Infertility

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[edit] Infertility

Edward H. Illions

Infertility is a relatively common disorder in the United States affecting 12% to 15% of married couples, many of whom seek medical care through their primary care physicians in their attempts to achieve a successful pregnancy outcome. The majority of managed care systems and insurance companies fail to provide adequate coverage for infertility evaluation and treatment, thereby placing undue financial and emotional stress on both the infertile couple and the physician. Although the percentage of infertile couples has not changed, the actual number of infertile patients seeking care has greatly increased in the last three decades, from 600,000 visits in 1968 to 1.35 million in 1988.^[1] Increased demand for infertility services mandates that primary care physicians develop an understanding of infertility tests and treatments.

Infertile couples are characterized by their inability to conceive within 1 year in the absence of contraception. Primary infertility reflects couples never having conceived, whereas couples with at least one successful conception are considered to have secondary infertility. The infertility evaluation commences after 1 year of unprotected coitus because approximately 50% of couples will conceive in 3 months, 75% at 6 months, and 88% to 90% will achieve a viable pregnancy after 1 year. Approximately 20% to 25% of couples will achieve a conception within a given menstrual cycle, referred to as fecundity. An increasing number of women over age 35 are seeking infertility services. In fact, one of every five U.S. women is having her first child after age 35, which reflects postponement of childbearing secondary to career and monetary issues. This aging infertile population represents a unique problem to infertility specialists and primary care physicians, given the well-documented age-related decline in fecundity. Tables 40-1 and 40-2 outline women's patient history and physical examination associated with fertility evaluation and infertility management.

Table 40-1 Female History and Fertility

✢Disrupts ovulation.

Table 40-2 Female Physical Examination and Fertility

✢Excess coarse terminal hair in midline distribution indicates increased androgen effects.

[edit] ETIOLOGIES

The reproductive potential of a female begins to decline in the early to middle 30s, with a marked reduction in fecundity beyond age 40. Career and financial considerations have prompted a delay in childbearing, along with associated factors, such as increased contraceptive use and increased prevalence of myoma and endometriosis in this age group. Ovarian function begins to diminish well in advance of the natural menopause and is the principal reason for diminished reproductive potential in this age group.^[2] Waning ovarian function is often indicated by progressive rise in serum follicle-stimulating hormone (FSH) levels obtained in the early proliferative phase of the menstrual cycle.^[3] Estrogen levels vary greatly in this age group and may be elevated. Collectively, these biochemical changes reflect ovarian reserve and provide indirect evidence of the functional capacity of the ovarian follicular apparatus.

An FSH value early in the proliferative phase is a useful screening test for ovarian reserve. FSH values are inversely related to successful pregnancy outcome. FSH values in excess of 20 mIU/ml indicate poor ovarian reserve, manifested by low clinical pregnancy rates with in vitro fertilization cycles.^[4] Determinations of both FSH and estradiol after the administration of Clomid (clomiphene citrate challenge test) provide a more expanded assessment of ovarian reserve.^[5]

[edit] Pelvic Infections

Postinfection tubal infertility accounts for approximately 30% to 40% of all female infertility. A steep rise in the incidence of sexually transmitted diseases (STDs) in the last 20 to 30 years has contributed greatly to both the risk of tubal infertility and the associated rise in ectopic pregnancies. Risk factors for pelvic inflammatory disease (PID) include young age, single marital status, multiple sexual partners, prior STD history, and illicit drug use. Chlamydia infection and gonorrhea are the two primary offending agents; however, many cases of PID involve polymicrobial infection. Prompt recognition and treatment are mandated because tubal factor infertility rises with subsequent tubal infections.

[edit] Lifestyle Factors

Lifestyle issues are associated with cigarette smoking, athletic activity and weight loss, alcohol, and illicit drugs. The detrimental effects on fetal development from cigarette smoking are well known. Despite a growing public awareness campaign linking these agents to adverse reproductive outcome, approximately 20% to 30% of young women continue to smoke. Cigarette smokers often experience early menopause because of oocyte depletion with a subsequent reduction in estradiol levels.^[6] Smoking cessation programs offer some promise; however, long-term compliance remains a significant health problem.

