CHAPTER 20: Treatment of the Infertile Couple

Infertility results from diseases of the reproductive system that impair the body’s ability to perform basic reproductive function. It is defined as the failure to achieve a successful pregnancy after 12 months or more of regular unprotected intercourse. Earlier evaluation and treatment may be justified based on medical history and physical findings and is warranted after 6 months for women older than 35 (American Society for Reproductive Medicine, 2012b). Ten to 15 percent of the reproductive-aged population is infertile, and men and women are equally affected.

Infertility treatment is a complex process influenced by numerous factors. Important considerations include duration of infertility, a couple’s age (especially the female’s), and diagnosed cause. Additionally, the level of distress experienced by a couple should be taken into account.

In general, a first step involves identification of a primary cause and contributing factors, and treatment is aimed at their direct correction. Most are treated with conventional therapies such as medication or surgery. In many cases, therapy can begin without a complete evaluation, especially if a cause is obvious. However, if pregnancy does not quickly follow, then more thorough testing is prudent.

In contrast, evaluation commonly may not yield a satisfactory explanation or may identify causes that are not amenable to direct correction. For such cases, recent advances in assisted reproduction have provided effective treatments. These approaches, however, are not without disadvantage. For example, in vitro fertilization (IVF) has been linked with higher rates of some fetal and maternal complications. Appropriate treatments may also pose ethical dilemmas for couples or their physician. For example, selective reduction of a multifetal pregnancy may improve survival chances for some fetuses but at the cost of others. Last, infertility treatment can be a financial burden, a significant source of emotional stress, or both. During consultation, an infertility specialist does not dictate treatment but offers and explains therapy options, which may include expectant management or even adoption.

Weight Optimization

Ovarian function is dependent on weight. Low body-fat content is associated with hypothalamic hypogonadism. In contrast, central body fat is associated with insulin resistance and contributes to ovarian dysfunction in many women with polycystic ovarian syndrome (PCOS). Lifestyle modification in overweight infertile women with PCOS leads to a reduction of central fat and improved insulin sensitivity, decreased hyperandrogenemia, lowered luteinizing hormone (LH) concentrations, and restoration of normal fertility in many cases (Hoeger, 2001; Kiddy, 1992). Even a 5 to 10 percent reduction in body weight has been shown to be successful in these women (Crosignani, 2003; Kiddy, 1992; Pasquali, 1989). Apart from diet, exercise can also improve insulin sensitivity. Weight loss and exercise are inexpensive and should be recommended as first-line management of obese women with PCOS.

Although pharmacologic options can effectively treat anovulation if weight cannot be lost, it should be noted that obesity is a significant risk factor for obstetric and perinatal complications. Some maternal risks include higher rates of gestational diabetes, cesarean delivery, preeclampsia, unexplained stillbirth, and surgical wound infection (Cunningham, 2014). Obesity also has been associated with an increased risk of birth defects (American Society for Reproductive Medicine, 2008). Therefore, strong consideration is given to delaying treatments in morbidly obese women until their body mass index (BMI) can be reduced below 40. This is especially true if treatments involve surgical risks or risk of multifetal gestation.

Weight-loss options are discussed in Chapter 1. If bariatric surgery is selected, conception is ideally delayed for 12 to 18 months (American College of Obstetricians and Gynecologists, 2013). This is because rapid weight loss during this time poses theoretical risks for intrauterine fetal-growth restriction and nutritional deprivation.

Undernutrition can also be a problem. The reproductive axis is closely linked to nutritional status, and inhibitory pathways suppress ovulation in subjects with significant weight loss. Anorexia nervosa and bulimia nervosa affect up to 5 percent of reproductive-aged women and may cause amenorrhea, infertility, and in those who do conceive, an increased likelihood of miscarriage. Fortunately, recovery may follow minimal acquisition of weight because energy balance has a more important effect than body fat mass.

Exercise

Physical activity has numerous health benefits. The relationship between exercise and fertility, however, is not straightforward. Competitive female athletes often experience amenorrhea, irregular cycles or luteal dysfunction, and infertility. This may be related not specifically to physical activity itself but rather to low body-fat content or physical stress associated with competition. At this time, insufficient data exist to support or discourage physical activity in infertile women without documented ovarian dysfunction associated with obesity or low body weight.

