Improving women’s healthcare providers’ knowledge about fragile X-associated primary ovarian insufficiency through a novel educational tool

Abstract

Purpose

Gaps in knowledge among women’s healthcare providers have contributed to diagnostic delays and delayed care for women with fragile X-associated primary ovarian insufficiency (FXPOI). The objective of this study was to assess if an educational tool could improve women’s healthcare providers’ knowledge of FXPOI.

Methods

A one-page educational tool about the premutation and FXPOI was developed. To assess the impact, a pre- and post-intervention survey was given to 95 providers. The post-intervention survey was emailed approximately 1 month after the pre-intervention survey. Surveys consisted of 12 knowledge-based questions (12 points total). Additional information collected included demographics, routine POI workup, comfort level explaining carrier screening results, and feedback on the tool.

Results

Provider knowledge significantly improved from 7.34/12 (± 1.75) to 8.66/12 (± 2.30) (p < 0.0001). Significant predictors of pre-intervention knowledge included provider type, specialty, presence of a genetic counselor (GC) in clinic, and graduation year. Physicians outperformed nurse practitioners and nurse midwives (p < 0.0128). Reproductive endocrinologists and maternal–fetal medicine providers outperformed other specialties (p < 0.0001). Providers with a GC in the clinic performed better than those without (p = 0.0128). Providers who graduated between 2010 and 2019 outperformed more recent graduates (p = 0.0348). No significant predictors were identified for post-intervention scores.

Conclusions

The implementation of our novel educational tool led to measurable improvement in provider knowledge regarding FXPOI and the fragile X premutation. The absence of significant demographic predictor variables on the post-intervention survey suggests that the educational tool may help reduce provider gaps in knowledge and ultimately reduce time to diagnosis and improve reproductive care for women with FXPOI.

Supplementary information

The online version contains supplementary material available at 10.1007/s10815-025-03734-9.

Introduction

A mutation in the 5′ untranslated region of the FMR1 gene can cause fragile X syndrome (FXS) or an increased risk for fragile X-associated conditions. Mutations in the FMR1 gene are unique because the symptoms of the condition correlate with the number of CGG repeats present. There are four FMR1 allele sizes: normal alleles (6–44 repeats), intermediate alleles (45–54 repeats), premutation (PM) alleles (55–200 repeats), and full mutation alleles (> 200 repeats). PM alleles increase the risk for fragile X-associated tremor-ataxia syndrome (FXTAS), fragile X-associated neuropsychiatric disorders (FXAND), and fragile X-associated primary ovarian insufficiency (FXPOI), whereas full mutation alleles cause FXS [1].

FXPOI is defined as irregular (i.e., cycling every 4–6 months) or absent menses along with specific menopausal lab results in women younger than 40 years of age (premature menopause) who carry an FMR1 PM. It is estimated that 1 in 151 women carry a PM, impacting over one million women in the United States [2]. The PM is the most common genetic cause of primary ovarian insufficiency (POI) [3]. Symptoms of FXPOI can include irregular or ceased menses, infertility, and menopausal symptoms such as hot flashes and night sweats. Women who have early menopause are also at an increased risk for cardiovascular disease, earlier mortality, osteoporosis, and earlier cognitive decline due to the hypoestrogenic environment [4]. Women with the highest risk for FXPOI are those with ~ 80 to 100 CGG repeats [5]. Approximately 20% of women with a PM experience FXPOI, and although FXPOI is the most common fragile X-associated disorder, it is the most underdiagnosed [6, 7].

A qualitative study by Poteet et al. [8] exploring the diagnostic experiences of 24 women with FXPOI revealed that many women reported having to advocate for their own diagnosis and care, often needing to visit multiple providers before receiving the appropriate evaluation. Most women with FXPOI reported needing to give FXPOI educational materials to providers and seeing a broad range of providers pre- and post-diagnosis, including geneticists, genetic counselors (GCs), reproductive endocrinology and infertility (REI) providers, and obstetricians and gynecologists (OBGYNs). Although OBGYNs are often the first providers that women with POI seek help from, some women expressed experiencing dismissal of POI symptoms, misdiagnosis, lack of hormone testing, and difficulty receiving recommended care such as hormone replacement therapy (HRT). Lack of provider knowledge about FXPOI was associated with perceived lack of empathy and support, leading to negative healthcare experiences and psychosocial challenges. Women with a PM expressed the need for clinicians to have more education and awareness about FXPOI to facilitate an earlier diagnosis, prevent misdiagnosis, and improve point-of-care service [8].

Any delay in diagnosis and/or underprescription of HRT may increase the risk of comorbidities of POI, but appropriate estrogen replacement may attenuate these, emphasizing the importance of a timely diagnosis [4]. Hipp et al. [4] found that women with a PM who experience POI onset at a younger age were more likely to have a longer time to diagnosis than women with POI onset at later ages. Ovarian insufficiency not only increases a woman’s risk for infertility but also for other conditions associated with a hypoestrogenic state, such as osteoporosis. Hipp et al. [4] further found that 46% of women with FXPOI had a diagnosis of low bone mineral density or osteoporosis. These findings highlight how women with FXPOI are at an increased risk for undertreatment with HRT, infertility, and other conditions associated with a hypoestrogenic state, stressing the need for increased provider education about POI and HRT. The study concluded that increased education about POI and HRT could decrease the time to diagnosis for women with FXPOI as well as attenuate their long-term health risks [4].

