Recommendations and Conclusions
The American College of Obstetricians and Gynecologists (ACOG) and the American Society for Reproductive Medicine (ASRM) make the following recommendations and conclusions:
- An infertility evaluation may be offered to any patient who by definition has infertility or is at high risk of infertility.
- Women older than 35 years should receive an expedited evaluation and undergo treatment after 6 months of failed attempts to become pregnant or earlier, if clinically indicated. In women older than 40 years, more immediate evaluation and treatment are warranted. If a woman has a condition known to cause infertility, the obstetrician–gynecologist should offer immediate evaluation.
- A comprehensive medical history, including items relevant to the potential etiologies of infertility, should be obtained from the patient and partner, should one exist.
- A targeted physical examination of the female partner should be performed with a focus on vital signs and include a thyroid, breast, and pelvic examination.
- For the female partner, tests will focus on ovarian reserve, ovulatory function, and structural abnormalities.
- Imaging of the reproductive organs provides valuable information on conditions that affect fertility. Imaging modalities can detect tubal patency and pelvic pathology and assess ovarian reserve.
- A women’s health specialist may reasonably obtain the male partner’s medical history and order the semen analysis. Alternatively, it is also reasonable to refer all male infertility patients to a health care specialist with expertise in male reproductive medicine.
Infertility, defined as failure to achieve pregnancy within 12 months of unprotected intercourse or therapeutic donor insemination in women younger than 35 years or within 6 months in women older than 35 years, (1, 2) affects up to 15% of couples (3). It is common for an infertile woman initially to seek care from her obstetrician–gynecologist. The basic infertility evaluation is summarized in Table 1. An infertility evaluation may be offered to any patient who by definition has infertility or is at high risk of infertility. Women older than 35 years should receive an expedited evaluation and undergo treatment after 6 months of failed attempts to become pregnant or earlier, if clinically indicated. In women older than 40 years, more immediate evaluation and treatment are warranted (4). Additionally, if a woman has a condition known to cause infertility, the obstetrician–gynecologist should offer immediate evaluation (1). Indications for immediate evaluation include the following:
- oligomenorrhea or amenorrhea
- known or suspected uterine, tubal, or peritoneal disease
- stage III or stage IV endometriosis and
- known or suspected male infertility
This Committee Opinion focuses on the evaluation of opposite-sex couples; for information on family building for lesbian, gay, bisexual, transgender, queer, intersex, asexual, and gender nonconforming individuals, see ACOG Committee Opinion No. 749, Marriage and Family Building Equality for Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual, and Gender Nonconforming Individuals and ASRM’s Access to Fertility Treatment by Gays, Lesbians, and Unmarried Persons (5, 6).
Prepregnancy Counseling and Evaluation
Prepregnancy care is important to reduce the risk of adverse health effects for the woman, fetus, and neonate by working with the woman to optimize health, address modifiable risk factors, and provide education about healthy pregnancy. The American College of Obstetricians and Gynecologists and ASRM provide an overview of prepregnancy counseling and recommendations for counseling, infectious disease screening, immunization, genetic counseling and screening, and more in Committee Opinion No. 762, Prepregnancy Counseling (7). This also is the opportunity to educate women about methods to maximize fertility, including timing and frequency of intercourse.
Female Factor Infertility
The obstetrician–gynecologist often is the first health care provider women will seek for evaluation or concerns about fertility. Essential components of an initial workup include a review of the medical history, physical examination, and additional tests as indicated.