Nutrition

In the absence of obesity or significant undernutrition, the role of diet in infertility is unclear. High-protein diets and gluten intolerance (celiac disease) have been investigated as underlying causes in women. However, studies sizes have been small, and conflicting results found (Collin, 1996; Jackson, 2008; Meloni, 1999). In men, dietary antioxidants have been proposed as a potential way to improve male reproductive outcomes by reducing oxidative damage in sperm DNA (Ross, 2010). Although the approach is promising, large well-designed studies to guide its clinical use are needed (Patel, 2008). Additionally, the nutritional supplement carnitine had been often touted as a potential benefit for male infertility. This finding, however, has not been confirmed by a randomized, prospective trial (Sigman, 2006).

Despite a lack of conclusive benefits to nutritional supplements or diet modification in infertile couples, it does seem reasonable to recommend daily multivitamin supplementation to both. Folic acid is contained in most multivitamins, and daily doses of 400 μg orally are recommended for women attempting pregnancy to reduce the incidence of neural-tube defects in their fetuses (American College of Obstetricians and Gynecologist, 2014b).

Herbal therapies including traditional Chinese medicine and acupuncture have been proposed to enhance fertility either alone or in conjunction with standard therapies including assisted reproductive technology (ART). Smith and associates (2010) found that 29 percent of infertile couples seeking pregnancy in the United States had used complementary and alternative medicine. At this time, however, current evidence does not support a benefit of herbal/botanical therapies or acupuncture for fertility as either a primary treatment modality or an adjunct to established therapies (Cheong, 2013).

Stress Management

Stress has been implicated in reproductive failure. Although severe stress can result in anovulation, less significant stress may also play a role, but a mechanism has yet to be defined. Patients with higher stress levels have been found to have lower pregnancy rates when undergoing IVF treatments (Thiering, 1993). Accordingly, screening all infertile couples for evidence of anxiety or depression is a consideration. Although pharmacologic management of stress is not typically recommended during infertility treatments, a “mind/body” approach that combines psychological counseling and meditation may be reasonable for those patients manifesting high levels of anxiety (Domar, 1990).

Hyperprolactinemia

Prolactin is a pituitary hormone that plays an important role in various reproductive functions, and elevated levels are commonly encountered in clinical endocrinology practice. If hyperprolactinemia is found, then physiologic, pharmacologic, or other secondary causes of hormone hypersecretion are sought (Table 12-2).

Dopamine agonists are the primary treatment of hyperprolactinemia (Chap. 15). Surgical therapies are only considered with prolactin-secreting adenomas resistant to medical therapy. During pregnancy, if hyperprolactinemia is not associated with a pituitary lesion or a lesion is less than 10 mm (microadenoma), then dopamine-agonist therapy is stopped because the tumor expansion risk is low (Molitch, 1999). If the tumor size is 10 mm or larger (macroadenoma), bromocriptine (Parlodel) use is advised during pregnancy to avoid significant tumor growth.

Hypothyroidism

Thyroid disorders are prevalent in reproductive-aged individuals and affect women four to five times more often than men. In women, oligomenorrhea and amenorrhea are frequent findings. Although ovulation and conception can still occur in those with mild hypothyroidism, treatment with thyroxine usually restores a normal menstrual pattern and enhances fertility.

Subclinical hypothyroidism may also be associated with ovarian dysfunction (Strickland, 1990). Lincoln and associates (1999) found a 2-percent incidence of elevated thyroid-stimulating hormone (TSH) levels in 704 asymptomatic women seeking evaluation for infertility. Correction of hypothyroidism in those with ovarian dysfunction and elevated TSH levels led to pregnancy in 64 percent of patients. In addition, subclinical hypothyroidism may also adversely affect pregnancy outcomes, but current evidence does not support that treatment of subclinical hypothyroidism during pregnancy improves these outcomes (Casey, 2014). That said, in women seeking treatment for infertility, early detection and treatment of hypothyroidism of any degree is advised.

Ovulation Induction

Ovarian dysfunction is the most common indication for the use of medications to induce ovulation. These agents can also be selected for ovulatory women to increase the likelihood of pregnancy in couples with other causes of infertility or unexplained infertility. Use of these medications to promote follicular development and prompt ovulation is called superovulation or ovulation enhancement. If these agents are administered solely to stimulate follicles and egg harvesting is completed by ART, then the termed controlled ovarian hyperstimulation is used. In contrast, we prefer the term ovulation induction to describe treatment with medications to stimulate normal ovulation in women with ovarian dysfunction.