Although there is no cure for FXPOI, timely treatment and management of symptoms can improve overall health and possibly improve reproductive outcomes. Several professional consensus guidelines currently address diagnosis, treatment, and management of FXPOI. The American College of Obstetrics and Gynecology (ACOG) recommends that women younger than 40 years old who have ovarian failure or an elevated follicle-stimulating hormone (FSH) without a known cause should have FMR1 testing [9]. The American Society of Reproductive Medicine recommends that women with POI use HRT until the usual age of menopause for primary prevention to reduce the risk of morbidity and mortality [10]. Hormone therapy can not only provide symptom relief but also support bone, cardiovascular, and sexual health in women with FXPOI [11].

Despite management guidelines, many women’s healthcare providers lack knowledge on FXPOI, and Singleton et al.’s [12] results helped define what some of these knowledge deficits are. In this study, a quantitative survey was completed by 121 women’s healthcare providers, and four questions about the PM signs/symptoms, reproductive outcomes, personal health risks, and CGG repeat number were scored. The average knowledge score was 43% (6.92/16 points), with maternal–fetal medicine (MFM) and REI providers scoring higher than those who practice in general obstetrics and gynecology, yet OBGYNs are the providers women with POI symptoms typically present to first. Providers with a GC in the clinic also scored higher than providers without a GC. These findings illustrate the need for broader education for women’s healthcare providers, specifically for OBGYNs since they are the primary providers for women with POI symptoms [12].

The objective of the present study was to assess whether women’s healthcare providers’ knowledge of PM and FXPOI symptoms, diagnostic testing, comorbidity risk, reproductive risk, and long-term management is improved after the implementation of an educational tool. We also surveyed general carrier screening practices and provider workup for POI, as carrier screening and proper POI workup can improve early diagnosis [13].

Methods

This was a prospective, interventional study that evaluated the effectiveness of an educational tool at improving women’s healthcare providers’ knowledge about FXPOI. The Emory Institutional Review Board reviewed the study’s design, protocol, and materials and determined that the study was exempt from further review (IRB#00005632).

Participants

Healthcare providers currently practicing in a women’s health specialty in the United States, such as obstetrics and gynecology or reproductive endocrinology and infertility, were eligible to participate in the study. Participants were recruited from May to September 2024 through multiple professional organizations’ listservs, monthly newsletters, website postings, and/or social media posts. Organizations included the National Association of Nurse Practitioners in Women’s Health, the Georgia OBGYN Society, the Society for Reproductive Investigation, the Society for Maternal–Fetal Medicine, the Cleveland Society of Obstetricians and Gynecologists, Bozeman Health, Wyoming Association of Physician Assistants (PA), RESOLVE, Prisma Health, Association of Physician Associates in Obstetrics and Gynecology, the Maine Association of PAs, the Mississippi State Medical Association, and the South Carolina Obstetrical and Gynecological Society. To increase response rates, over 500 direct emails were also sent to addresses gathered through healthcare institutions’ websites, OBGYN residency program websites, and MFM and REI fellowship program websites.

Study procedures

The pre- and post-intervention surveys and educational tools were designed with involvement from a genetic counseling student, a GC, an REI fellow, an REI, and the senior research investigator, who has studied FXPOI for over 20 years. A copy of both surveys and the educational tool is included in supplemental materials. We piloted the pre-intervention survey and educational tool with two REI fellows, three REIs, three nurse practitioners (NPs) specializing in general obstetrics and gynecology, one NP specializing in reproductive endocrinology, and one resident physician specializing in general obstetrics and gynecology. We revised and implemented the feedback about the survey and educational tool that we received, which consisted of restructuring the layout of the tool, revising the wording in certain sections of the tool, and rewording several survey questions for clarity.

The pre- and post-intervention surveys were adapted from the survey used in Singleton et al.’s [12] 2024 study. The pre-intervention survey included knowledge questions about FXPOI, questions about general carrier screening practices and provider workup for POI, and demographic questions. Demographic information included type of healthcare provider, medical specialty, location of medical education, medical education graduation year, practice environment, sex, primary type of patient insurance, genetics exposure in training, and the presence of a GC in the clinic. The post-intervention survey included the same knowledge questions on FXPOI and three questions (two free response and one multiple choice) to provide feedback about the educational tool. An email address was collected to link pre- and post-intervention surveys.

Participants were emailed the educational tool approximately 1 week after the pre-intervention survey was administered. The educational tool was one page, to minimize burden on healthcare providers, and was created using Canva (https://www.canva.com). The tool is a brief educational guide that highlights key information about FXPOI to serve as a clinical reference for providers and further provides several QR codes to review more detailed information on FXPOI. The tool defines FXPOI, identifies which individuals are at the highest risk for FXPOI, FXPOI signs and symptoms, FXPOI management guidelines, statistics on FXPOI prevalence, provider resources on FXPOI, and PM/FXPOI comorbidity and reproductive risks. The management guidelines include recommended screening for women at risk, management once diagnosed with FXPOI, and long-term care. These guidelines were created based on literature review and ACOG guidelines. The Flesch-Kincaid measurement tool indicated that the educational tool was understandable at a college reading level (https://goodcalculators.com/flesch-kincaid-calculator).

Approximately 1 month after receiving the educational tool, participants were emailed the post-intervention survey. Two reminder emails were sent at 1- to 2-week intervals if the participant did not complete the post-intervention survey. Participants who completed the pre- and post-intervention surveys were entered into a lottery to win one of five $50 Amazon e-gift cards.