Significant data exist linking alcohol consumption to adverse reproductive outcome in both sexes. In utero fetal exposure to alcohol increases the incidence of growth retardation, craniofacial abnormalities, and developmental delay, collectively known as fetal alcohol syndrome. Males experience decreased testosterone levels, abnormal spermatogenesis, and subnormal sexual performance.^[7]

Strenuous exercising and low body weight (alterations in percentage of body fat) are independent risk factors for ovulatory dysfunction in young women.^[8] Major hypothalamic- pituitary-gonadal dysfunction with diminished gonadotropin and estradiol levels can occur when both risk factors are combined.

Anorexia nervosa represents an extreme example of hypothalamic-pituitary dysfunction. Serum gonadotropin levels are frequently undetectable in this setting. Intense psychologic counseling aimed at lifestyle changes may restore ovulatory function.

[edit] Ovulatory Dysfunction

Ovulatory dysfunction accounts for 25% to 30% of all female infertility. Ovulatory status should be assessed early in the infertility evaluation (Fig. 40-1). Ovulatory dysfunction may be clinically obvious (e.g., anovulation) or subtle (e.g., luteal-phase defect). Often a combination of ovulation tests is necessary to precisely delineate the nature of the disorder. Table 40-3 lists various tests available to physicians to monitor ovulation.

Figure 40-1 Infertility evaluation.

Table 40-3 Tests to Determine Ovulation

[edit] Ovulation.

The normal menstrual cycle in a female is divided into three distinct phases: follicular, periovulatory, and luteal. Follicle selection and growth commences in the late luteal phase of the preceding cycle, when a new cohort of follicles are recruited. The follicle growth continues in the early proliferative phase of the cycle, directed through a complex interplay of hypothalamic-releasing factors and peptides secreted from the anterior pituitary. Hypothalamic release of gonadotropin-releasing hormone (GnRH) directs both synthesis and release of FSH and luteinizing hormone (LH) from the anterior pituitary. FSH action on the ovary is crucial for follicle development (folliculogenesis), and LH augments FSH-directed follicle development, directs the periovulatory events, and stimulates gonadal steroid production. Through unclear mechanisms a dominant follicle is selected by cycle day 5 or 6. With continued growth of this dominant follicle, estrogen levels rise, prompting a midcycle LH surge culminating in ovulation.

The midcycle gonadotropin surge causes resumption of meiosis, luteinization of theca and granulosa cells within the ovary, and activation of certain proteolytic enzymes vital to follicle extrusion. Follicle release results in the formation of a corpus luteum, with subsequent production of progesterone and 17-hydroxyprogesterone. Corpus luteum formation marks the onset of the luteal phase, characterized by progestational support of the endometrium in preparation for implantation of a fertilized oocyte. The length of the luteal phase in primates is constant (10 to 16 days) in the absence of conception. A new cohort of follicles is recruited when gonadal steroid levels abruptly drop in the late luteal phase. The dissolution of the corpus luteum (luteolysis) marks the end of the luteal phase as endometrial vascular changes ensue, resulting in menstruation.

[edit] Luteal-phase Defect.

Luteal-phase defect (LPD) is a relatively uncommon disorder and arises from either subnormal progesterone levels (inadequate luteal phase) or a shortened duration of action of progesterone on the endometrium (shortened luteal phase). A shortened or inadequate luteal phase often results from inadequate folliculogenesis. Treatment is therefore directed toward improving the follicular phase of the menstrual cycle. Specifically, prolactin and androgen excess as well as a variety of hypothalamic disorders may impair follicular function, leading to LPD.