Frequent causes of ovarian dysfunction include PCOS and diminished ovarian reserve. Less often, central (hypothalamic or pituitary) disorders or thyroid dysfunction can result in infertility (Table 16-3). Rarely, ovarian tumors or adrenal abnormalities lead to abnormal ovarian function. Treatment of ovarian dysfunction is based on the identified cause and the results of any prior attempted therapy.

Clomiphene Citrate

Clomiphene citrate (CC) is the initial treatment for most anovulatory infertile women. Chemically similar to tamoxifen, CC is a nonsteroidal triphenylethylene derivative that demonstrates both estrogen agonist and antagonist properties. Antagonist properties predominate except at very low estrogen levels. As a result, negative feedback that is normally produced by estrogen in the hypothalamus is reduced (Fig. 20-1). Gonadotropin-releasing hormone (GnRH) secretion is altered and stimulates pituitary gonadotropin release. The resulting increase in follicle-stimulating hormone (FSH) levels, in turn, drives ovarian follicular activity.

Tamoxifen has also been used successfully for ovulation induction. However, it is not approved by the Food and Drug Administration (FDA) for this indication and has not been demonstrated to have significant advantage compared with CC.

Clomiphene citrate is administered orally, typically starting on the third to fifth day after the onset of spontaneous or progestin-induced menses. Ovulation rates, conception rates, and pregnancy outcome are similar regardless whether treatment begins on cycle day 2, 3, 4, or 5. Prior to therapy, sonography is advisable to exclude signs of significant spontaneous follicular maturation or residual follicular cysts. In general at our institution, clomiphene can be administered if no follicle is >20 mm and the endometrium is less than 5 mm. A pregnancy test is also indicated after spontaneous menses. Although not a proven teratogen, CC is classified as category X by the FDA and thus is contraindicated in suspected or documented pregnancy.

The dose required to achieve ovulation correlates with body weight. However, there is no reliable way to accurately predict which dose will be required in an individual woman (Lobo, 1982). Consequently, CC is titrated empirically to establish the lowest effective dose for each patient. Treatment typically begins with a single 50-mg tablet taken daily for 5 consecutive days. Doses are increased by a 50-mg increment in each subsequent cycle until ovulation is induced. The dose of CC should not be increased if normal ovulation is confirmed. Thus, lack of pregnancy alone does not justify a dose increase. The effective dose of CC ranges from 50 mg/d to 250 mg/d, although doses in excess of 100 mg/d are not approved by the FDA. Some studies have suggested that adjunctive therapy with glucocorticoids may benefit some patients not responsive to CC alone (Elnashar, 2006; Parsanezhad, 2002). The precise mechanism is unclear, although several direct and indirect actions of dexamethasone have been suggested. This therapy may be empiric or individualized based on elevated dehydroepiandrosterone sulfate (DHEAS) levels.

In general, women failing to ovulate with 100 mg/d dosing or failing to conceive following 3 to 6 months of ovulatory response to CC should be considered candidates for alternative treatments. In a retrospective study including 428 women who received CC for ovulation induction, 84.5 percent of pregnancies achieved with treatment occurred during the first three ovulatory cycles (Gysler, 1982).

Insulin-sensitizing Agents

Although PCOS appears to be a heterogeneous disorder, many women with this condition exhibit insulin resistance (Chap. 17). Insulin resistance leads to compensatory hyperinsulinemia and dyslipidemia. Given the strong evidence that hyperinsulinemia plays a pivotal pathogenic role in development of PCOS, it is reasonable to assume that interventions that reduce circulating insulin levels in women with PCOS may restore normal reproductive endocrine function. As discussed, weight loss, nutrition, and exercise have clearly led to reduced hyperinsulinemia, resolution of hyperandrogenism, and in some cases, resumption of ovulatory function in overweight women with PCOS. However, women may be poorly compliant, and weight loss is rarely maintained over time.

Insulin-sensitizing agents show promise in the treatment of PCOS. When administered to insulin-resistant patients, these compounds act to increase target tissue responsiveness to insulin, thereby reducing the need for compensatory hyperinsulinemia (Antonucci, 1998). Current insulin-sensitizing agents include the biguanides and thiazolidinediones (Chap. 17).

Of these, studies suggest that metformin (Glucophage), given 500 mg orally three times daily or 850 mg twice daily with meals and administered to women with PCOS, increased the frequency of spontaneous ovulation, menstrual cyclicity, and ovulatory response to CC (Nestler, 1998; Palomba, 2005; Vandermolen, 2001). In contrast, a large, prospective, randomized, multicenter trial does not support the hypothesis that metformin, either alone or in combination with CC, improves the live-birth rate in women with PCOS (Legro, 2007).