Statistical analyses

The pre- and post-intervention surveys were scored using the same method. The scoring guide is included in the supplemental materials. Knowledge was scored on a scale of 0 to 12, with higher scores indicating more knowledge. The knowledge score was based upon answers to nine multiple-choice questions, two check-all-that-apply questions, and one true/false question. Questions included clinical-based questions about FXPOI signs and symptoms, CGG repeat size, FXPOI comorbidity risks, reproductive risks of having an FMR1 PM expansion, FMR1 PM personal health risks, FXPOI genetic testing, and FXPOI long-term management. One point was awarded for each correct multiple-choice response and a correct response to the true/false question. For the first check-all-that-apply question (Q7), 1 point was awarded for selecting a correct answer, 1 point for not selecting an incorrect answer, and 0 points for selecting an incorrect answer. Points were summed and divided by 6, as there were six answer choice options. For the second check-all-that-apply question (Q8), points were awarded in the same manner as Q7; however, if the answer choice “There is no risk to personal health because it is not a full mutation” was chosen, the participant was automatically awarded 0 points. Points were summed and divided by 5, as there were five answer choice options.

Data analysis was conducted using SAS 9.4. Only surveys that were at least 95% complete were included in the analyses. Descriptive statistics were generated for all variables. A paired t-test was used to analyze the mean change in knowledge scores between pre- and post-intervention surveys. To identify biases among those who only completed the pre-intervention survey versus those who completed the pre- and post-intervention surveys, a chi-square test was used to compare the demographics between these two groups. An independent t-test was used to determine whether the knowledge scores on the pre-intervention survey were significantly different between those who went on to complete the post-intervention survey vs those who did not. In addition, we tested for associations with general demographic variables, such as type of healthcare provider and specialty. To better summarize several demographic variables, certain provider types, specialties, graduation years, and graduate/medical school locations were grouped together. ANOVA models were used to identify significant predictors of knowledge for pre- and post-intervention scores. Significant differences between groups were determined using Tukey’s post hoc analysis to control for multiple testing. A p-value of 0.05 was used to determine statistical significance. In models where multiple variables were included, we confirmed that multicollinearity was not affecting the model.

Results

Demographics

In total, 166 women’s healthcare providers completed the pre-intervention survey and 95 completed the post-intervention survey. Participant demographics are shown in Table 1. Most participants who completed both the pre- and post-intervention surveys were female physicians, PAs, or NPs who specialize in general obstetrics and gynecology and work in an academic medical center. Most physicians had exposure to genetics training either in medical school, residency, and/or fellowship; however, less than half of advanced practice providers had exposure to genetics in their training.

Table 1.

Comparison of mean knowledge scores by participant demographics

Knowledge score based on independent variables	n	Pre-intervention survey (n = 95); total score (max = 12; mean ± SD)	Post-intervention survey (n = 95); total score (max = 12; mean ± SD)	T-test p-value
Total population	95	7.34 ± 1.75	8.66 ± 2.30	0.0001
Type of healthcare provider
Physician	32	7.94 ± 1.82	8.90 ± 2.36	0.0729
Fellow	3	9.53 ± 2.00	10.67 ± 2.14	0.5396
Resident physician	8	7.49 ± 1.23	9.11 ± 2.11	0.0868
Physician assistant	22	6.83 ± 1.43	8.69 ± 2.00	0.0051
Nurse practitioner	26	6.46 ± 1.72	8.16 ± 2.40	0.0039
Nurse midwife	3	7.02 ± 1.25	8.69 ± 2.00	0.6958
Other (NP student)	1	5.83	3.5	0
Specialty
General OBGYN	65	7.08 ± 1.50	8.53 ± 2.29	< 0.0001
Reproductive endocrinology	8	9.23 ± 1.90	10.16 ± 1.49	0.2956
Maternal–fetal medicine	10	8.63 ± 1.60	8.92 ± 2.66	0.7713
Female pelvic medicine and reconstructive surgery	2	8.03 ± 0.05	9.50 ± 1.84	0.3765
Family planning	5	6.03 ± 1.30	8.30 ± 3.14	0.1746
Other	3	5.10 ± 2.75	7.18 ± 1.18	0.2951
Graduate/medical school graduation year
1975–1999	17	7.29 ± 1.87	8.16 ± 2.44	0.2541
2000–2009	17	7.73 ± 2.07	9.15 ± 1.98	0.0508
2010–2019	33	7.76 ± 1.66	8.71 ± 2.46	0.0349
≥ 2020	24	6.52 ± 1.17	8.32 ± 2.45	0.0023
Practice environment
Academic center	49	7.78 ± 1.72	9.02 ± 2.11	0.002
Community hospital	6	7.36 ± 1.36	8.83 ± 2.17	0.1891
Private practice	26	6.83 ± 1.72	7.95 ± 2.37	0.055
Other	14	6.73 ± 1.78	8.63 ± 2.77	0.0409
Genetic counselor in clinic
Yes	30	8.00 ± 1.65	9.06 ± 2.23	0.0414
No	65	7.04 ± 1.72	8.48 ± 2.33	0.0001
Sex
Male	9	8.12 ± 2.34	8.28 ± 3.23	0.9039
Female	84	7.26 ± 1.68	8.65 ± 2.21	< 0.0001
Prefer not to say	2	7.32 ± 2.10	10.80 ± 0.00	0.1433
Exposure to genetics in training
Yes (all providers except physicians)	20/47	7.12 ± 1.19	7.92 ± 2.34	0.1838
No (all providers except physicians)	27/47	6.75 ± 1.90	8.37 ± 2.33	0.0007
Yes (in medical school, residency, or fellowship)	38/43	7.98 ± 1.79	9.04 ± 2.41	0.0337
No (in medical school, residency, or fellowship)	5/43	8.01 ± 1.48	9.29 ± 1.14	0.1659
Patient insurance
Medicaid	37	6.95 ± 1.32	8.59 ± 2.28	0.0003
Private insurance	47	7.46 ± 1.94	8.48 ± 2.33	0.0228
Other	11	8.12 ± 2.02	9.65 ± 2.22	0.1059
Graduate/medical school location
Midwest	19	7.26 ± 1.61	8.75 ± 2.32	0.028
Northeast	20	6.74 ± 1.12	8.52 ± 2.15	0.0022
South	32	7.95 ± 1.97	9.06 ± 2.46	0.0508
Southwest	3	6.76 ± 0.83	6.49 ± 1.47	0.7976
West	14	7.23 ± 2.02	8.64 ± 2.15	0.0855
Other	3	8.09 ± 0.87	8.82 ± 1.08	0.411