A comprehensive medical history, including items relevant to the potential etiologies of infertility, should be obtained from the patient and partner, should one exist. Key historical factors to elicit from the patient include the following (3):
- duration of infertility and results of any previous evaluation and treatment
- menstrual history (including age at menarche, cycle interval, length, and characteristics; presence of molimina [mild premenstrual symptoms and changes]; and onset and severity of dysmenorrhea), signs of ovulation including positive ovulation tests, cervical mucus changes, or biphasic basal body temperatures
- pregnancy history (gravidity, parity, time to pregnancy, fertility treatments, pregnancy outcome, delivery route, and associated complications)
- previous methods of contraception
- coital frequency and timing
- sexual dysfunction
- past surgery (procedures, indications, and outcomes) focused on abdominal and pelvic procedures
- previous hospitalizations, serious illnesses, or injuries
- gynecologic history (eg, pelvic inflammatory disease, sexually transmitted infections, endometriosis, leiomyomas)
- sexual history
- review of organ systems, including history of thyroid disease, galactorrhea, hirsutism, pelvic or abdominal pain, and dyspareunia
- previous abnormal cervical cancer screening tests and any subsequent treatment
- current medications and supplements, with an emphasis on identifying allergies and potential teratogens
- family history of birth defects, developmental delay, early menopause, or reproductive problems
- occupation and exposure to known environmental hazards and
- use of nicotine products, alcohol, and recreational or illicit drugs
A targeted physical examination of the female partner should be performed with a focus on vital signs and include a thyroid, breast, and pelvic examination. Key physical factors include the following (3):
- weight, body mass index, blood pressure, and pulse
- thyroid enlargement and presence of any nodules or tenderness
- breast secretions and their character
- signs of androgen excess
- tanner staging of breasts and pubic and axillary hair
- vaginal or cervical abnormality, secretions, or discharge
- pelvic or abdominal tenderness, organ enlargement, or masses
- uterine size, shape, position, and mobility
- adnexal masses or tenderness and
- cul-de-sac masses, tenderness, or nodularity
Additional Evaluation for Etiology of Infertility
The infertility workup includes laboratory and imaging tests. For the female partner, tests will focus on ovarian reserve, ovulatory function, and structural abnormalities. Certain fertility tests have a low yield in identifying modifiable diagnoses, do not distinguish women who will and will not become pregnant, add significant expense, or are associated with harms that outweigh demonstrable benefit (Box 1). Although there may be other reasons for these tests to be done, they are low yield for infertility evaluation. Imaging of the reproductive organs provides valuable information on conditions that affect fertility. Imaging modalities can detect tubal patency and pelvic pathology and assess ovarian reserve.
Diminished Ovarian Reserve
The reproductive potential of the ovaries, termed ovarian reserve, represents the number of oocytes available for potential fertilization at that point in time and may be assessed by serum tests or ultrasonography. The presence of decreased ovarian reserve predicts future response to ovarian stimulation (8). The results of ovarian reserve tests should be considered in the context of the patient’s age. Although there are no definitive criteria for diminished ovarian reserve, the following values may be considered consistent with diminished ovarian reserve:
- antimüllerian hormone (AMH) value less than 1 ng/mL
- antral follicle count less than 5–7 and
- follicle-stimulating hormone (FSH) greater than 10 IU/L or
- a history of poor response to in vitro fertilization stimulation (fewer than four oocytes at time of egg retrieval).
Ovarian reserve can be assessed by measuring estradiol and FSH between cycle days 2–5. Follicle-stimulating hormone values greater than 10 IU/L are associated with a less robust response to ovarian stimulation (9). Estradiol serves as an aid for interpreting FSH results. Basal estradiol levels typically should be less than 60–80 pg/mL; elevated estradiol levels may have a suppressive effect on FSH levels and are indicative of decreased ovarian reserve (3). Serum AMH is produced by the granulosa cells of antral follicles and, therefore, is another serum marker of ovarian reserve. Because AMH levels remain relatively stable throughout the menstrual cycle, they can be assessed on any day of the menstrual cycle (10, 11). Antimüllerian hormone is similar to antral follicle count in its ability to predict response to ovarian stimulation and pregnancy in infertile women (12). Ovarian reserve tests are good predictors of response to ovarian stimulation, but poor results do not necessarily predict inability to achieve a live birth (3, 13, 14). If a woman has unexplained ovarian insufficiency or failure or an elevated FSH level before age 40 years, fragile X carrier screening is recommended to determine whether she has an FMR1 premutation (15).
