interquartile range (IQR) and compared using unpaired t-tests. Multivariable logistical regression was used to compare multiple categorical variables. Statistical analyses were performed using GraphPad Prism version 9.3.1 (GraphPad Software, Inc., San Diego, CA) and JMP Statistical software version 16.2.0 (JMP, Cary, NC). Graphical representations of survey results were made using R package ggplot2 (v3.4.2).

Results

Cohort Demographics

In total, 121 individuals with germline CDH1 P/LP variants aged 18 to 49 years completed surveys on family planning and pregnancy. The majority of participants were female (74%, 90/121) and White (93%, 113/121), with a median age of 38 years (IQR 31–41) at the time of survey completion (Table 1). Seventy-nine percent (96/121) and 75% (91/121) of participants had a family history of gastric (including signet ring cell (SRC) lesions detected on endoscopy and total gastrectomy specimens) and breast cancers, respectively. Median age at CDH1 P/LP variant diagnosis was 33 years (IQR 27-37 and IQR 26-36, p=0.75) for females and males, respectively. Sixty-two individuals (51%, 62/121) had previously undergone PTG for management of hereditary gastric cancer risk and 59 (49%) participants elected for active endoscopic surveillance. Due to increased risk of lobular breast cancer, 27% (24/90) of females underwent prophylactic (17%, 15/90) or therapeutic mastectomy (10%, 9/90). Seventeen percent (15/90) of individuals surveyed elected for both prophylactic gastrectomy and mastectomy. Almost all individuals had occult SRC foci detected on final PTG specimen (92%, 56/61) compared to 39% (23/59) on endoscopic surveillance, consistent with previous reports.^19,20 Most individuals had biological children (58%, 70/121) at the time of survey completion. Rates of biological children were similar among female (59%, 53/90) and male (55%, 17/31, p=0.83) participants. Most participants conceived before CDH1 diagnosis (74%, 52/70), whereas 10 conceived after CDH1 diagnosis, and 8 conceived children both before and after CDH1 diagnosis.

Table 1:

Demographics of CDH1 P/LP variant carrier study participants.

Age at study cutoff, median, IQR	38 (31–41)
Age	n (%)
18 – 29	22 (18%)
30–39	55 (45%)
40–49	44 (36%)
Age at CDH1 diagnosis, median, IQR	33 (27–36)
Gender	n (%)
Female	90 (74%)
Male	31 (26%)
Race	n (%)
White	113 (93%)
Multi-racial	5 (4%)
Asian	2 (2%)
Other	1 (1%)
Ethnicity	n (%)
Non-Hispanic/Latino	116 (96%)
Hispanic/Latino	5 (4%)
Family History Gastric Cancer	96 (79%)
Family History of Breast Cancer	91 (75%)
Current relationship status	n (%)
Single	30 (25%)
Married/partnered	89 (74%)
Divorced/separated	2 (1%)
Have biological children	n (%)
Yes	70 (58%)
No	51 (42%)
Biological children before CDH1 diagnosis only	52
Biological children after CDH1 diagnosis only	10
Biological children before and after CDH1 diagnosis	8
Personal cancer management strategy	n (%)
Prophylactic total gastrectomy	62 (51%)
SRC lesions identified on PTG, n, %*	56 (92%)
Active endoscopic surveillance	59 (49%)
SRC lesions identified on EGD, n, %	23 (38%)
Prophylactic Mastectomy	15 (17%)
Therapeutic Mastectomy	9 (10%)