Significant associations (p<0.05) between pre- and post-intervention knowledge scores are indicated

Knowledge

Table 2 shows a breakdown of the questions, answer choices, and number of participants who selected each answer choice for the 12 knowledge score questions. In the pre-intervention survey, participants were most knowledgeable about FXPOI symptoms and long-term care after an FXPOI diagnosis (Q12, Q14; Table 2). Participants were least knowledgeable about how many CGG repeats place an individual who is assigned female at birth (AFAB) at the highest risk for FXPOI and patient indications that warrant FMR1 testing (Q10, Q11, Q16; Table 2).

Table 2.

Result summary of FXPOI knowledge questions with percent of participants who selected each answer choice

Question	Answer choices
Multiple choice
Q5. A 25-year-old assigned female at birth presents with inconsistent menstrual cycles, what is the best next step?	Prescribe birth control	Measure hormone levels	Perform a mental health assessment	Reassure the patient that this is normal	Recommend daily vitamin D and iron
Pre-intervention survey (N = 95)	11 (11.6%)	77 (81.0%)	2 (2.1%)	4 (4.2%)	1 (1.0%)
Post-intervention survey (N = 95)	15 (15.8%)	72 (75.8%)	3 (3.2%)	5 (5.3%)	0 (0%)
Q6. Which of the following would raise suspicion for fragile X premutation status and prompt further testing if a patient had no other remarkable personal or family history?	Sister with breast cancer	Elevated estrogen levels in the patient	Nephew with intellectual disability	Decreased FSH levels in the patient	Elevated progesterone levels in the patient
Pre-intervention survey (N = 95)	0 (0%)	2 (2.1%)	69 (72.6%)	22 (23.1%)	2 (2.1%)
Post-intervention survey (N = 95)	3 (3.2%)	2 (2.1%)	75 (78.9%)	14 (14.7%)	1 (1.0%)
Q9. How many CGG repeats in the FMR1 gene constitutes a premutation?	5–44	45–54	55–200	Over 200
Pre-intervention survey (N = 92)	20 (21.7%)	15 (16.3%)	46 (50.0%)	11 (12.0%)
Post-intervention survey (N = 95)	9 (9.5%)	16 (16.8%)	66 (69.5%)	4 (4.2%)
Q10. How many CGG repeats in the FMR1 gene puts assigned females at birth at the highest risk to be affected by FXPOI?*	80–100	100–125	150–200	60–75
Pre-intervention survey (N = 45)	7 (15.9%)	5 (11.4%)	30 (68.2%)	2 (4.5%)
Post-intervention survey (N = 66)	41 (62.1%)	1 (1.5%)	24 (36.4%)	0 (0%)
Q11. In the setting of absent menstrual cycles and an elevated FSH, which test would be indicated as a next step?	A hormone panel	Urinary organic acid analysis	FMR1 genetic testing	Karyotype	Prolactin and thyroid function test
Pre-intervention survey (N = 94)	13 (13.8%)	1 (1.1%)	18 (19.1%)	23 (24.5%)	39 (41.5%)
Post-intervention survey (N = 95)	14 (14.7%)	0 (0%)	47 (49.5%)	16 (16.8%)	18 (18.9%)
Q12. What is the best step taken for long-term care after a diagnosis of FXPOI?	REI visit every 1–2 years for possible HRT and hormone evaluation, monitored care by other specialists	Mammograms every 6–12 months starting at 35, physical therapy, DEXA scans	Hysterectomy and bilateral oophorectomy, REI visit every 3–5 years	Annual DEXA scans, physical therapy, endometrial ablation	Consistent use of a blood-thinner, birth control, and specialized diet
Pre-intervention survey (N = 94)	89 (94.7%)	3 (3.2%)	1 (1.1%)	1 (1.1%)	0 (0%)
Post-intervention survey (N = 95)	92 (96.8%)	0 (0%)	0 (0%)	2 (2.1%)	1 (1.0%)
Q13. What comorbidity risks are associated with FXPOI?	Anemia, headaches	Anxiety/depression, osteoporosis	Hypertension, increased blood clotting	Vision loss, anxiety/depression	Diabetes
Pre-intervention survey (N = 94)	0 (0%)	78 (83.0%)	4 (4.3%)	7 (7.4%)	5 (5.3%)
Post-intervention survey (N = 95)	1 (1.0%)	83 (87.4%)	2 (2.1%)	3 (3.2%)	6 (6.3%)
Q14. What are symptoms of FXPOI?	Irregular menses, hot flashes, night sweats	Sleep apnea, chronic fatigue, weight loss	Full body muscle cramps, nausea	Migraines, breast pain, and edema	Increased bleeding at menses, constipation, vomiting
Pre-intervention survey (N = 95)	92 (96.8%)	1 (1.0%)	2 (2.1%)	0 (0%)	0 (0%)
Post-intervention survey (N = 95)	92 (96.8%)	2 (2.1%)	0 (0%)	1 (1.0%)	0 (0%)
Q16. Which individual(s) is at the highest risk for FXPOI?**	I	II	III	II & III	All are at equal risk
Pre-intervention survey (N = 94)	0 (0%)	17 (18.1%)	30 (31.9%)	18 (19.1%)	29 (30.8%)
Post-intervention survey (N = 94)	1 (1.1%)	17 (18.1%)	36 (38.3%)	26 (27.7%)	14 (14.9%)
True/false
Q15. All assigned females at birth who are younger than 40 years old and are experiencing unexplained ovarian insufficiency or elevated FSH levels > 40 mIU/mL should have FMR1 genetic testing?	True	False
Pre-intervention survey (N = 95)	81 (85.3%)	14 (14.7%)
Post-intervention survey (N = 95)	92 (96.8%)	3 (3.2%)
Check all that apply
Q7. What are important reproductive counseling points to discuss with an assigned female at birth who is a premutation carrier?	Increased risk for reduced fertility	Increased risk for gestational diabetes	Increased risk of having a child with intellectual disability	Increased risk of having a child who is at an increased risk for pediatric cancer	Increased risk of having a child with hearing and vision loss	Increased risk for preeclampsia
Pre-intervention survey (N = 95)	71 (74.7%)	10 (10.5%)	85 (89.5%)	9 (9.5%)	31 (32.6%)	9 (9.5%)
Post-intervention survey (N = 95)	84 (88.4%)	9 (9.5%)	88 (92.6%)	6 (6.3%)	27 (28.4%)	11 (11.6%)
Q8. What are some of the personal health risks an assigned female at birth with an identified premutation may have?	Mental health complications	Tremor and ataxia	Type II diabetes	Hearing loss	There is no risk to personal health because it is not a full mutation
Pre-intervention survey (N = 95)	40 (42.1%)	26 (27.4%)	13 (13.7%)	21 (22.1%)	33 (34.7%)
Post-intervention survey (N = 95)	62 (65.3%)	44 (46.3%)	11 (11.6%)	17 (17.9%)	20 (21.0%)