Ultrasonographic assessment of the antral follicle count is determined by the number of follicles that measure 2–10 mm in both ovaries. Low antral follicle count may be defined as fewer than 5–7 follicles and is associated with poor response to ovarian stimulation (16). However, antral follicle count is a relatively poor predictor of future ability to become pregnant. Antral follicle counts may be elevated in women with polycystic ovary syndrome (PCOS) or depressed in those women with hypothalamic amenorrhea or those using certain hormonal contraceptives (17).
Ovulatory dysfunction (defined as a history of oligomenorrhea or amenorrhea or as luteal progesterone levels repeatedly less than 3 ng/mL, or both) accounts for a significant proportion of female infertility (18). For many women, menstrual history may be enough to assess ovulatory function. Clinical history can be used to assess ovulatory cycles because most ovulatory women will have regular menstrual cycles every 25–35 days accompanied by moliminal symptoms (3). However, up to one third of women with normal menstrual cycles are anovulatory; therefore, confirmation of ovulation should be considered (19). Objective quantification of ovulation also can be obtained with a midluteal progesterone measurement, positive luteinizing hormone tests, biphasic basal body temperatures, or cervical mucus changes. A progesterone value greater than 3 ng/mL is evidence of ovulation (20). Progesterone production from a postovulatory corpus luteum is dependent on luteal hormone stimulation and is, therefore, highly pulsatile above this minimal threshold of 3 ng/mL (21). Because luteal serum progesterone levels can fluctuate by sevenfold over a few hours, a single progesterone value greater than 3 ng/mL should be used to confirm ovulation and not to assess the quality of the luteal phase (3, 21).
Anovulation may be related to obesity, hypothalamic and pituitary dysfunction, PCOS, and other etiologies. Polycystic ovary syndrome is the most common cause of ovulatory infertility (22, 23). There is no universally accepted definition of PCOS; however, it may be diagnosed based on the National Institutes of Health, Rotterdam, or Androgen Excess and PCOS Society criteria (24–26). Although many women with PCOS will present with a chief report of infertility, obstetrician–gynecologists and other gynecologic care providers should be mindful of other potential health risks. Women in whom PCOS has been diagnosed are at increased risk of metabolic syndrome, related adverse cardiovascular events, and poor pregnancy outcomes (27). All women in whom PCOS is diagnosed should be screened for metabolic syndrome with measurements of waist circumference, blood pressure, fasting lipid panel, and glucose tolerance testing.
Thyroid disease and hyperprolactinemia can cause ovulatory dysfunction, ranging from an inadequate luteal phase to oligo-ovulation to amenorrhea. Serum thyrotropin should be measured in women with ovulatory dysfunction, infertile women, or those with signs of thyroid disease. Serum prolactin should be measured in infertile women with irregular menses or other signs and symptoms of hyperprolactinemia.
Hysterosalpingography (HSG), a procedure used to view the uterus and fallopian tubes by injecting radiopaque contrast through the cervix during fluoroscopy, is most commonly used for determination of tubal patency. Proximal and distal tubal occlusion, peritubal adhesions, and salpingitis isthmica nodosa may be seen with HSG. The positive predictive value and negative predictive value of HSG for assessing tubal patency have been estimated as 38% and 94%, respectively (28). Given the low positive predictive value, an HSG that demonstrates nonpatency may require further evaluation to confirm tubal occlusion (3).
Sonohysterography is the visualization of the uterus and adnexa ultrasonographically with the infusion of fluid through a transcervical catheter (29). An extension of sonohysterography, hysterosalpingo-contrast sonography determines tubal patency with the use of fluid through a transcervical catheter. The technique often uses a contrast agent with air bubbles to aid in identification of the tubes, which are not usually seen ultrasonographically. There are no U.S. Food and Drug Administration-approved contrast agents for hysterosalpingo-contrast sonography; however, studies have been performed using agents such as perflutren lipid microspheres and sulfur hexafluoride lipid-type A microsphere, as well as agitated saline. The accuracy of hysterosalpingo-contrast sonography may be more dependent on operator experience than HSG. The sensitivity of hysterosalpingo-contrast sonography for determination of tubal patency ranges from 76% to 96%, although the specificity ranges from 67% to 100% (30, 31). The role of contrast sonohysterography in determining tubal patency is evolving as more data on its use are available.
