Infertility is the inability to achieve pregnancy after 12 months of trying to conceive. Infertility workup should begin immediately if any risk factors exist, or begin after 6 months of trying to conceive for females age 35 to 39, or after 12 months if younger than age 35. Workup for females includes a comprehensive medical history with examinations, laboratory tests, and imaging to assess ovulation, ovarian reserve, uterine anatomy, and tubal patency. The authors would like to highlight our use of “female” and “male” as referring to reproductive anatomy or sex assigned as birth and not gender identity.
Key points
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Primary care providers can offer initial infertility evaluation and medical treatments to their patients.
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Factors contributing to infertility include both female and male factors, with most factors possible to identify with an initial laboratory and imaging workup.
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Female infertility is most commonly caused by ovulatory dysfunction, but may also be caused by structural disease of pelvic organs.
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Medications such as letrozole can induce ovulation and increase fertility rates.
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Access to fertility care in primary and speciality care centers is limited by many barriers, and advocacy is needed to promote a person’s ability to start a family.
| AMH | anti-Mullerian hormone |
| ART | assisted reproductive technology |
| CD | cycle day |
| FSH | follicle stimulating hormone |
| HSG | hysterosalpingogram |
| HyCoSy | hysterosalpingo-contrast sonography |
| IUI | intrauterine insemination |
| IVF | in vitro fertilization |
| LH | luteinizing hormone |
| MLP | mid-luteal progesterone |
| OPK | ovulation prediction kit |
| PCP | primary care physician |
| RJ | Reproductive Justice |
| TSH | thyroid stimulating hormone |
| TVUS | transvaginal ultrasound |
| WHO | World Health Organization |
Definitions
Infertility is clinically defined as the inability to achieve pregnancy within 12 months of trying to conceive for females under the age of 35, within 6 months if age 35 to 39, or sooner if age 40 and above.
Burden of disease
Clinical infertility affects about 10% to 15% of heterosexual couples, and the CDC estimates about 11% of females and 9% of males of childbearing age struggle with infertility. In the United States, approximately 12% of reproductive age females have received infertility services, and the use of assisted reproductive technology (ART), has increased approximately 25% in the last decade. ,
Barriers to care
Disparities exist in access to infertility care. Compared with White women in the United States, Black women experience higher rates of infertility, a longer time to evaluation, lower treatment utilization, and poorer treatment outcomes. , Sexual or gender minorities and unpartnered individuals may also need fertility assistance for family building but do not always meet definitions of clinical infertility to qualify them for infertility services. Sexual and gender minorities, individuals who are not married, individuals with lower incomes, and individuals with disabilities face heightened barriers and discrimination in accessing infertility care. ,
SisterSong defines Reproductive Justice (RJ) as “the human right to maintain personal bodily autonomy, have children, not have children, and parent the children we have in safe and sustainable communities.” In the United States, about 12 million people experience infertility, with only approximately 1500 fellowship trained reproductive endocrinologists available, although mostly concentrated in urban areas. By expanding access to fertility care in the primary care setting, we support the full embodiment of RJ, by supporting those seeking to build families despite intersecting barriers to care.
Many primary care physicians (PCPs) currently provide a wide range of reproductive health care to patients who may not otherwise have access, including prenatal care, long acting reversible contraceptives, vasectomy procedures, and labor and delivery. Starting the conversation about fertility and first steps of diagnosis with a trusted PCP can increase access, equity, and alleviate barriers for our patients seeking to grow families.
Most insurances cover diagnostic workup of infertility, but because these services are not universally considered medically necessary, only 15 states require private insurers to cover some infertility treatment, with only one state requiring medicaid coverage for diagnostic workup and prescription drug coverage. , Experts in reproductive endocrinology (REI) and Obstetrics & Gynecology agree that in many cases, it is appropriate for PCPs to initiate the infertility evaluation. Lack of insurance coverage is still a barrier that prevents many PCPs from offering these services. In addition, lack of training in the diagnostic workup, medical treatment, and navigating insurance barriers also contributes to barriers in access to fertility care in the primary care setting.