Correct answers/choices are in bold emphases

^*A reduced sample size due to participants only being asked this question if question 9 was answered correctly

^**The pedigree in supplemental materials

Significant associations (p <0.05) between pre- and post-intervention knowledge scores are indicated

There was a high baseline knowledge for six questions on the pre-intervention survey. At least 80% of participants correctly answered the questions about FXPOI symptoms, long-term care, comorbidity risks, reproductive outcomes, and hormone levels indicative of FMR1 testing (Q5, Q7, Q12, Q13, Q14, and Q15; Table 2). On average, knowledge scores increased by 1.33 points from 7.34/12 points (61.2%) on the pre-intervention survey to 8.66/12 points (72.2%) on the post-intervention survey (p < 0.0001) (Fig. 1).

Fig. 1.

Mean change in knowledge score from pre- to post-intervention survey

No significant difference in pre-intervention score was seen between those who completed the post-intervention survey versus those who only took the pre-intervention survey. The mean time to complete the post-intervention survey was 38.13 ± 9.76 days. There was no significant correlation between the post-intervention test score and the number of days it took for a participant to complete the survey.

Educational tool impact

There were three multiple-choice questions, one check-all-that-apply question, and one true/false question that showed a significant increase in knowledge after the educational tool intervention. The proportion of participants who correctly answered, “How many CGG repeats in the FMR1 gene constitutes a premutation?” (Q9), increased from 46/92 (50%) on the pre-intervention survey to 66/95 (70%) on the post-intervention survey (p < 0.0066). Only the participants who correctly answered the question above were asked the question, “How many CGG repeats in the FMR1 gene puts assigned females at birth at the highest risk to be affected by FXPOI?” (Q10). There was an increase in the number of participants who answered this correctly, from 7/45 (16%) to 41/66 (62%) (p < 0.0001). The proportion of individuals who correctly answered, “In the setting of absent menstrual cycles and an elevated FSH, which test would be indicated as a next step?” (Q11), increased from 18/94 (19%) to 47/95 (49.5%) (p = 0.0001) (Fig. 3). The number of individuals who correctly answered, “All assigned females at birth who are younger than 40 years old and are experiencing unexplained ovarian insufficiency or elevated FSH levels > 40 mIU/mL should have FMR1 genetic testing.” (Q15), increased from 81/95 (85%) to 92/95 (97%) (p = 0.0052). Lastly, the mean score for the check-all-that-apply question which asked, “What are some of the personal health risks an assigned female at birth with an identified premutation may have?” (Q8), increased from 0.46/1 to 0.64/1 point (p = 0.0014). When asked on the post-intervention survey if participants would be printing the tool, the majority reported that they would be.

Fig. 3.

Comparison of knowledge on the pre- vs. post- intervention survey for Question 11: “In the setting of absent menstrual cycles and an elevated FSH, which test would be indicated as a next step?”