^*Excludes one patient with unknown PTG pathology

Impact of Germline CDH1 P/LP Variant Diagnosis on Family Planning

We first explored whether diagnosis of a germline CDH1 pathogenic variant affected reproductive decision-making. Half of individuals (50%, 60/121) reported that CDH1 diagnosis impacted family planning, irrespective of an individual’s biological sex (p=0.92), choice of endoscopic surveillance or PTG (p=0.58), or mastectomy (p=0.48) for management of personal gastric or breast cancer risk. With increased participant age, the odds of CDH1 impacting family planning decreased (OR 0.88, 95% CI 0.82–0.93). At the time of survey completion, 74% (89/121) of participants were married or partnered, and 26% (32/121) were single or divorced/separated. A minority (18%, 6/34) of single participants stated their “CDH1 diagnosis made it difficult to find a partner.” Individuals who reported that CDH1 diagnosis impacted family planning were significantly more likely to report difficulty finding a partner than those who reported otherwise (p=0.01) (Figure 1). Difficulty eating in social situations, changes in body image after gastrectomy, and difficulty finding a partner who understands hereditary diffuse gastric cancer and its impact on lifestyle were reported as contributing factors. Most participants agreed or strongly agreed with the statement that “My spouse/partner and I agree on if/how to expand our family” (87%, 79/91) and “My extended family and I agree about my decisions regarding having children” (63%, 76/121) (Figure 1). Four percent (5/121) of participants disagreed with their spouse’s desire to have children, timing of pregnancy, and/or method of conception. Pregnancy was delayed in 12% (15/121) of individuals due to endoscopic surveillance procedures (n=7) or PTG (n=8). Four women (4%, 4/90) reported that they delayed pregnancy because of mastectomy.

Figure 1.

Perception about partnering, family expansion, passing the CDH1 variant to offspring, and genetic testing amongst A) male and female CDH1 germline variant carriers, B) individuals with a family history of gastric cancer and/or C) breast cancer, and by reported D) impact of CDH1 diagnosis impacted family planning. Additional stratification by germline CDH1 variant carrier E) marital status, F) childbearing status, G) detection of signet ring cell lesions on surveillance upper endoscopy or total gastrectomy specimen, and in individuals who elected for H) prophylactic total gastrectomy.

Guilt Associated with Reproductive Decision-Making

Almost half of participants 47% (57/121) agreed (n=16) or strongly agreed (n=41) to the statement “I am concerned about passing my CDH1 variant to my children” (Figure 1). There was no difference in heritability concerns between females (47%, 42/90) and males (48%, 15/31, p=0.99), or among participants who elected for PTG (50%, 31/62) compared to endoscopic surveillance (44%, 26/59, p=0.59). Overall, of the 70 individuals with biological children, the majority (74%, 52/70) experienced guilt related to the potential to pass their CDH1 variant to offspring. Women with germline CDH1 variants were more likely than men to experience guilt (OR 3.74, 95% CI 1.1–12.9, p=0.037). Feelings of guilt ranged from almost always (4%, 2/52), often (12%, 6/52), sometimes/other (23%, 12/52), occasionally (27%, 14/52), to almost never (35%, 18/52). Notably, of participants who experienced guilt, the majority (71%, 37/52) conceived a child before germline CDH1 diagnosis, whereas 15% (8/52) conceived after diagnosis. Thirteen percent (7/52) of participants who conceived both before and after CDH1 diagnosis reported guilt. Impact of CDH1 diagnosis on family planning was significantly more likely in individuals with guilt (OR 7.9 95% CI 1.01–61.72, p=0.049). Most participants (89%, 62/70) who conceived children also reported stress, anxiety, and/or depression related to CDH1 diagnosis.

When participants with biological children conceived before CDH1 diagnosis were asked “Since learning of my CDH1 variant, my plans for future children have changed,” 22% (13/60) agreed or strongly agreed, 15% (9/60) neither disagreed or agreed, and 23% (14/60) disagreed or strongly disagreed. Six individuals stated, “I do not plan to have any children in the future since learning of my CDH1 variant” and three reported “I plan to not conceive children naturally in the future, but instead to conceive by other methods.” Two individuals reported plans to pursue adoption. Current international consensus guidelines recommend genetic testing at ages 16 to 18.⁶ Over a third of individuals (37%, 26/70) agreed (n=10) or strongly agreed (n=16) with the statement “I have difficulty knowing that, in most cases, my children will not receive genetic testing until adult age” (Figure 1).

