Moira Kyweluk, Ph.D., M.P.H.1, Eve C. Feinberg, M.D. 2
1University of Pennsylvania Perelman School of Medicine, Department of Medical Ethics and Health Policy
2Northwestern University Feinberg School of Medicine, Division of Reproductive Endocrinology and Infertility
Direct-to-consumer (DTC) hormone-based ovarian reserve testing is widely available in the United States through online companies operating in 47 states (New York, New Jersey and Rhode Island limit DTC testing). Hormone profiles vary by company; some include follicle stimulating hormone (FSH) and estradiol (E2) but all more controversially measure anti-Mullerian hormone (AMH). Increased focus on ovarian reserve screening parallels increased interest in planned oocyte cryopreservation (OC; i.e. egg freezing) and a multitude of companies are capitalizing on this market.
Companies currently offering testing in the United States include Modern Fertility, Future Family, LetsGetChecked, EggQ, and many others. Interested consumers input basic contact information and payment online; prices range from approximately $79-$399 USD and can often be paid for using a Flexible Spending Account (FSA) or Health Savings Account (HSA). A clinician affiliated with the company orders laboratory tests to be completed at a convenient local diagnostic laboratory (i.e., Quest, LabCorp) or via an at-home finger prick kit to be sent back to the company for in-house processing. Limited research by DTC testing companies and independent clinical investigations indicate that laboratory values obtained from finger prick kits are validated, and are comparable to samples obtained from venous blood draws (1–3). However, research into commercially-available assays indicates issues with the reliability of AMH measurement and issues with intra-subject reproducibility, and highlights issues with sample preparation and storage that may compromise test results (4). Furthermore, lack of an international guideline for laboratories or a standard reference preparation complicates comparison and subsequent interpretation of AMH results (4).
Direct-to-consumer ovarian reserve testing services are limited to hormone analysis, and do not include other tests such as an ultrasound with measurement of antral follicle count. Detailed reports with an explanation of the uses and limitations of test results as well as follow-up consultations vary by company. Testing is frequently marketed as a “fertility assessment” or “fertility hormone testing,” but these are misnomers as hormone levels indicate ovarian reserve, not fertility status. This distinction is critically important, but not necessarily understood by the consumer or adequately portrayed by company materials. AMH levels can neither be used to predict time to conception nor success of fertility treatment. (5,6). Practice guidelines from the American College of Obstetricians and Gynecologists discourage AMH testing in the general population (7). Similarly, committee guidelines published in 2015 from the American Soceity for Reproductive Medicine conclude the use of AMH as a routine screening tool in a low-risk population is not advisable (8).
Despite these data and recommendations, women in the US still seek hormone measures as baseline assessment for fertility potential. Hormone testing in a clinical setting, without medical insurance, can cost upwards of $1,500 (9). Medical insurance coverage for elective ovarian reserve assessment and OC procedures is limited in the US, since patients must typically receive an infertility diagnosis and seek care with a reproductive endocrinology and infertility (REI) specialist (10).
Direct-to-consumer medical tests are a key component of the emerging internet-facilitated reproductive health care market offering “physician expertise—without the clinic price,” (11). DTC testing companies purport to fill a perceived gap in reproductive healthcare, catering to consumers not yet ready to conceive, but who are interested in future biological parenthood. These companies primarily target women concerned about age-related fertility decline, those who are not partnered, or individuals who are prevented from attempting to conceive by barriers including gender identity or sexual orientation, or whose insurance status or financial circumstances prevent donor insemination attempts or preclude access to infertility care, notably LGBTQ+ individuals.
Disclaimers on DTC ovarian reserve testing and other fertility hormone assessment included by companies indicate the tests are only to be used for “wellness monitoring” and do not substitute for medical care. Nevertheless, these tests measure the same hormones offered by traditional reproductive healthcare providers. Company-affiliated providers may endorse re-testing hormones on a regular basis, regardless of the individual’s age or prior results, to detect any changes. Presently there are no data to support routine ovarian reserve assessment, and there are also no data to support repeated annual testing.