LPD is confirmed when two late luteal endometrial biopsies performed 10 to 12 days after ovulation demonstrate at least a 2-day histologic lag in endometrial development. Basal body temperatures and midluteal progesterone levels are less sensitive indicators of luteal-phase dysfunction. Luteal-phase temperature elevations of less than 11 days suggest LPD, as does subnormal progesterone levels (less than 10 ng/ml). Recent data demonstrate that transvaginal sonography and urinary LH kits most consistently agree with late luteal histologic dating. Basal body temperature charting and chronologic dating of the next menstrual cycle predicted ovulation only 77% and 65% of the time, respectively.^[9] Therefore ultrasound monitoring of follicular development and use of commercially available LH kits more precisely predict ovulation compared with all other ovulatory testing.

Treatment for LPD is directed toward the underlying disorder. Clomiphene, 50 to 100 mg/day from cycle days 5 to 9, augments follicular development. Progesterone therapy yields similar results, and recent U.S. Food and Drug Administration (FDA) approval of a new locally administered vaginal progesterone gel (Crinone) offers additional treatment routes. Crinone's success rates parallel more traditional routes of progesterone administration even in the absence of systemic absorption.^[10] Patients with LPD from androgen excess or hyperprolactinemia should receive treatment for these disorders.

[edit] Hyperprolactinemia.

Prolactin excess disrupts hypothalamic function with clinical presentation ranging from complete anovulation to LPD. A variety of physiologic and pathologic conditions increase anterior pituitary production and secretion of prolactin (Box 40-1). Clinically, patients with hyperprolactinemia demonstrate both ovulatory dysfunction (anovulation or oligoovulation) and galactorrhea.

Most patients with hyperprolactinemia have physiologic or pharmacologic etiologies. Pituitary microadenomas (prolactinomas) are the most common pathologic cause of prolactin excess. Women with prolactin-producing tumors often have prolactin levels in excess of 150 or 200 ng/ml and require detailed radiographic imaging of the pituitary and surrounding areas. Treatment of anovulation and galactorrhea secondary to hyperprolactinemia is directed toward the underling etiology. Pharmacologic causes are best treated with discontinuation of the medication, if clinically indicated. Most other causes respond favorably to medical management. Since prolactin production and secretion are controlled through tonic inhibition by central nervous system (CNS)– derived dopamine, contemporary medical regimens restore this inhibition through activation of the dopamine receptor.

Dopamine agonists are frequently used to lower prolactin levels and shrink prolactinomas. Recurrence rates are exceedingly high when medication is discontinued. In addition, approximately 30% of patients experience side effects from dopamine agonists, including nausea, vomiting, and orthostatic hypotension. Fortunately, most patients with idiopathic hyperprolactinemia and microadenomas have indolent courses; 30% of untreated patients regain ovulatory function.^[11] Patients with macroadenomas (tumor size in excess of 10 mm) present a special challenge, especially during pregnancy. Approximately 15% to 20% of macroadenomas increase in size during pregnancy, risking suprasellar extension and subsequent compression of the optic chasm. Some researchers recommend continuation of dopamine agonists during pregnancy for patients with macroadenomas, whereas others suggest transsphenoidal resection before conception. Patients with longstanding hyperprolactinemia from any cause are often hypoestrogenic due to suppression of hypothalamic GnRH. Estrogen supplementation often preserves bone mineral density in these patients and prevents additional sequelae of hypoestrogenism.

[edit] Hyperandrogenism.

Patients with androgen excess often present with ovulatory dysfunction and hirsutism. Ovarian and adrenal androgens as well as peripheral conversion of other gonadal steroids constitute the total androgen pool in females.

Ovarian and adrenal androgen production rates are best screened by obtaining total testosterone and dehydroepiandrosterone sulfate (DHEAS) levels. Total testosterone in excess of 200 ng/dl or DHEAS over 600 μg/dl raise clinical suspicion for an androgen-producing tumor and mandate radiographic imaging. Androgen-producing tumors often cause virilization (temporal balding, clitorimegaly, deepening of voice, increased muscle mass) from the rapid rise in serum androgen levels. Free testosterone levels are increased in most hirsute patients and therefore offer limited clinical utility in the evaluation of hyperandrogenism.

