Physicians who care for women having difficulty conceiving must understand the devastation their patients feel while knowing how to define infertility, when (and when not) to advise an evaluation, and offer evidence-based treatment options. Analogous to a mother desiring an antibiotic prescription for her child’s common cold, infertility patients can be desperate for an evaluation and treatment, despite the lack of an indication. This month’s article addresses the diagnosis and management of unexplained infertility.
Dr. Mark P. Trolice
The chronological age of a woman is the leading prognostic factor for successful reproduction. The definition of infertility remains 1 year of an inability to conceive in a couple who have no demonstrable risk factors, such as ovulation dysfunction, prior infertility, or known male factor. In women less than age 30, monthly fecundity rates are between 20% and 37% during the first 3 months of trying to conceive. The chance of success increases to 80% after 1 year and 90% after 2 years of trying to conceive, according to the American Society of Reproductive Medicine. Nevertheless, following unsuccessful attempts at conception by a couple, the physician should offer an evaluation based on the woman’s age – 1 year for women less than age 35, 6 months for women aged 35-39, and 3 months for women aged 40 and older. Testing can be initiated earlier if there are predisposing factors impairing fertility.
The basic infertility evaluation consists of a thorough history of the couple, a review of medical records, and an assessment of ovulation, fallopian tube patency, and sperm parameters on analysis. In the interest of efficiency, given that couples are typically anxious, these three areas can be evaluated within 1 month. In years past, a diagnostic laparoscopy was considered the gold standard of necessity to provide the diagnosis of exclusion, that is, unexplained infertility. This surgical procedure has fallen out of favor given the low diagnostic yield in a woman with a normal hysterosalpingogram, pelvic ultrasound, and no risk for a pelvic factor; for example, prior abdominal myomectomy, bowel surgery, or strong suspicion for endometriosis based on symptoms including significant pelvic pain affecting activities of daily living.
Initial laboratory testing should be judiciously ordered by recommending only those that will affect management, that is, prenatal labs to assess immunity to rubella and varicella along with a baseline thyroid-stimulating hormone, CBC, blood type, and Rh and antibody screen. In a woman with monthly ovulatory menstrual cycles and no signs of hirsutism or galactorrhea, the clinical utility of obtaining follicle-stimulating hormone, luteinizing hormone (LH), estradiol, prolactin, total and free testosterone, and dehydroepiandrosterone lack evidence. Further, a random anti-Müllerian hormone (without prior chemotherapy, radiation, or ovarian surgery) lacks value as the natural pregnancy rate does not appear to be affected, although low AMH has been associated with an increased risk for miscarriage.
Although not typically screened, measles can cause significant complications in pregnancy including an increased risk of maternal hospitalization and pneumonia, as well as miscarriage, stillbirth, low birth weight, and increased risk of preterm delivery.
Education is an important tool to guide patients and begins with an explanation of urine LH timed intercourse. From the onset of the LH surge, the oocyte is released in 24-36 hours, i.e., the actual day of ovulation is estimated to be the day after the urine LH surge. The “fertile window” appears to be the 5 days before plus the day of ovulation but the highest chance of conception occurs within the 2 days before and including the day of ovulation.
Empiric treatment may be offered when no demonstrable etiology has been identified, lifestyle factors have been addressed (for example, elevated female body mass index, tobacco use by the couple), and medical conditions have been optimized. Reproductive capability declines with continued attempts at conception such that, by 2 years, the approximate monthly fecundity rate is 3%-4%.
The first-line treatment of unexplained infertility is clomiphene citrate (CC) with intrauterine insemination. Letrozole, while not Food and Drug Administration approved for infertility treatment, has been shown in multiple studies to be equally effective as CC and to have a good safety profile. In a recent study, the cumulative live-birth rate over three cycles with CC and IUI, compared with expectant management was 31% versus 9%, respectively. Further, multiple studies failed to show a difference in pregnancy outcomes when comparing CC and IUI with letrozole and IUI.
It is vital to note that, for women who ovulate, studies do not support the use of CC without the addition of intrauterine insemination (IUI). The monthly fecundity rate of a cycle of CC without IUI is similar to natural conception attempts with urine LH timed intercourse, that is, without ovarian stimulation.
Recommendations (along with the level of evidence) from ASRM guidelines
- 1. Natural cycle, that is, without ovarian stimulation, timed with IUI is equivalent to expectant management (strong)
- 2. CC or letrozole with timed intercourse is no more effective than a natural cycle (good)
- 3. Pregnancy rates using gonadotropins with timed intercourse have not been shown to be superior to oral ovarian stimulating medications but risks multiple gestation (insufficient)
- 4. CC plus standard-dose gonadotropins results in higher pregnancy rates, there is good evidence for an increased risk of multiple gestation (fair)
- 5. Treatment with gonadotropins alone with IUI is superior to CC or letrozole with IUI; the risk of a multiple gestation rate remains significant (insufficient)
- 6. IUI can be performed between 0 and 36 hours following human chorionic gonadotropin trigger and performing one IUI in a cycle has equivalent success as two (fair)
- 7. Immediate IVF in women older than 38 years may be associated with a higher pregnancy rate and shorter time to pregnancy, compared with ovarian stimulation/IUI cycles before IVF (good)
Conclusion
It is recommended that couples with unexplained infertility initially undergo a course (typically three or four cycles) of ovarian stimulation with IUI using oral agents (CC or letrozole). For those unsuccessful with ovarian stimulation and IUI treatments with oral agents, in vitro fertilization is recommended rather than ovarian stimulation and IUI with gonadotropins to reduce the risk of a multiple gestation.
Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. Email him at obnews@mdedge.com.