Gonadotropins

Clomiphene citrate is easy to use and leads to ovulation in most patients (Hammond, 1983). However, pregnancy rates are disappointing and approximate ≤50 percent (Raj, 1977; Zarate, 1971). Lower than expected pregnancy rates with CC have been attributed to its long half-life and peripheral antiestrogenic effects, mainly on the endometrium and cervical mucus. For such individuals, who are often classified as “clomiphene resistant,” the next step is traditionally the administration of exogenous gonadotropin preparations via injections.

As with CC, the goal of ovulation induction with gonadotropins is simply to normalize ovarian function. Ideally, the dose used is the minimum required to cause normal development of a single dominant follicle. Because the response to gonadotropins can vary greatly from individual to individual and even from cycle to cycle, intensive monitoring is required to adjust dosage and timing of ovulation.

Gonadotropin preparations vary in terms of their source (urinary or recombinant) and by the presence or absence of LH activity (Table 20-1). Traditional urinary-derived human menopausal gonadotropin (hMG) preparations contain both FSH and LH. These are extracted and purified from the urine of postmenopausal women, in whom FSH and LH levels are normally high. These preparations also contain human chorionic gonadotropin (hCG), which is mainly derived from normal pituitary secretion in postmenopausal women. LH and hCG both bind to the same receptor (luteinizing hormone/chorionic gonadotropin receptor [LHCGR]).

In contrast, in purified hMG, hCG serves as the primary source of the LH activity, although significant LH is also present in the older, nonhighly purified hMG products (Filicori, 2002). Highly purified urinary preparations allow for administration via subcutaneous route with minimal or no reaction at the injection site. Alternatives to hMG include highly purified urinary gonadotropin preparations and purified recombinant FSH.

Both LH and FSH activity are required for normal ovarian steroidogenesis and follicular development. In many cases, pure FSH preparations can be used because of adequate endogenous LH production. However, for ovulation induction in patients with hypogonadotropic amenorrhea, LH activity must be provided from an exogenous source. Thus, options include hMG, recombinant LH, low-dose (diluted) urinary or recombinant hCG. Ovulation induction in women with PCOS can be performed either with FSH-only containing products or those containing both LH and FSH activity. At present, data do not support the superiority of one preparation over another.

Gonadotropin development will likely continue. A long-acting FSH is commercially available outside the United States. This recombinant molecule was created by adding a DNA sequence to the human FSH gene. This extra sequence allows for more glycosylation and hence a prolonged clearance. Low-molecular-weight molecules (nonproteins) have been identified that activate the FSH and LH receptors. However, these compounds are still in early stages of clinical development. Advantages of these nontraditional gonadotropins include oral delivery.

Most clinicians begin ovulation induction attempts at a low gonadotropin dosage of 50 to 75 IU injected daily. This is gradually increased if no ovarian response (as assessed by serum estradiol measurements) is noted after several days (Fig. 20-2). This is referred to as a “step-up” protocol. A “step-down” protocol can also be used with the advantage of a decreased duration of stimulation. However, the risk of excessive ovarian response, such as multiple follicle development or ovarian hyperstimulation syndrome, may be increased with this method. With either approach, if a patient fails to conceive, subsequent cycles may be started at higher doses based on prior response.

In general, gonadotropin stimulation in women with PCOS is less successful than in patients with hypogonadotropic amenorrhea (Balen, 1994). Women with PCOS have ovaries highly sensitive to gonadotropin stimulation. They have a higher risk of excessive ovarian response and of multifetal pregnancy than those with normal ovaries (Farhi, 1996).

Aromatase Inhibitors

Gonadotropins are associated with more effective ovulation induction and higher pregnancy rates than CC. However, gonadotropins are expensive and carry higher risks for ovarian hyperstimulation syndrome and multifetal gestation. Accordingly, aromatase inhibitors have been investigated as ovulation-inducing agents (Fig. 20-3). These drugs were originally developed for breast cancer treatment and effectively inhibit aromatase, a cytochrome P450 hemoprotein that catalyzes the rate-limiting step in estrogen production. Aromatase inhibitors are orally administered, easy to use, relatively inexpensive, and associated with typically minor side effects (Chap. 10).