Uterine factors associated with infertility include endometrial polyps, synechiae, müllerian anomalies, and leiomyomas. Leiomyomas with a surgically modifiable effect on fertility include those with a submucous or endometrial cavity-distorting component (32). Myomectomy generally is not advised to improve pregnancy outcomes in asymptomatic infertile women with noncavity-distorting myomas (32). Using sonohysterography, the uterine cavity usually is easily defined, and abnormalities such as endometrial polyps, submucosal fibroids, and intrauterine adhesions can be seen. More than 16% of infertile women and 40% of women with abnormal uterine bleeding will have an abnormality on sonohysterography (33). Sonohysterography has a sensitivity and specificity of 91% and 84%, respectively, for the detection of intrauterine structures that may be polyps or leiomyomas (34). Transvaginal ultrasonography aids in detection of uterine leiomyomas that affect the uterine cavity. Size, number, and location of uterine leiomyomas can be determined with sonohysterography, which may aid in planning fertility treatment. Use of three-dimensional ultrasonography improves detection of müllerian anomalies and is comparable to pelvic magnetic resonance imaging in diagnostic accuracy for this condition (35).
Direct visualization of the uterine cavity by hysteroscopy provides the most definitive method for diagnosis of endometrial polyps, uterine synechiae, and submucosal fibroids. Hysteroscopy is not as commonly used for initial evaluation of women with infertility because of cost and access considerations. Additionally, other methods of uterine cavity assessment, such as ultrasonography, offer the advantage of concurrent imaging of the adnexa. Hysteroscopy is indicated to confirm and treat intracavitary lesions detected by other imaging modalities.
Hysterosalpingography is limited in its ability to identify uterine cavity masses or adhesions because these structures are not radio-opaque. Thus, HSG relies on visualization of the mass effect of uterine lesions to identify an abnormality. The sensitivity of HSG for uterine cavity polypoid lesions is only 50% (36). Müllerian anomalies can be detected with HSG, although other imaging modalities are needed to differentiate and confirm the final diagnosis. Magnetic resonance imaging and three-dimensional ultrasonography provide more accurate definition of müllerian anomalies.
Male Factor Infertility
Male factor is a cause of infertility in 40–50% of couples (37). Given the high prevalence of male factor in infertile heterosexual couples, a basic medical history and evaluation of the male partner are warranted from the outset. The minimal evaluation of the male partner includes a reproductive history and semen analysis (38) (Table 2). A women’s health specialist may reasonably obtain the male partner’s medical history and order the semen analysis. Alternatively, it is also reasonable to refer all male infertility patients to a health care specialist with expertise in male reproductive medicine. Any abnormality noted on the male history or semen analysis warrants referral to a specialist trained in male infertility (eg, a reproductive urologist or reproductive endocrinologist) for a complete evaluation (38).
The following list details the specific key male historical factors to elicit (38):
- coital frequency and timing
- any evidence of sexual dysfunction, including erectile or ejaculation issues
- duration of infertility
- prior fertility
- childhood illness and developmental history
- systemic medical illness
- previous surgery (eg, cryptorchidism with or without surgery)
- medication use, including anabolic steroids and supplements (eg, testosterone), and allergies
- sexual history and sexually transmitted infections and
- exposure to gonadal trauma or toxins.
Semen analysis is the quantitative microscopic evaluation of sperm parameters. Two to five days of abstinence are optimal before semen analysis. Ideally, the sample is obtained by masturbation in the laboratory collection room. Semen collection at home is possible if the sample is transported at room or body temperature for evaluation within 1 hour. Abnormalities on semen analysis warrant repeat testing and further investigation. Several methods for evaluating semen analysis exist (Table 2).
Unexplained infertility may be diagnosed in as many as 30% of infertile couples (39). Unexplained infertility occurs when the definition of infertility is met, the basic infertility evaluation is performed, and all the tests results are normal. At a minimum, these patients should have evidence of ovulation, tubal patency, and a normal semen analysis (39).
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