Many clinically hirsute patients with or without ovulatory dysfunction have normal circulating androgen levels and are considered to have idiopathic hirsutism. Increased androgen receptor sensitivity within the hair follicle and increased enzymatic conversion of testosterone to more active metabolites (dihydrotestosterone) account for the clinical expression in these individuals. Clinically hirsute patients with ovulatory dysfunction and elevated serum testosterone levels have ovarian hyperandrogenism, also known as polycystic ovarian syndrome (PCOS). These individuals experience elevated ovarian androgen production, presumably from abnormal feedback within the hypothalamic-pituitary-ovarian axis.^[12] Tonic increases in pituitary-derived LH directly stimulate the ovarian stromal compartment, with a subsequent rise in total testosterone levels. Increased intraovarian androgen levels prompt early follicular destruction (atresia) and subsequent anovulation.

Recent studies demonstrate that most patients with ovarian hyperandrogenism have hyperinsulinism secondary to peripheral insulin resistance.^[13] Despite hyperinsulinism, most patients with PCOS demonstrate normal carbohydrate metabolism. Recent evidence suggests, however, that 30% will eventually demonstrate glucose intolerance, and 7% to 10% will develop type II diabetes.^[14] Ovulation induction using clomiphene (Clomid) effectively induces ovulation in approximately 70% of patients. Clomid, 50 mg daily, is administered from cycle days 5 to 9, with ovulation typically occurring 7 to 10 days after completing therapy. Clomiphene-resistant patients are best treated with parenteral gonadotropin therapy. Recently, insulin-sensitizing agents used to reduce hyperinsulinism have proved clinically effective in reducing serum androgen levels and promoting ovulation.^[15] Metformin (Glucophage) and troglitazone (Rezulin) are two such agents and ostensibly either promote gluconeogenesis or increase the intracellular response to insulin, respectively.

[edit] Endocrine Disorders.

Certain untreated endocrine disorders disrupt ovulation, resulting in infertility. Thyroid dysfunction, hypercortisolism, and diabetes mellitus are three such disorders for which prompt recognition and intervention favorably impact pregnancy rates and obstetric outcome.^[16]Hypothyroidism accounts for only 1% of all cases of secondary amenorrhea, but prompt thyroid replacement restores normal cyclic menses. Hypothyroid individuals often present with weight gain, increased lethargy, decreased energy level, and cold intolerance. Hypothyroidism disrupts ovulation by elevating prolactin levels and lowering sex hormone–binding globulin levels, with subsequent alterations in circulating free gonadal steroids.

Patients with hypercortisolism often present to the gynecologist or primary care physician complaining of anovulation and hirsutism. Other common physical signs include dorsocervical hump, supraclavicular fat pads, truncal obesity, facial plethora, moon facies, hypertension, glucose intolerance, abdominal striae, and proximal muscle wasting. Initial screening tests (e.g., 24-hour urinary free cortisol level, overnight dexamethasone suppression) are needed to confirm hypercortisolism, with additional tests to localize the source. Treatment is directed toward the underlying etiology, with pituitary-producing adrenocorticotropic hormone (ACTH) adenomas most frequently encountered. Exceedingly high cure rates occur with transsphenoidal resection of pituitary ACTH-producing adenomas.^[17]

Approximately 1% to 5% of reproductive-age hirsute women have late-onset congenital adrenal hyperplasia (LOCAH). Although relatively common, this autosomal recessive condition is frequently misdiagnosed as PCOS. Proliferative-phase elevations of 17-hydroxyprogesterone in excess of 800 ng/dl confirm the diagnosis; whereas values greater than 200 ng/dl prompt confirmatory testing with a 1-hour ACTH stimulation test. Glucocorticoid treatment often normalizes the elevated androgen levels, thereby restoring ovulation. Prenatal diagnosis is available to at-risk couples; however, the vast majority of affected offspring arise de novo without any antecedent family history. Patients at high risk for LOCAH should be treated during pregnancy with glucocorticoids to minimize or prevent virilization of a potentially affected female fetus in utero. Glucocorticoid therapy is initiated preferably before 5 weeks' gestation and is discontinued when antenatal testing (amniocentesis, chorionic villus sampling) identifies either a male or unaffected female fetus in utero.

