Women’s healthcare providers’ knowledge and practices surrounding fragile-X associated primary ovarian insufficiency (FXPOI)

Primary ovarian insufficiency (POI) is clinically defined as oligomenorrhea or amenorrhea with increased gonadotropins and decreased estradiol prior to age 40 years [1]. POI affects approximately 20–30% of women with a fragile X premutation, making it one of the most common causes of POI. The fragile X premutation occurs when there are 55–200 CGG repeats in the 5′ untranslated region (UTR) of the FMR1 gene. It is estimated that 1 in 148 women carry a premutation, impacting over one million women in the USA [2]. Women with 80–100 CGG repeats have the highest FXPOI risk of all premutation carriers [3]. In addition to the risk of POI, women with a premutation, on average, experience menopause about 5 years earlier than noncarriers [4]. Hipp et al. showed that only 15% of women were diagnosed with a premutation due to personal or family history of POI, while 84% learned they were premutation carriers due to a family member diagnosis with fragile X syndrome (FXS) [5]. This study also found that women who were younger at the time of suspected POI diagnosis were likely to experience a longer delay until clinical diagnosis.

FXPOI was first reported in the literature in 1998, finding that women with a fragile X premutation more frequently reported POI compared to control groups. The authors recommended screening women with POI to identify women whose children are at risk of having FXS [6]. FXS is the leading inherited form of intellectual disability and autism spectrum disorder. Premutation carriers are at risk of having children with FXS due to premutation expansion to the full allele (> 200 CGG repeats). Presentation of FXS can include severe behavioral challenges, including hyperactivity, impulsivity, and anxiety, as well as poor language development and seizures [7].

In 2006, the American College of Obstetrics and Gynecology (ACOG) first recommended in a Committee Opinion that all women with ovarian insufficiency or elevated follicle stimulating hormone (FSH) levels have FMR1 testing, which has since been reaffirmed [8, 9]. It is unknown whether FXPOI diagnoses are missed by not offering FMR1 testing according to the guideline.

FXPOI workup is often first offered to patients by obstetrician-gynecology providers, which for many women can be a nurse practitioner (NP) or nurse midwife (NM) in addition to physicians [10]. In previous literature, women with FXPOI reported providing educational materials to their gynecologists after their initial concerns about POI symptoms were dismissed [5]. Dismissal of POI symptoms has been shown to negatively impact patients’ perceptions of their providers’ FXPOI knowledge level [10]. The difficulty experienced by women in receiving a FXPOI diagnosis has been shown to have a negative psychosocial impact for women with FXPOI, which may be due to lack of education and clinician training [10]. There is a demonstrable need for increased education for women’s healthcare providers to help guide the diagnosis of POI and understand the related health implications of the diagnosis, including an increased risk for infertility, osteoporosis, and cardiovascular disease [5]. Beyond personal health risks, many women (62%) reported that knowledge of their premutation status impacted their reproductive decisions with planned use of contraception, early prenatal testing, or pursuit of gamete donation [5]. Due to the potential need for follow-up care and changes in reproductive decision-making, it is essential that any healthcare provider ordering genetic testing that includes FMR1 CGG repeat size and/or seeing women with abnormal menses understands both personal and reproductive risks that come with a premutation [3].

This study aims to understand women’s healthcare providers’ knowledge of and practices surrounding workup and diagnosis of FXPOI. We hope to understand where gaps in knowledge lie and measure which demographic factors are facilitators to FXPOI knowledge so that providers can be properly educated. Additionally, we aim to observe practice patterns surrounding POI workup to see if providers are taking measures to rule out or make a diagnosis of FXPOI.

An online survey completed by 121 participants resulted in a mean Knowledge Score of 6.92 (± 2.19) out of a possible 16 points based on knowledge of FXPOI reproductive risks, personal health risks, clinical manifestations, and CGG repeat size. Descriptive variables about the study population are shown in Table 1, and a breakdown of the responses to each of these questions is shown in Table 2. In general, the majority of participants were physicians that practiced in an academic setting. The most frequently reported specialty was general OBGYN (n = 60). The majority had exposure to genetics in training and felt somewhat or extremely comfortable explaining carrier screening results.

Forty-seven percent of participants reported having a genetic counselor employed in their clinic. This group scored 1.65 points (27%) higher than participants that did not have a genetic counselor in their clinic, proving to be the strongest predictor of FXPOI knowledge (p = 0.0001). Additionally, providers that practice in MFM and REI scored significantly higher (p = 0.0189 and 0.0288, respectively) than providers that practice in OBGYN using an ANOVA model to compare the individual groups (Fig. 1). In addition, medical school graduation year was a significant predictor for knowledge score (p = 0.0397). In general, Knowledge Score increased over time with graduation year, except for the group that graduated between 2000 and 2009, which scored the highest (Fig. 1). The following variables did not show significant differences when analyzed: gender, number of patients with POI seen per year, exposure to genetics in training, location of medical education and training, comfort level explaining reproductive carrier screening, and type of healthcare provider.

Based on significant predictor variables of Knowledge Score, we created an overall model that adjusted for the significant variables. Interaction terms between variables were also tested. The frequency of having a genetic counselor in the clinic was significantly different based on specialty; 35% of OBGYNs, 39% of REIs, and 95% of MFMs reported having a genetic counselor employed in their clinic. Therefore, an interaction term between these two variables was included in the final model. This interaction term did not reach significance (p = 0.0557); however, specialty and genetic counselor in clinic both maintained statistical significance (p = 0.0123 and p = 0.0117, respectively) (Table 3).