Barriers to and Utilization of Resources for Family Planning

Next, we investigated potential barriers to family planning in individuals with germline CDH1 P/LP variants. Approximately half of individuals with CDH1 P/LP variants (47%, 56/119, two patients omitted this question) reported at least one barrier to family planning; 21% (12/56) of individuals reported 4 or more barriers, 21% (12/56) reported at least 3 barriers, 29% (16/56) and 25% (14/56) reported two or one barrier(s), respectively. The most common barrier to family planning reported was anxiety (36%, 43/119), followed by stress (33%, 39/119), financial cost (20%, 24/119), insurance coverage (13%, 15/119), and depression (11%, 13/119) (Figure 2). Additional barriers reported by participants included finding a partner who understands hereditary diffuse gastric cancer and the significant changes in lifestyle after PTG. For individuals who conceived after CDH1 diagnosis (n=18), almost all (83%, 15/18) experienced at least one barrier to family planning. We queried family planning resources that were utilized by CDH1 variant carriers. One third (32%, 39/121) of participants consulted with a healthcare provider during their family planning journey (Figure 2). Genetic counselors (n=32), primary care providers ( n=18), and reproductive endocrinologists (n=8) were the most common healthcare providers utilized (Figure 2). Low utilization of healthcare providers may be secondary to participants (50%, 60/121) who conceived before their CDH1 variant diagnosis, and furthermore may have completed childbearing prior to seeking help from a pre-natal genetic counselor. Of those who conceived after CDH1 diagnosis (n=18 individuals), 50% (9/18) sought care from genetic counselors and 28% (5/18) from reproductive endocrinologists.

Figure 2.

A) Barriers and B) resources utilized for family planning in germline CDH1 variant carriers by sex.

Fertility, Methods of Contraception, and Conception

The impact of germline CDH1 variants on fertility is unknown. Participants were asked if they “experienced difficulty trying to conceive naturally before or after CDH1 diagnosis,” and most neither disagreed or agreed (48%, 58/121) or disagreed or strongly disagreed (40%, 49/121). A small portion of participants (12%, 14/121) reported difficulty conceiving naturally. Of all 90 women in the study cohort, 26 (29%) reported at least one miscarriage, and 5 women reported 2 or more miscarriages. Thirty-eight percent (46/121) of individuals wishing to expand their family considered natural conception compared to 35% (42/121) considered in vitro fertilization with pre-implantation genetic testing (IVF-PGT) (Figure 2). Adoption was considered by 26% (31/121) of participants. Males with CDH1 P/LP variants preferred natural conception more often (62%) than females (33%) (Figure 3). More females with CDH1 P/LP variants preferred IVF-PGT and adoption compared to male carriers. The most frequently used forms of contraception by participants and their partners were condoms (36%, 44/121), oral contraceptive pills (26%, 31/121), intrauterine devices (25%, 30/121), vasectomy (17%, 21/121), tubal ligation (6%, 7/121), and other forms of birth control (18%, 22/121).

Figure 3.

Methods of conception considered (percent of total) amongst male and female CDH1 germline variant carriers.

Perinatal Maternal and Fetal Outcomes after PTG

A total of nine women conceived after PTG; however, only 6 women had pregnancies that resulted in live births. Of these women, 7 (78%, 7/9) experienced at least one miscarriage and three reported multiple miscarriages after PTG. Six women gave birth after PTG at a median age of 27 years (IQR 26-31) and were diagnosed with CDH1 at age 26 years (IQR 22-30). The median time from PTG to pregnancy was 24 months (IQR 20-44), with the shortest interval being 18 months. Of the six women who gave birth after PTG, three had one live birth, two had two live births and one had three live births. Half of women (3/6) with pregnancies that resulted in live births reported difficulty eating and weight loss during pregnancy. Median weight gain during pregnancy was 9.30 kg (IQR 9.1-14.7), which does not meet perinatal weight gain recommendations for baseline underweight and normal weight women.²² Specifically, inadequate maternal weight gain, as defined by Centers for Disease Control and Prevention weight gain recommendations, was identified in 6 of the 10 pregnancies.²² Despite compliance with recommended micronutrient supplementation, 50% (3/6) of pregnant women required additional iron infusions and a third (33%, 2/6) required monthly vitamin B12 injections throughout pregnancy after PTG. Post-gastrectomy symptoms were exacerbated by pregnancy in most individuals. New onset or worsened bile reflux was reported by 83% (5/6) of women during pregnancy. Stress, anxiety, and depression were also reported in 2 of the 6 women during pregnancy. Of the nine women who became pregnant after PTG, five reported symptoms “experienced during pregnancy affected future family planning decisions.” Two participants stated post-gastrectomy symptoms negatively impacted their desire for future biological children. Three perinatal complications were reported in six women, including pre-eclampsia at 36 weeks gestation, gestational diabetes, and vaginal prolapse following birth. Of the combined 10 live births after PTG that were reported, 9 were vaginal and one was via cesarean section. Median gestational age was 39 weeks (IQR 38.15-39), with a median birthweight of 3.40 kg (IQR 3.2-3.8). Most infants (90%, 9/10) were born full-term. No adverse fetal outcomes were described. The majority (83%, 5/6) of women breastfed after pregnancy except one woman who previously elected for prophylactic bilateral mastectomy. One woman (20%, 1/5) attributed difficulty breastfeeding due to PTG. Lactation consultants (83%, 5/6), followed by CDH1 support groups (17%, 1/6) were the most common breastfeeding resources utilized. Median follow-up from most recent birth to study cutoff was 14 months (IQR 10-18).

