By Michael A. Thomas, MD

Professor, Reproductive Endocrinology and Infertility; Director, Division of Reproductive Endocrinology and Infertility, University of Cincinnati College of Medicine

Dr. Thomas reports he receives grant/research support from Berlex, Agile, Medicines360, and Therapeutics MD.

Synopsis: Early follicular phase antral follicle count as a method of analyzing ovarian reserve is not helpful in predicting subsequent pregnancy in women with normal cycles.

Source: Ripley M, et al. Does ovarian reserve predict egg quality in unstimulated therapeutic donor insemination cycles? Fertil Steril 2015;103:1170-1175.

When couples or single women present to our offices with difficulty achieving pregnancy, we do everything we can — obtain a history, a thorough physical examination, limited laboratory testing, and imaging — to get an accurate picture of their chances of achieving pregnancy. If there is a male partner, it becomes somewhat easy to rule in or rule out a problem in the semen by obtaining a semen analysis. In contrast, evaluation of female infertility requires the clinician to address multiple factors, including ovulation potential, tubal patency, uterine cavity architecture, and hormonal issues. As part of the standard workup, healthcare providers increasingly rely on the use of ovarian reserve testing to assess the “number of eggs that are remaining.” Tests commonly used include either antral follicle count (AFC; transvaginal ultrasound assessment of antral follicles present in the early follicular phase), serum follicle-stimulating hormone (FSH; assessed on cycle day 3), or a serum anti-Müllerian hormone (AMH; assessed at any time during the menstrual cycle).1,2 Each of these has its merits and they often are used in combination.

With this in mind, investigators from Canada performed a retrospective cohort analysis of 459 eumenorrheic women who underwent 1107 unstimulated donor insemination cycles over 7 years. These women did not have a diagnosis of infertility, had a normal uterine cavity with patent tubes, and were either single, in a same-sex relationship, or had a partner with a severe male factor. All couples used cryopreserved sperm from a commercial sperm bank. Timing of insemination was performed using a urine luteinizing hormone (LH) surge test or by monitoring daily serum LH levels. AMH was not routinely used in their center and, therefore, was not measured in the study. All women underwent an AFC in the early follicular phase (cycle day 2-4). During this process, transvaginal ultrasound was used to count the number of follicles in both ovaries measuring 2-9 mm. A low AFC was determined to be 0-12 follicles, medium AFC 13-23 follicles, and high AFC 24 follicles. The age range was 23-46 years, and subjects were divided into three different age groups: 35 years of age (Group 1), 36-39 years of age (Group 2), and 40 years of age (Group 3). Participants were observed up to three cycles and a cumulative pregnancy rate was calculated. Clinical pregnancy was defined as a fetus with a heartbeat between 6-8 weeks. Miscarriage was defined as a positive beta hCG and no fetal heartbeat noted up to 10 weeks’ gestation. A total of 127 pregnancies was observed, with an overall clinical pregnancy rate of 12.46% and a multiple rate of 1.6%. Twenty of the 127 pregnancies resulted in miscarriage (13.61%). Pregnancy rates were noted to decline with increasing maternal age. However, within the same age group, the pregnancy rate was not different whether the AFC was low, medium, or high. Even when a secondary analysis was done where the AFC was further subdivided between very low, low, medium, and high, no difference in pregnancy rate was noted. Although miscarriage rates increased with increasing age, no differences were noted within age groups when AFC was analyzed.

COMMENTARY

Since most healthcare plans fail to cover fertility care, cost is an important factor to discuss with any woman/couple pursuing fertility treatments. Most of these treatment protocols include the use of clomiphene citrate, letrozole, and/or injectable gonadotropins with timed intercourse, insemination, or in vitro fertilization. This all amounts to costs ranging from hundreds to thousands of dollars. Since nearly all couples have failed to achieve pregnancy with natural or unstimulated cycles, this current Canadian trial may not be applicable to the usual couple pursuing fertility treatment in America.

In this country, neither patients nor health professionals have the time, financial resources or patience to undergo three full cycles without some type of intervention. Couples are distraught, expectations run high, and fertility practices compete vigorously for patients. Practices advertise their expertise (and higher-than-imaginable pregnancy rates) via social media, television ads, and carrier pigeon.

However, this study demonstrates that the majority of eumenorrheic women with normal uteri and open tubes who only need donor sperm really do not need the million-dollar workup. The use of ovarian reserve testing to predict the number of eggs still available is unnecessary. According to the latest guidelines by the Practice Committee of the American Society of Reproductive Medicine and a previous publication, all of the commonly used ovarian reserve tests available (day 3 FSH, AMH, or AFC) primarily help to predict how well someone will respond to ovulation induction medications rather than specifically predicting pregnancy outcomes.2,3 The Ripley study reviewed here provides additional evidence that ovarian reserve testing does not benefit women with normal cycles.

In essence, results from this study demonstrate that ovarian reserve testing is not a crystal ball to predict future pregnancy. This is an important clinical pearl. Although an older nulliparous woman may hope to gain confidence from ovarian reserve testing, it’s important to realize the clinical applicability of these tests. What you really do is counsel that fertility first begins with ovulatory cycles, a normal uterus, open tubes, and sperm. As we have known for many years, up to 85% of women younger than 35 years of age who are regularly exposed to sperm over 12 months will get pregnant.1 We continue to have a population explosion around the world due to this fact alone. The fertility process has been highly commercialized, and the Internet has exploded with numerous websites by trained and untrained “experts” who prey on the fears of people who may not actually have a problem. Therefore, it is difficult for American women to figure out who to trust when they have difficulty conceiving. The best bet for the majority of women may be regular timed intercourse with normal sperm (from a partner or donated) — no medications, no injections, and no testing, just reassurance and education from a healthcare provider who has her best interest at heart.

REFERENCES

  1. Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: A committee opinion. Fertil Steril 2012;98:302-307.
  2. Practice Committee of the American Society for Reproductive Medicine. Testing and interpreting measures of ovarian reserve: A committee opinion. Fertil Steril 2015;103:e9-e16.
  3. Chang MY, et al. Use of the antral follicle count to predict the outcome of assisted reproductive technologies. Fertil Steril 1998;69:505-510.