Predictors of knowledge

Significant differences between pre-intervention knowledge score and post-intervention knowledge score are shown in Table 1. There were four significant predictors of knowledge on the pre-intervention survey: provider type, provider specialty, the presence of a GC in the clinic, and graduate/medical school graduation year (Fig. 2A–D). For the provider type ANOVA model, four groups were compared: (1) physicians, (2) trainee physicians (fellows and residents), (3) PAs, and (4) NPs and nurse midwives. Physicians performed significantly better than NPs and nurse midwives, scoring on average 1.2 points (10%) higher (p < 0.0128). Physicians on average scored a 7.9/12 (66%); whereas, on average, NPs and nurse midwives scored a 6.6/12 (55%) (Fig. 2A). For provider specialty, three groups were compared: (1) General OBGYN, (2) REIs and MFMs, and (3) all other specialties (see Table 1). REIs and MFMs performed significantly better than both other groups (p < 0.0001). The average REI/MFM score was 8.9/12 points (74%) (Fig. 2B). All other specialties scored below 67%. Providers who had a GC in the clinic scored one point higher, 8.0/12 (67%), than providers with no GC in the clinic, 7.0/12 (58%) (p = 0.0128) (Fig. 2C). Lastly, four groups were compared based on the year providers graduated from graduate/medical school: (1) 1975–1999, (2) 2000–2009, (3) 2010–2019, and (4) 2020 or later. Providers who graduated between 2010 and 2019 had a significantly higher knowledge score of 7.8/12 (65%) compared to those who graduated in 2020 or later, scoring 6.5/12 (54%) (p = 0.0348) (Fig. 2D). Variables that did not show significant differences include practice environment, provider sex, exposure to genetics in training, geographic location, and patient insurance type. There were no predictors of knowledge identified for the post-intervention survey.

Fig. 2.

A–D Mean knowledge scores of significant predictor variables on the pre-intervention survey. Significant differences between groups as determined by Tukey’s post hoc analysis are indicated in brackets; NP, nurse practitioner; CNM, certified nurse midwife; PA, physician assistant

Because these predictors of pre-intervention knowledge could be correlated, we tested a final ANOVA model with all significant predictors (i.e., provider type, provider specialty, the presence of a GC in the clinic, and graduate/medical school graduation year). We then used a backwards elimination method to identify which variable(s) showed the highest level of significance. The final model included specialty (p = 0.0002) and graduation year (p = 0.1464). Although the variable for school graduation year did not reach significance, Tukey’s post hoc test identified a significant difference between the 2010–2019 and ≥ 2020 groups, as previously described.

POI questions

To better understand if providers are aware of the characteristic POI symptoms and explore their typical workup for a patient who has POI symptoms, we asked two additional questions on the pre-intervention survey. The majority of participants (72/96, 75%) were able to correctly identify irregular menstrual cycles and decreased AMH as signs/symptoms of POI. Few participants correctly identified all components of a comprehensive workup for POI (6/96, 6%), with only one third selecting that they would do FMR1 genetic testing as part of their workup (34/96, 35%), despite FMR1 testing being part of ACOG guidelines for POI diagnostic workup [11].

Carrier screening questions

Due to current carrier screening recommendations and the inclusion of FMR1 on expanded carrier screening panels, we asked about when/if providers offer this testing and how comfortable they are with explaining carrier screening results in general [9, 14, 15]. Most participants (79/95, 83%) reported offering carrier screening in the preconception setting and during pregnancy. The majority of participants indicated that they were somewhat comfortable (41/95, 43%) or extremely comfortable (10/95, 11%) explaining carrier screening results in general; however, one third reported that they were somewhat uncomfortable (17/95, 18%) or extremely uncomfortable (14/95, 15%) explaining these results. There was not a significant relationship between demographic factors and carrier screening practices or comfort levels.

Discussion

This study was the first to examine the impact of an educational tool on women’s healthcare providers’ knowledge about FXPOI. Our results demonstrated that after being provided with this tool, women’s healthcare providers’ knowledge about FXPOI increased. It is encouraging that the majority of our 95 participants were OBGYNs (68%) and that they showed a significant increase in knowledge, from 59 to 71% (< 0.0001), since they are typically the initial providers a woman with POI symptoms may see [8]. The pre-intervention knowledge score supports previous research demonstrating the lack of women’s healthcare providers’ knowledge on FXPOI [8, 12, 16]. Our study aligns with previous data on the effectiveness of educational tools for patients and healthcare providers regarding their ability to improve knowledge [17, 18].

The pre-intervention survey noted several significant demographic associations with knowledge, including provider type, specialty, presence of a GC in the clinic, and graduate/medical school graduation year. These are in line with Singleton et al.’s [12] 2024 study results, which also found that MFM and REI providers scored significantly higher, and clinics with a GC employed in their clinic significantly outperformed those without one [12]. Our research found that physicians significantly outperformed NPs and nurse midwives, but not PAs, fellows, or resident physicians. Over half of the advanced practice providers (57%) reported that they did not have exposure to genetics in training, whereas 88% of physicians reported that they did have exposure to genetics in training.

Genetics is not a course that is typically mandatory in nursing school, and NPs choose a specific specialty to be further educated and trained in, which may or may not include genetics education [19, 20]. The American Association of Colleges of Nursing (AACN) requires nursing programs to incorporate the 45 “competencies” of nursing by AACN, which include “apply individualized information, such as genetic/genomic, pharmacogenetic, and environmental exposure information in the delivery of personalized health care” [21, 22]. Due to Women’s Health NPs becoming increasingly involved in offering and discussing carrier screening and other genetic tests, further genetics education may be needed [23]. The lack of required genetics exposure may explain some of these knowledge gaps in the pre-intervention survey.