Diabetes mellitus exists when fasting glucose levels exceed 126 mg/dl. Marked derangements in glucose metabolism disrupt ovulation, but even modest preconceptual glucose elevations increase the risk of major congenital malformations by threefold. Meticulous glucose control often prevents these adverse events.^[16]

A variety of lifestyle situations, such as extreme weight loss, exercise, and stress, disrupt ovulation by altering GnRH pulsatility. Individuals manifesting ovulatory dysfunction secondary to CNS aberration in GnRH release have hypothalamic amenorrhea. Anorexia nervosa represents an extreme variant, and many patients are refractory to conventional therapy. Intense counseling that successfully alters lifestyle habits may restore ovulation. Since these patients are often hypoestrogenic, treatment is directed at either ovulation induction or long-term estrogen replacement to prevent osteoporosis and cardiovascular disease. The intense hypoestrogenic state often precludes successful ovulation induction with clomiphene, so patients often require parenteral gonadotropin therapy. Untreated patients with hypothalamic amenorrhea typically fail to bleed to a progestin challenge, thereby distinguishing them from most other anovulatory individuals.

[edit] Uterine, Tubal, and Peritoneal Disorders

The 30% incidence of tubal dysfunction in the infertile population parallels a 20-year rise in STDs. Ascending infections from the lower genital tract can affect the uterine lining (endometrium) and fallopian tubes. Although acute and/or chronic endometritis is a rare cause of infertility, significant endometrial scarring, as seen in Asherman's syndrome, may impede sperm motility and disrupt implantation of a fertilized oocyte. Postpartum instrumentation of an infected uterus represents a significant risk factor for the development of intrauterine scarring. Affected patients often present with amenorrhea, oligomenorrhea, and infertility.

Ascending pathogens destroy tubal mucosa, affect intraluminal cilia function, and eventually obliterate the tubal fimbria. Untreated cases of salpingitis may result in significant peritoneal involvement (PID). Clinical presentations often include significant abdominal pain, leukocytosis, and fever with an eventual perihepatitis (Fitz-Hugh–Curtis syndrome). Infertility is common secondary to occluded fallopian tubes and peritubal adhesions restricting tubal mobility. Prompt and aggressive multiagent antibiotic therapy eradicates existing PID but cannot reverse significant tubal and peritoneal scarring.

Endometriosis is characterized by the ectopic location of endometrial glands and stroma and most often involves dependent pelvic structures. Endometriosis arises from either retrograde tubal menstruation or coelomic metaplasia.^[18] As in PID, endometriosis-related infertility may result from disruption of ovum selection and reduced embryo transport caused by peritubal disease. Decreased fertility in patients with mild and minimal endometriosis results from subtle defects in ovulation and alterations in the peritoneal fluid environment.^[19]

Treatment is based on the severity and stage of endometriosis. Significant disease disrupting pelvic anatomy requires surgical correction either by laparoscopy or laparotomy. Successful surgical treatment of endometriosis-related infertility correlates with the surgeon's ability to normalize pelvic anatomy. Whereas 70% of patients with stage I or II disease conceive within 2 years of surgery, only 30% to 40% with severe endometriosis conceive.^[20] Patients unable to conceive after surgery often require in vitro fertilization (IVF). Infertile women with minimal endometriosis have essentially normal pelvic anatomy. Expectant management is often warranted, whereas superovulation combined with intrauterine insemination (IUI) is reserved for refractory cases.