Etiology
Causes of infertility include a broad range of factors including female factors (37%), male factors (8%), a combination of factors (35%), and unexplained factors (5%). , Common causes of female factor infertility are listed in Table 1 .
| Uterine factor (6%) | Endometrial polyps Leiomyomas (submucosal) Uterine synechiae Congenital uterine malformations |
| Tubal factor (14%) | Tubal obstruction or impaired tubal motility (secondary to sexually transmitted infections, pelvic inflammatory disease, abdominal or pelvic surgery, endometriosis) |
| Cervical factor (3%) | Stenosis Postsurgical scarring Decreased cervical mucus |
| Ovulatory dysfunction (21%) | WHO Class 1 (5%–10%)—hypogonadotropic hypogonadal anovulation (ie, excess/low body weight, decreased gonadotropin-releasing hormone [GnRH]) WHO Class 2 (70%–85%)—normogonadotropic normoestrogenic anovulation (ie, PCOS) WHO Class 3 (10%–30%)—hypergonadotropic hypoestrogenic anovulation (ie, primary gonadal failure) |
Infertility workup
Indications for Infertility Workup
Given 85% of infertility cases have an identifiable cause, workup should be offered once a patient meets clinical criteria for infertility. Workup should begin :
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After 12 months of trying to conceive if the female is younger than 35 years
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After 6 months of trying to conceive if the female is between age 35 and 40 years
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Immediately for females aged 40 and older
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Immediately for those in need of sperm donors (single people capable of pregnancy, same-sex couples)
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Immediately for those with risk factors for infertility (previous ovarian or tubal surgery, exposure to cytotoxic drugs such as chemotherapy, exposure to pelvic radiation, autoimmune disease, family history of early menopause or premature ovarian failure, endometriosis, testicular trauma, adult mumps, or evidence of sexual dysfunction)
For those who have not yet met the clinical definition of infertility, it is not recommended to initiate evaluation with laboratories or imaging. For females, evidence of functional ovulation is an excellent proxy for fertility. This is best demonstrated by regular monthly menstrual cycles with premenstrual symptoms such as chest tenderness, ovulatory pain, or bloating. General counseling on optimizing general health, preconception care, and counseling on timed intercourse should be offered.
The workup for females is described later, but it is suggested to initiate workup for each couple trying to conceive simultaneously as about 35% of infertility cases are due to a combination of factors.
Female Factor Infertility Workup
The general approach to clinical workup of female factor infertility involves evaluating 4 main physiologic and anatomic factors :
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Ovulation
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Ovarian reserve
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Uterine anatomy
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Tubal patency
Elements of history gathering and physical examination are shown in Table 2 .
| History | Elements of Examination |
|---|---|
| Medical history: sexually transmitted infections, pelvic inflammatory disease, abnormal pap smears and any follow-up treatment, hyper/hypothyroid symptoms, galactorrhea, hirsutism, chemo/radiation therapy, autoimmune disease, uterine fibroids, ovarian cysts, uterine polyps Surgical history: prior abdominal, uterine, or pelvic surgery Obstetric History Menstrual history: menarche, cycle length, presence of molimina, dysmenorrhea, oligo/amenorrhea, menopausal symptoms Sexual history: frequency of sperm introduction, dyspareunia Family history: Fragile X, premature ovarian failure, infertility Lifestyle: occupational/environmental exposures, exercise, stress, diet, smoking, alcohol | BMI Extremes Hypogonadic hypogonadism: primary amenorrhea with incomplete secondary sexual characteristics Turner syndrome: short body habitus, square chest, absent periods Endocrinopathy: thyroid examination, breast examination for galactorrhea Androgen excess: hirsutism, acne, male pattern baldness, virilization Chronic pelvic inflammatory disease or endometriosis: tenderness/masses in adnexae/posterior cul-de-sac, uterosacral ligaments, or rectovaginal septum Mullerian anomaly: vaginal/structural abnormality Uterine anatomic anomaly: uterine enlargement, irregularity, lack of mobility |
Laboratory infertility workup involves evaluation of ovulation and ovarian reserve as summarized in Table 3 . A history of oligomenorrhea or amenorrhea is clinically sufficient to establish anovulation, and further testing of ovulatory status is not needed. Ovulation can be confirmed by measuring serum mid-luteal progesterone (MLP). This test is best measured 1 week prior to menses, around cycle day (CD) 19 through CD 23. An MLP level above 3 to 5 ng/mL suggests the presence of ovulation. MLP levels above 10 to 12 ng/mL are usually needed to sustain pregnancy. A urinary home ovulation prediction kit (OPK) is another tool to confirm ovulation by measuring the physiologic surge in luteinizing hormone (LH) that occurs about 2 days prior to ovulation. If an MLP level or OPK does not suggest ovulation has occurred, laboratory workup for anovulation should follow, including a thyroid stimulating hormone (TSH), prolactin level, and workup for hyperandrogenism or polycystic ovarian syndrome (PCOS).
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