Recent 2018 practice recommendations by the ASRM recommended planned OC for all women concerned about age-related fertility decline. Increased consumer demand spurred the rise of clinics that cater exclusively to egg freezing patients. In the US, the average out-of-pocket cost without medical insurance of one cycle of oocyte retrieval and initial cryopreservation was $9,253 in 2017 (12). Startup companies offer out-of-pocket rates as low as $6,000 per cycle, including ovarian reserve testing assessing AMH, FSH, and estradiol levels, an ultrasound to measure antral follicle count, monitoring visits, egg retrieval, vitrification, and one year of storage (13). These clinics often solicit patients by offering free or steeply discounted ovarian reserve testing and consultation appointments. For example, Kindbody a New York-based private practice specializing in egg freezing, made headlines in 2018-2019 for operating a mobile company-branded “fertility van” in New York City, offering free AMH testing and brief consultations to interested women .
The unfortunate irony of the focus of ovarian reserve testing as a means to recruit patients for egg freezing is that patients with the lowest AMH will have the highest cycle cancellation rates and poorest outcomes when trying to freeze eggs (14). Those with average or robust ovarian reserve measures may mistakenly assume they are not at risk for age related fertility decline and forgo OC. Ovarian reserve markers predict performance during gonadotropin stimulation; age remains the best predictor of fertility potential and fecundability and should be the main metric used to open a clinical discussion about egg freezing (13). Ultimately, the decision to pursue OC must be separated from a one-time or repeat assessment of ovarian reserve.
The growing use of blood serum AMH level alone as a screening test for infertility is inappropriate. Screening tests are used to determine whether an asymptomatic individual has an undetected disease or condition. A good screening test has the ability to detect disease at a stage when treatment would be more effective than after symptoms are present. The utility of a screening test is evaluated by sensitivity and specificity. Sensitivity is the probability that a patient with a positive test result has the disease, and specificity is the probability that a patient with a negative test does not have the disease. Sensitive tests are used to rule-in disease and specific tests are used to rule-out disease. In this case, infertility would be the undetected disease, but AMH testing does not meet criteria for a screening test as it neither rules in nor rules out infertility. In addition to these factors, the disease prevalence must also be taken into consideration. An abnormal AMH in a young patient is less worrisome for the risk of infertility than an abnormal AMH in an older patient. The positive predictive value of AMH will increase with the higher prevalence of infertility in an older population. However, the inclusion of AMH testing does not augment the predictive value of age alone (5).
The widespread proliferation of hormone-based “fertility assessments” by clinics and the availability of online DTC ovarian reserve testing in a healthy population should be directly addressed by the American Society for Reproductive Medicine. Surprisingly, some clinicians continue to call for more widely available AMH testing, encouraging all women—both those who have experienced infertility and those who are unaware of their fertility status—to be more aware of measures of ovarian reserve (15). Studies have demonstrated women are extremely interested in ovarian reserve testing and may modify their plans for childbearing if they receive results that suggest their ability to have children in the future may be at risk (16–18) . Many DTC companies support this framework as the judicious, responsible, and public health-focused use of ovarian reserve testing. Questions about patient/consumer autonomy, choice, and freedom in accessing biological information must remain separate from best practice guidelines supported by high-quality clinical research. Using unnecessary hormone testing to encourage patient awareness about proactive family planning or age-related fertility decline exploits a potentially vulnerable population. The ASRM can encourage public conversation and balanced media coverage about reproductive ageing and fertility preservation options without supporting widespread ovarian reserve testing. Low AMH level test results can cause alarm or unnecessary anxiety for patients with diminished ovarian reserve. Conversely, these tests may provide false reassurance to older patients about age-related fertility decline. It is critical for these patients to fully understand the limitations of these tests and that they do not predict fertility or time to conception. Similarly, leaving comprehensive counseling and follow-up care options to companies with a financial interest in encouraging one time or repeat ovarian reserve testing is not in the best interest of the patient/consumer.
The rapid increase in DTC and internet-facilitated medical care in the United States during the last decade, and more specifically DTC hormone testing options relevant to REI requires the ASRM to provide evidence-based guidelines for prospective consumers and patients seeking care outside of traditional medical encounters. An updated recommendation must also prepare member clinicians to counsel patients who present with test results obtained through DTC testing or other avenues, and to be sensitive to the needs and concerns of patients who pursue such testing.
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