Hysterosalpingography (HSG) evaluates the uterine cavity and documents fallopian tube patency. HSG is performed early in the infertility evaluation, along with the semen analysis and determination of ovulatory status. This fluoroscopic evaluation, performed in the early proliferative phase of the menstrual cycle, involves introduction of a water-soluble radiopaque dye into the uterine cavity. Patients with previous reactions to iodine are better assessed initially with a combined laparoscopic-hysteroscopic approach. A similar diagnostic approach is recommended for individuals at risk for PID. Post-HSG infections are uncommon (1% to 3%), and prophylactic antibiotics may reduce their occurrence. HSG readily identifies myomas, polyps, müllerian anomalies, and Asherman's syndrome. Except for Asherman's syndrome, intrauterine pathology rarely causes infertility. Abnormal findings should be confirmed by hysteroscopy. Hysteroscopic resection of Asherman's syndrome corrects amenorrhea in 70% of patients while improving fertility rates.^[21]

Instillation of sterile saline into the uterine cavity under ultrasound guidance (sonohysterography) is an attractive alternative to HSG. Compared with HSG, sonohysterography is less expensive, avoids ionizing radiation, and has similar sensitivity and specificity for detecting intrauterine pathology.

Both proximal and distal tubal pathology is readily identified with HSG. Abnormal fallopian tubes are best evaluated laparoscopically. The laparoscopic identification of peritubal adhesions and endometriosis increases diagnostic acumen beyond that of HSG alone. Laparoscopic adhesiolysis with restoration of tubal patency increases pregnancy rates in select individuals. Those with extensive pelvic adhesions, thick-walled fallopian tubes, and lack of normal tubal mucosa often fail to respond to laparoscopic surgery and require IVF. Patients with both proximal and distal tubal disease (bipolar tubal disease) should similarly be referred for IVF.

[edit] MALE FACTOR INFERTILITY

Abnormalities in sperm production or transit account for 30% to 40% of all cases of infertility. These data mandate early evaluation of the male and underscore that infertility is truly a couple's disorder. Tables 40-4 and 40-5 outline men's patient history and physical examination associated with fertility evaluation and infertility management.

Table 40-4 Male History and Fertility

Table 40-5 Male Physical Examination and Fertility

A semen analysis is performed on all males as an initial screening test. Multiple semen analyses are often required because of marked variability in spermatogenesis and in collection technique. Proper collection and abstinence techniques are crucial when evaluating semen analyses. A masturbated specimen is collected into a wide-mouth jar after 48 to 72 hours of abstinence. Prompt laboratory evaluation is necessary, and Table 40-6 delineates normal semen parameters as suggested by the World Health Organization (WHO). Low semen volumes may indicate retrograde ejaculation, ductal obstruction, or absence of the seminal vesicles. Rectal probe ultrasound evaluates both the prostate and the seminal vesicles. Absence of fructose in the semen specimen suggests either obstruction or congenital absence of seminal vesicles. A vasogram will confirm partial or total ductal obstruction in the male. Retrograde ejaculation is confirmed when sperm are found in a postejaculate urine specimen.

Table 40-6 Normal Semen Analysis

Individuals with sperm counts between 10 and 20 million/ml are classified as having mild oligospermia. Pregnancies in this group frequently occur, and as such, these individuals are classified as subfertile rather than infertile. Males with sperm counts below 5 million/ml have severe oligospermia. Such individuals, as well as azoospermic males, require an endocrine evaluation. FSH, LH, thyroid-stimulating hormone (TSH), prolactin, testosterone, and estradiol levels should be obtained. FSH and LH values in excess of 40 mIU/ml indicate primary testicular failure, which is refractory to treatment. Donor sperm or adoption should be recommended to these couples. Low FSH, LH, and testosterone levels indicate a hypothalamic-pituitary disorder, requiring radiographic imaging of the sella turcica.

A variety of conditions, such as genital infections and varicoceles, adversely affect sperm motility. Most varicoceles are readily diagnosed on physical examination, whereas ultrasound-directed Doppler studies of the scrotum identify subclinical varicoceles. Significant numbers of white blood cells in semen (greater than 1 million/ml) constitute leukocytospermia by WHO criteria. Antibiotic therapy is indicated for these males as presumptive treatment for infection, since seminal fluid cultures prove unreliable and are expensive. Antisperm antibodies, especially when bound to the sperm tail, may adversely affect sperm motility. Diminished fertilization rates occur when significant numbers of antisperm antibodies bind to the sperm head.