Baseline knowledge of POI was assessed by question 9, an open-ended question that reads, “What symptoms would make you suspicious of POI?” Of 107 survey respondents, 106 responded to this question. Two incorrect responses included vasovagal symptoms and symptoms beginning before age 45 years. The other 104 responses included correct POI symptoms such as amenorrhea, irregular menses, infertility, and vasomotor symptoms.

To assess practices surrounding a common POI presentation, survey question 3 reads, “A 25-year-old female patient presents with inconsistent menstrual cycles, what are your next steps?” Participants were asked to select all answers that apply. The six answer choices represent two categories. The first category includes steps that would help providers to collect information that is informative for a FXPOI workup. The second category includes next steps that would not collect more information for a FXPOI workup (Fig. 2). REIs selected the most responses that would provide information relevant to a FXPOI workup, followed by MFMs and OBGYNs.

Survey questions 5 and 6 assess knowledge of premutation-associated risks. Participants were asked to select all answers that apply. Question 5 reads, “What reproductive counseling would you give to a female patient with an identified fragile X premutation?” assessing knowledge of premutation associated reproductive risks. Seventy percent of responses were correct and 30% of responses were incorrect. Question 6 reads, “What personal health risks would you discuss with a female patient with an identified fragile X premutation?” assessing knowledge of premutation-associated personal health risks. Thirty-four percent of responses were correct, and 66% of responses were incorrect (Fig. 3). Together, these findings indicate that women’s healthcare providers have a better understanding of the reproductive risks compared to the personal health risks for women with a premutation.

Results of this study demonstrate that women’s healthcare providers have limited knowledge on FXPOI, consistent with patients’ reports when interviewed in previous literature [4, 5, 10]. The average Knowledge Score was 6.92 (43%) out of a possible 16. The minimum was 1 (6%), and the maximum was 11 (69%).

Predictor variables for knowledge of FXPOI include medical specialty, medical school graduation year, and having a genetic counselor employed in the clinic in which they practice. Providers that practice in maternal fetal medicine scored significantly higher than those who practice in general obstetrics and gynecology in the final model that was adjusted for all covariates. Typically, however, patients first report POI symptoms to their OBGYN, not to a specialist, which may contribute to delayed time to diagnosis [10].

Except for medical school graduation years between 2000 and 2009, who scored highest, Knowledge Scores increased gradually over time. This is likely due in part to an increasing amount of research and recommendations surrounding FXS and FXPOI. ACOG’s current Committee Opinion on carrier screening for genetic conditions recommends carrier screening to assess whether a premutation is present in women with unexplained ovarian insufficiency or failure or an elevated follicle-stimulating hormone level before 40 years of age. This recommendation was originally introduced in 2006, republished in 2017, and most recently reaffirmed in 2023 [9]. More recent additions to this Committee Opinion include that all identified fragile X premutation carriers should be provided follow-up genetic counseling to discuss the risk to their offspring of inheriting an expanded full mutation fragile X allele and to discuss fragile X-associated disorders [9].

Eighty-eight percent of participants reported having exposure to genetics in their medical training, clinical education, or both. This high percentage should be encouraging but showed no effect on Knowledge Scores. The 2023 Accreditation Council for Graduate Medical Education (AAMC) Medical School Graduate Questionnaire reported that 26% of medical students did not feel that their didactic genetics coursework prepared them well for their clinical clerkships, which has remained consistent over the past 5 years [11]. Previous research has shown that application of genetics knowledge is not often stressed in medical school, and medical students do not see their preceptors using genetics knowledge in clinical rotations [12]. Additionally, a 2014 survey of North American medical school course directors shows that a majority of formal genetics education occurs in the first 2 years of medical school and has declined in the latter 2 years since 2005 (26% vs. 47%) [13, 14]. Furthermore, genomics is a required core content area in US OBGYN residency programs accredited by the AAMC, and OBGYN resident physicians are expected to acquire knowledge and skills in several areas, including the role of genetics in the development and evaluation of infertility and genetic counseling [15].

Employment of a genetic counselor in women’s health clinics proved to be the variable that showed the strongest statistical significance in facilitating FXPOI knowledge (p = 0.0001). This variable was tested for each of the individual questions included in the knowledge score, and there was a significant improvement in scores for all of the questions for individuals that reported having a genetic counselor in their clinic. This suggests that providers who work with genetic counselors are more educated on fragile X-associated conditions and can be a better resource for affected patients. However, genetic counselors are currently more likely to be employed in specialty clinics, including MFM and REI, than in a general OBGYN clinic. Delivering genetics education to healthcare professionals is a curriculum requirement for genetic counseling graduate programs accredited by the Accreditation Council for Genetic Counseling [16]. Genetic counselors continue to employ this skill throughout their careers as effectively communicating genetics information to colleagues is part of the practice-based competencies for genetic counselors [17]. Due to their expertise in both genetic knowledge and education, genetic counselors prove to be an asset to the care team of patients and families with fragile X premutations and FXS.

Based on POI symptom responses, providers seem to understand what symptoms to associate with primary ovarian insufficiency; gaps lie in connecting personal health risks with a diagnosis of FXPOI as well establishing the diagnosis. The mean time from symptom onset to achieving a FXPOI diagnosis is 1.12 years and is longer for women that are younger at the time of symptom onset. Time to diagnosis has not shown improvement in the last three decades. Even when patients were aware of their premutation status, average time to diagnosis after symptom onset is 0.75 years [5].

This study builds upon data collected in previous qualitative research. When asked how their diagnostic and care experience could be improved, all interviewees in the study completed by Poteet et al. discussed the need for increased premutation education and awareness by clinicians [10]. Experiences from these 24 participants have now been quantified by directly surveying providers.