Regarding specialty, physicians who work in reproductive endocrinology and maternal–fetal medicine had significantly higher knowledge scores than other specialty providers, including OBGYNs, despite genetics being part of the curriculum according to the Council on Resident Education in Obstetrics and Gynecology [24]. A study looking at OBGYN residents’ training, attitudes, and comfort level regarding genetics showed that 42% of OBGYN residents (n = 32/76) indicated their genetics education in residency was not sufficient [25]. Maternal–fetal medicine providers are required to spend 2 months of their fellowship in genetics, and the current REI standards recommend that fellowship programs consider experience in genetics as part of their core curriculum [26, 27]. The required/recommended genetic education and experience during REI and MFM fellowship likely contribute to their stronger knowledge of FXPOI. Our results emphasize the need for broader education among other specialties.

Providers who reported having a GC the in clinic had a significantly higher knowledge score than those without a GC the in clinic, scoring 8% higher on the pre-intervention survey than those without one (p = 0.0083). This result suggests that GCs are an asset to the healthcare team and providers who work with a GC are more educated on FXPOI. This aligns with the role of a GC, which includes sharing their knowledge and collaborating with members of the care team [28], as well as previous research that suggested providers who work with GCs are more educated on fragile X-associated conditions [12]. In addition to this, about one third of participants (33%) reported not feeling fully comfortable explaining carrier screening results to patients. GCs are thoroughly educated on carrier screening, the technology involved, and how to interpret results for patients. According to the “Practice Based Competencies for Genetic Counselors,” analyzing family history to estimate genetic risk and demonstrating knowledge of genetic testing methodologies and variant interpretation are both competencies that a GC should have [28].

There are only about 7000 GCs in the U.S. with about 25% of them working in the reproductive setting, meaning there are not enough GCs to provide individual education to each patient about carrier screening results [29]. Due to the gap in knowledge on the fragile X PM among women’s healthcare providers and the lack of feeling comfortable when explaining carrier screening results, further education is needed to improve providers’ ability to explain complex carrier screening results.

Lastly, there was a significant difference in knowledge score on the pre-intervention survey for providers who graduated between 2010 and 2019 versus those who graduated in 2020 or later. Providers who graduated between 2010 and 2019, on average, scored 65% compared to those who graduated in 2020 or later, who scored an average of 54% (p = 0.0348). Two possible reasons for this knowledge difference may be due to the providers who graduated earlier than 2020 having more clinical experience and/or the impact of COVID on provider education from 2020 to 2022. A survey that was taken by 104 first- and second-year medical students at the University of California San Diego School of Medicine in March 2020 revealed that most students felt that the remote learning transition somewhat or very negatively affected the quality of their instruction. Notably, 43.3% of second-year students felt unprepared for their clerkships, and 56.7% did not feel prepared for their United States Medical Licensing Examination Step 1 exam. Most students (66.2%) were not satisfied learning practice-oriented subjects such as anatomy online [30, 31]. Regardless, this significant difference is still surprising due to increasing research on FXS and fragile X-associated conditions as well as professional organizations recommending carrier screening that includes the FMR1 gene [9].

A statistically significant increase was seen for 5/12 questions, including how many CGG repeats constitute a PM, how many CGG repeats place an individual who is AFAB at the highest risk for FXPOI, what abnormal hormone testing is confirmatory for POI and warrants FMR1 genetic testing, and what personal health risks are for an individual who is AFAB with a PM (Q8, Q9, Q10, Q11, Q15). Although the other survey questions regarding symptoms of FXPOI, family history that raises suspicion for a fragile X PM, appropriate long-term care for FXPOI, comorbidity risks associated with FXPOI, reproductive considerations for women with a PM, and pedigree analysis for what CGG repeat number places women at the highest risk for FXPOI were not statistically significant, the majority of these questions had a high baseline knowledge score (Q5, Q6, Q7, Q12, Q13, Q14, Q16). Information regarding all the questions stated above is in the educational tool. If women’s healthcare providers can incorporate this knowledge into their clinical practice, women with FXPOI may be diagnosed sooner, have a more positive experience with their healthcare provider, and have improved health outcomes.

Awareness of the number of CGG repeats that place women at the highest risk for FXPOI can improve management by allowing for a more personalized risk assessment for age at menopause, which is important for family planning, establishing specialty care sooner, and potentially reducing the psychological burden that many women experience with the FXPOI diagnostic odyssey [5, 8]. We saw a significant increase in knowledge score in providers recognizing that women with 80–100 repeats are at the highest risk for FXPOI, increasing from 15.9 to 62.1%.

Knowing recommended genetic testing procedures after specific abnormal hormone testing results have confirmed a POI diagnosis is vital, as this can lead to an earlier FXPOI diagnosis. When participants were asked which test they would order in the setting of absent menstrual cycles and elevated FSH, 19.1% on the pre-intervention survey and 49.5% on the post-intervention survey answered correctly with FMR1 testing (Fig. 3). The American College of Obstetricians and Gynecologists recommends that all women with unexplained ovarian insufficiency or elevated FSH levels before age 40 have carrier screening to determine if an FMR1 PM is present [9]. While the significant increase seen is encouraging, we acknowledge that this may be an oversimplification for this complex medical diagnosis. Several of the other options may be tests that a clinician chooses to do first or concurrently with FMR1 testing, depending on the clinical scenario. This finding is consistent with previous research. Poteet et al. [8] found that women with FXPOI who presented to an OBGYN with menopause symptoms would often have their symptoms dismissed and fail to receive a proper hormone workup and FMR1 testing, delaying an FXPOI diagnosis. Singleton et al. [12] found on a survey question which reads, “A 25-year-old woman presents with inconsistent menstrual cycles, what are your next steps?” that many of the women’s healthcare providers do not complete an informative FXPOI workup, as many did not select the ACOG recommended FMR1 testing.