Discussion

Herein we analyzed reproductive decision-making in 121 individuals of reproductive age with germline CDH1 P/LP variants. We demonstrate that diagnosis of a germline CDH1 variant impacted family planning in half of participants. This finding was irrespective of the individual’s biologic sex and whether individuals elected for PTG or endoscopic surveillance for management of personal gastric cancer risk. Individuals often reported guilt related to passing their CDH1 variant to offspring. We also identified a variety of psychosocial and financial barriers to family planning, such as insufficient health insurance coverage for assisted reproductive technologies, and general anxiety, stress, and/or depression related to family planning. In the current study, over half of individuals with germline CDH1 P/LP variants had biological children. Of those who conceived before their CDH1 diagnosis, approximately 1 in 5 individuals reported that their plans for having more children changed after learning of their CDH1 diagnosis. Six women had live births after prophylactic total gastrectomy and most experienced micronutrient deficiencies, worsened bile reflux, and inadequate weight gain during pregnancy. However, most infants (90%) were born full-term, and no adverse fetal outcomes were reported.

Management of gastric and breast cancer risk among carriers of germline CDH1 variants is associated with emotional and financial costs.⁸ We found that delays in family planning were common among individuals who wished to prioritize management of their personal risk of cancer through enhanced cancer surveillance or prophylactic surgery. Similar to other hereditary cancer syndromes, individuals with CDH1 variants in this study expressed difficulty navigating between personal cancer risk management and life goals.²³ Overall concern about passing a pathogenic gene variant to offspring was frequently reported in our study, which has been reported also in BRCA1, BRCA2, and MEN2 variant carriers.^23,24 Stress, anxiety, and depression are often experienced by individuals with cancer predisposition syndromes.²⁵ In our study, almost half of individuals with CDH1 variants reported at least one barrier to family planning, with anxiety most frequently reported. In general, cost and variation in coverage among health insurers for assisted reproductive technologies, such as IVF-PGT, have reportedly impeded family planning in individuals with hereditary cancer syndromes.^26,27 The use of PGT may also be influenced by social and religious preferences, particularly in individuals with hereditary conditions, as partners and family members may have differing opinions from the variant carrier.¹⁵ Previous reports have suggested that individuals with germline CDH1 P/LP variants view IVF-PGT as an acceptable form of limiting transmission of cancer risk, with up to 40% of individuals considering personal use.^28,29 In our study, 35% of participants considered IVF-PGT and 14% considered IVF alone. While oncofertility programs have increased general awareness of assisted reproductive technologies available, improved patient access to these programs are desperately needed.^30,31 In the current study, even though most participants reported at least one barrier to family planning, approximately 1 in 3 individuals sought care from medical providers to help address reproductive health concerns. Our study underscores the nuanced reproductive challenges faced by individuals with CDH1 P/LP variants and supports the need for improved access to family planning resources in this population.