With the advent of new IVF laboratory techniques, sperm morphology may be considered the most important seminal parameter. Strict morphologic criteria more accurately assess and predict sperm function compared with traditional WHO criteria. Under this system, adequate IVF fertilization rates occur when at least 14% of sperm have normal strict morphology.^[22] Males with extremely abnormal semen, including those with severe oligospermia, poor motility, and a high percentage of abnormally shaped sperm, benefit from IVF. The recent advent of intracytoplasmic sperm injection (ICSI) allows treatment for males who have no motile sperm and less than 4% normal strict morphology.^[23]

[edit] CERVICAL FACTOR INFERTILITY

Infertility secondary to cervical factor abnormalities is rare, accounting for approximately 3% to 5% of all etiologies. Normal cervical mucus production is vital to filter bacteria and debris from seminal fluid and to assist sperm transport to the upper genital tract. At midcycle, cervical mucus is abundant, acellular, and nonviscous, thereby facilitating sperm transport to coincide with ovulation. Cervical mucus quality and sperm-mucus interaction are initially assessed with a postcoital test (PCT). Patients with prior histories of cervical cone biopsies, loop excisions of the transformation zone, and multiple dilation and curettage procedures are at risk for poor cervical mucus production. Also, antisperm antibodies bound to sperm membranes decrease sperm motility, thereby adversely affecting sperm-mucus interaction.

PCTs must be performed in the periovulatory phase of the menstrual cycle. Commercially available ovulation predictor kits enable precise timing, increasing test reliability. Couples should have intercourse the evening of the LH surge. A PCT is performed early the next morning, when the examining physician can evaluate cervical mucus using appropriate guidelines.^[24] Part two of the PCT assesses the number of motile sperm per high-power field of cervical mucus, which indirectly measures cervical mucus competency. However, poorly designed studies, inconsistent methodology, and variable interpretation have largely invalidated PCT results, which also fail to correlate with pregnancy rates.^[25]

Intrauterine insemination involves placement of washed sperm into the uterine cavity, bypassing the cervix. Pregnancy rates are acceptable when IUI is used to treat cervical factor infertility and unexplained infertility.

[edit] UNEXPLAINED INFERTILITY

Unexplained infertility identifies about 10% of infertile couples having no identifiable cause. This diagnosis is one of exclusion and mandates completion of a detailed and accurate infertility assessment. Subtle defects in ovulation, poor sperm function, and altered ovum selection may escape detection by currently available infertility testing. IVF has identified defective gametes and fertilization failure in some couples with unexplained infertility.^[26] Some physicians use secondary testing (e.g., antisperm antibodies, specialized sperm function tests, transvaginal sonography) to evaluate infertility when initial testing remains normal.

Without an identifiable cause, treatments are largely empiric. Three to five cycles of controlled ovarian hyperstimulation with fertility drugs combined with IUI increase conception rates.^[27] Ovarian stimulation with clomiphene yields an 8% to 10% per cycle pregnancy rate when combined with IUI, and parenteral gonadotropin therapy increases success to 12% to 15% per cycle. Approximately 23% to 25% of couples with unexplained infertility will conceive after three cycles of superovulation and IUI with gonadotropins, which equals the success seen after one IVF cycle.^[28] Although superovulation with IUI remains the initial treatment for couples with unexplained infertility, those who fail often benefit from more advanced reproductive technology (e.g., IVF).

[edit] ASSISTED REPRODUCTIVE TECHNOLOGIES

Assisted reproductive technology (ART) includes all procedures in which male and female gametes are artificially combined. IVF is indicated for couples with severe tubal disease, advanced endometriosis, severe male factor, refractory ovulatory dysfunction, and those patients with unexplained infertility failing to conceive with controlled ovarian hyperstimulation and IUI. Patients with unexplained infertility, because of their normal pelvic anatomy, are also candidates for a variety of tubal transfer procedures, such as gamete intrafallopian transfer (GIFT) and zygote intrafallopian transfer (ZIFT). Current data from the Society for Assisted Reproductive Technology (SART) delineate success rates for various ART procedures expressed in terms of delivery rates per retrieval: IVF, 22.5%; GIFT, 27%; and ZIFT, 27.9%.^[29]