Lastly, understanding the personal health risks associated with a PM can lead to improved outcomes for women. The average score for identifying personal health risks for an individual who is AFAB with a PM was 46% on the pre-intervention survey and 64% on the post-intervention survey, indicating that despite the significant increase seen, there is room for providers to become more knowledgeable in this area (Q8). Women with FXPOI are at risk of osteoporosis, cardiovascular disease, and infertility, most of which have recommended preventative and therapeutic measures if a patient with POI is diagnosed promptly [4, 10]. Women with a PM are not only at risk for FXPOI, but also many other health complications, including but not limited to mental health problems, tremor, and ataxia [5].

According to ACOG guidelines, FMR1 testing should be a part of the diagnostic POI work-up. Despite these guidelines, only 35% of participants reported including this as part of their workup [9]. This indicates that providers may not be following the recommendations for steps to take after diagnosing POI. A potential nuance to this question may be the wording of the question. The check-all-that-apply question asked what the provider’s comprehensive workup was for a patient exhibiting POI symptoms, but providers may have only answered which steps they take to diagnose POI rather than all steps taken for diagnosing POI, including post-diagnosis tests.

We further investigated when/if carrier screening was offered and how comfortable providers were when explaining any type of result to patients, since ACMG recommends that FMR1 is included in carrier screening offered to patients and ACOG recommends it for women with a family history of fragile X-related conditions or intellectual disability suggestive of fragile X syndrome [9, 15]. If providers are regularly offering carrier screening before or during pregnancy, then women can be informed of their PM status earlier and be educated on the personal and reproductive risks associated with it. Furthermore, over half of the participants in our survey reported feeling “somewhat comfortable” or “extremely comfortable” (51/95) with explaining carrier screening results. If providers are not confident in their understanding of carrier screening or other genetic tests, patients may not be receiving the appropriate education regarding their PM status, further delaying proper clinical management.

This study further defines the knowledge gap seen in Singleton et al.’s [12] 2024 study and shows that our educational tool helped to bridge knowledge gaps seen among different provider types and other predictor variables. The significant improvement in knowledge regarding how many FMR1 CGG repeats place a woman at the highest risk for FXPOI, that FMR1 testing should be done after certain hormone levels and clinical signs and symptoms are seen, and personal health risks associated with a PM are promising results to see, as this knowledge can all lead to an earlier diagnosis and improved care for women with FXPOI. In addition, it is encouraging that there was a high baseline knowledge score and an increase in the knowledge score seen regarding FXPOI symptoms, long-term care, comorbidity risks, reproductive outcomes, and hormone levels indicative of FMR1 testing. However, there is still room for continued education, specifically regarding family history suggestive of a PM, when FMR1 testing should be ordered, and personal health risks associated with a PM. Our research suggests that our educational tool will be a useful resource for women’s healthcare providers and contribute to improved care for women with FXPOI.

Conclusions

In summary, we have created an educational tool that has helped bridge gaps in knowledge about FXPOI among women’s healthcare providers. Women with FXPOI are at an increased risk for infertility and other health complications associated with a hypoestrogenic state, but often experience a diagnostic odyssey. If providers continue to refer to this tool and share it among colleagues, POI symptoms could be recognized sooner, potentially improving the personal and reproductive health of women with FXPOI.

Limitations

Due to the recruitment methods, the study sample may be limited due to the possibility of self-selection bias. For participants who chose to be part of our study, they may have more knowledge or experience regarding FXPOI. Therefore, these results may not be generalizable to other specialties. A second limitation of this study is that participants were asked the same knowledge score questions on the pre- and post-intervention survey, meaning that the participants were aware of the questions prior to the post-intervention survey. While this can introduce a test–retest effect, we chose the paired effects design to control for individual differences to reduce variability. In addition, due to limited sample sizes for some predictors of knowledge variables, some groups were collapsed for analysis, which may limit interpretations specific to distinct groups (e.g., nurse midwives and nurse practitioners). Lastly, the relationship between provider survey answers and clinical practice behaviors is unknown. While the study may demonstrate an improvement in provider knowledge, this does not necessarily translate to a corresponding improvement in patient care.

Future directions

This study revealed the need for further education among OBGYNs and other advanced practice providers. Specific areas for further education should include FMR1 PM personal health risks and which symptoms and hormone levels indicate FMR1 testing. Other modes of education may include a live or recorded course on the PM and FXPOI, as well as education on other fragile X-associated conditions, such as FXTAS and FXAND. Lastly, further research could be focused on the impact of educational tools on clinical practice behaviors and whether knowledge is sustained over time.

Supplementary information

Below is the link to the electronic supplementary material.

Author contributions

EP and EGA conceived and designed the research with input from ALS, JM, DB, HH, NA, and LL. EP collected the data. EP and EGA analyzed the data. EP wrote the manuscript. All authors read and approved the manuscript.

Funding

Funding was provided by the National Fragile X Foundation, Georgia Association of Genetic Counselors, and the National Institute of Child Health and Human Development (P50HD104463).

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

The Emory Institutional Review Board reviewed the study’s design, protocol, and materials and determined that the study was exempt from further review (IRB#00005632).

Conflict of interest

Emily Peery, Alexandra Singleton, Jamie Merkison, Emily Allen, Heather Hipp, and Lauren Lichten declare that they have no conflicts of interest. Deanna Brockman is employed by Color Health. Nadia Ali has received research support from Sanofi Genzyme, Shire Takeda, BioMarin, Amicus, and Pfizer, as well as lecturers’ honoraria from Sanofi Genzyme, BioMarin, Amicus, and Vitaflo. These activities are monitored and in compliance with conflict of interest policies at Emory University.