There is extremely limited data exploring outcomes of pregnancy after total gastrectomy.^17,18 In this study, we demonstrated that individuals with CDH1 P/LP variants can conceive and deliver healthy infants after prophylactic total gastrectomy.⁸ Over half of our study participants conceived biological children, including six women who gave birth after PTG. However, we demonstrated that pregnancy was associated with exacerbation of post-gastrectomy symptoms in almost all women who conceived after PTG. Micronutrient deficiencies, worsened bile reflux, and inadequate weight gain were most commonly reported. Despite regular counseling by a registered dietitian about compliance with recommended bariatric multivitamins after PTG, we documented nutritional deficiencies that required additional supplementation.^32,33 Women who conceive after bariatric surgery face similar challenges of micronutrient deficiency and inadequate pregnancy weight gain.^34,35 Xu and colleagues demonstrated that women with prior bariatric surgery gained less weight with pregnancy compared to matched controls, with worse outcomes associated with shorter surgery-to-conception interval (<1 year).³⁶ We recommend close perinatal monitoring by a maternal-fetal-medicine specialist and experienced dietitian and a surgery-to-conception interval of least one year after PTG, which is when weight typically stabilizes.³² Additionally, recent studies demonstrate active endoscopic surveillance over PTG as a safe and effective alternative cancer management strategy for individuals with CDH1 P/LP variants.^8,20,37,38 Furthermore, the co-authors strongly suggest consideration of endoscopic surveillance in individuals of reproductive age who are concerned about the long-term sequelae of PTG and who are interested in starting and/or expanding their family in the near future.

In the current study, 29% of women reported having at least one miscarriage, which is consistent with the reported national rate of 10–40%.^40,41 Among women who became pregnant after PTG, seven out of nine women reported at least one early pregnancy loss. While the miscarriage rate of this cohort appears elevated, additional studies are needed to explore this further. Snoek et al. demonstrated no difference in rates of miscarriage after bariatric surgery, however, risk of vitamin deficiencies was increased.⁴² Rates of preterm birth among women with a history of bariatric surgery is reportedly higher compared to those without prior bariatric surgery.⁴³ In our study, even though inadequate weight gain and micronutrient deficiencies occurred in women after PTG, most infants were born at full term without complications. These findings underscore the importance of micronutrient monitoring throughout pregnancy to allow for adequate supplementation and to reduce the risk of poor pregnancy outcomes.¹⁸

Our study was limited by a relatively small sample size and potential recall bias in survey responses. Future surveys may be conducted over multiple time points and closer to time of childbearing to minimize recall bias and reliance on memory. Additional large-scale studies, specifically focused on pregnancy after total gastrectomy, with a more diverse patient population, are needed to corroborate our findings.

There is an unmet need for additional research on reproductive challenges in individuals with germline CDH1 P/LP variants, particularly in the current era of widespread genetic testing and increased early detection of cancer predisposition syndromes. We demonstrate that multidisciplinary, coordinated care for individuals with CDH1 P/LP variants navigating the reproductive decision-making process is essential. Women with germline CDH1 variants of reproductive age who are considering PTG should be counseled on post-gastrectomy symptom management and additional nutritional requirements, as well as undergo frequent micronutrient assessment during pregnancy.³³ Our study also demonstrates the significant psychosocial challenges individuals with CDH1 variants face during family planning. Improved access to reproductive technologies and standardized referral to Reproductive Endocrinologists should be performed for individuals with CDH1 P/LP variants of childbearing age. Prenatal genetic counseling should also be offered to help ameliorate concerns for individuals with inherited cancer syndromes such as hereditary gastric cancer.

Key messages.

What is already known on this topic –

• Diagnosis of a deleterious germline variant can have significant psychosocial ramifications, particularly in young adults.

• Individuals with a CDH1 P/LP variant are frequently recommended to undergo prophylactic total gastrectomy (PTG) at age 20 to 30 years, which is a common time for family planning.

• PTG has many long-term sequelae; however, little is known about the impact of CDH1 diagnosis on reproductive decision-making and fertility.

What this study adds –

• Diagnosis of a germline CDH1 variant impacted reproductive decision-making, and many patients reported a change in family planning after learning of their diagnosis.

• Guilt about passing the variant to offspring, barriers to reproductive decision-making, and exacerbation of post-gastrectomy syndromes during pregnancy were common among individuals with a CDH1 P/LP variant.

• Natural conception is possible, even after PTG; however, careful monitoring is required to mitigate post-gastrectomy syndromes and nutritional deficiencies in women who become pregnant after PTG.

How this study might affect research, practice or policy –

• Improved access to reproductive specialists can help ameliorate concerns of individuals with inherited cancer syndromes like hereditary diffuse gastric and lobular breast cancer syndrome.

• Endoscopic surveillance (versus PTG) should be considered in women planning to start or expand their family given the exacerbation of post-gastrectomy sequelae during pregnancy.

Data Availability:

Deidentified data supporting this study are available from the corresponding author upon reasonable request.