[edit] PRECONCEPTUAL COUNSELING

The primary care physician may uncover various risk factors for future pregnancies by obtaining a detailed history of reproductive performance, significant medical conditions, and familial disorders. Obstetric complications such as first-trimester miscarriages, second-and third-trimester fetal losses, postpartum hemorrhage, and premature labor may indicate a recurrent disorder. Prompt identification and treatment may ultimately reduce the risk of recurrence. A detailed family history may reveal certain genetic disorders and identify the need for carrier testing. Carrier screening can be offered based on ethnicity, racial background, and gender. All genetic disorders are uniformly noncorrectable, but their identification by carrier testing allows for adequate patient education and preparation before delivery (Table 40-7).

Table 40-7 Genetic Disorders and Carrier Status

A variety of medical problems may pose significant risks during pregnancy. Some chronic illnesses exacerbate either during pregnancy or immediately postpartum. Alternatively, others adversely affect pregnancy outcome (Table 40-8).

Table 40-8 Selected Medical Conditions and Preconception Recommendations

A detailed social evaluation may identify couples at risk for domestic abuse, a situation likely to exacerbate during pregnancy and increase the risk of placental separation, bleeding, and premature labor and delivery. The marked prevalence of cigarette smoking and alcohol consumption represents significant social concerns, negatively impacts reproductive function, and poses significant risk to a developing fetus. Alcohol, tobacco, cocaine, and other drugs are well-described fetal teratogens.^[30] Persistent use of these agents may adversely affect spermatogenesis in men as well as ovulatory and fallopian tube function in women. Effective preconceptual counseling may reduce their use. Less common environmental toxins, such as heavy metals, pesticides, and organic solvents, also pose significant risk to a developing fetus, and obtaining an adequate occupational history in the infertile couple is important.

Patients who significantly restrict their caloric intake by following unusual diets place the fetus at risk for developmental delay and growth retardation. The American College of Obstetrics and Gynecology has established guidelines for caloric intake and calcium supplementation in reproductive-age females. At least 0.4 mg (400 μg) of folic acid daily is necessary to reduce the risk of neural tube defects in patients contemplating pregnancy. These requirements are increased to 4 mg daily in women with a previously affected offspring. Folic acid supplementation should be initiated at least 1 month before conception.

Certain infectious disorders pose significant risks to a developing fetus. Susceptible individuals should be vaccinated when possible to reduce perinatal transmission and congenital birth defects. Rubella screening is mandatory in reproductive-age women because significant birth defects occur in 50% to 80% of fetuses in first-trimester maternal infection. Health care workers and child care attendants, including teachers, are at increased risk for hepatitis B, tuberculosis, and cytomegalovirus. At-risk women should be screened and counseled when indicated. Women susceptible to toxoplasmosis infection should be counseled to avoid handling cat feces and consuming raw meat. Reproductive-age women should be offered human immunodeficiency virus (HIV) screening; approximately 30% to 50% of offspring born to untreated HIV-infected women are seropositive.^[31][32] Prompt identification of HIV-positive pregnant women is vital because retroviral therapy may reduce vertical transmission to the fetus.^[33] Screening for other STDs (e.g., Chlamydia, syphilis, gonorrhea) are indicated in the appropriate clinical setting.

[edit] SUMMARY

Infertility affects 12% to 15% of married couples in the United States, underscoring the need for systematic and thorough evaluation. Treatment should be etiology based; however, some couples with normal testing (unexplained infertility) benefit from empiric therapy with superovulation and IUI. Indications for ART continue to expand as innovations occur. The recent advent of ICSI enables reproductive specialists to treat previously refractory male factor. Adoption, psychologic counseling, and infertility support groups benefit many infertile couples. An integrated approach to infertility effectively treats a large number of infertile couples.

[edit] REFERENCES