The most widely used aromatase inhibitor to induce ovulation in anovulatory and ovulatory infertile women is letrozole (Femara). Compared with CC, its use is associated with higher pregnancy rates following ovulation induction (Legro, 2014). When used in combination with gonadotropins, letrozole leads to lower gonadotropin requirements and may achieve pregnancy rates comparable to gonadotropin treatment alone (Casper, 2003; Mitwally, 2004). The typical dosage used is 2.5 mg to 5 mg orally daily for 5 days.

Data suggesting that letrozole use for infertility treatment might be associated with a higher risk of congenital cardiac and bone malformations in the newborn are contradictory (Biljan, 2005; Tulandi, 2006). However, in 2005, the manufacturer issued a statement to physicians worldwide advising that letrozole use in premenopausal women, specifically its use for ovulation induction, is contraindicated (Fontana, 2005). As a result, it is not likely that letrozole will gain FDA approval or widespread acceptance for ovulation induction in the near future. Larger, well-designed randomized prospective trials that confirm their safety are still needed (Franik, 2014).

A second aromatase inhibitor, anastrozole, is of the same compound class as letrozole and has also been approved for treatment of women with breast cancer. At this time, no concerns have been raised regarding its teratogenicity. However, experience with anastrozole (Arimidex) in ovulation induction at this time is limited, and ideal dosages are currently unknown. Two trials comparing anastrozole to clomiphene have not found it to be more effective than clomiphene (Tredway, 2011a,b).

Complications of Fertility Drugs

Ovarian Hyperstimulation Syndrome

This is a clinical symptom complex associated with ovarian enlargement resulting from exogenous gonadotropin therapy. Symptoms may include abdominal pain and distention, ascites, gastrointestinal problems, respiratory compromise, oliguria, hemoconcentration, and thromboembolism. These symptoms may develop during ovulation induction or in early pregnancies that were conceived through exogenous ovarian stimulation.

The etiology of ovarian hyperstimulation syndrome (OHSS) is complex, but hCG, either exogenous or endogenous (derived from a resulting pregnancy), is believed to be an early contributing factor. Development of OHSS involves increased vascular permeability and loss of fluid, protein, and electrolytes into the peritoneal cavity, which leads to hemoconcentration. Increased capillary permeability is felt to result from vasoactive substances produced by the corpus luteum. Vascular endothelial growth factor (VEGF) is thought to play a major role, and angiotensin II may also be involved. Hypercoagulability may be related to hyperviscosity following hemoconcentration. Alternatively, it may be secondary to the high estrogen levels present, and these high levels can increase coagulation factor production. Predisposing factors for OHSS include multifollicular ovaries such as with PCOS, young age, high estradiol levels during ovulation induction, and pregnancy.

Abdominal pain is prominent and caused by ovarian enlargement and accumulation of peritoneal fluid. Although sonographic examination of women with OHSS usually reveals enlarged ovaries with numerous follicular cysts and ascites, OHSS is a clinical diagnosis (Fig. 20-4). Several different classification schemes have been proposed to categorize the severity of this syndrome, and Table 20-2 lists one.

Treatment of OHSS is generally supportive. Paracentesis is typically performed transvaginally as an outpatient and can ameliorate abdominal discomfort and relieve respiratory distress. Reaccumulation of ascites may prompt additional paracenteses or rarely placement of a percutaneous “pigtail” catheter for continuous drainage. Untreated hypovolemia can lead to renal, hepatic, or pulmonary end-organ failure. Thus, fluid balance must be maintained by replacement with an isotonic fluid such as normal saline. Monitoring of electrolytes is critical. Because of hypercoagulability in these women, prophylaxis for thromboembolism is strongly considered with severe OHSS.

During exogenous ovulation, strategies to avoid OHSS induction include decreasing follicular stimulation (a decreased FSH dose), “coasting” (withholding FSH administration for one or more days prior to the hCG trigger injection), prophylactic treatment with volume expanders, and substitution of hCG for FSH during the final days of ovarian stimulation. With this last strategy, low-dose hCG administration can support maturation of larger ovarian follicles but is postulated to directly or indirectly increase atresia rates of small antral follicles and thereby lower OHSS rates. However, during ovulation induction, if concern for OHSS develops, then the hCG trigger can be withheld, resulting in cycle cancellation. For these patients, IVF should often be considered rather than further attempts at ovulation induction.

OHSS can also develop with ART therapy, and the risk can be substantially reduced with appropriate precautions. Predicted high responders (e.g., high numbers of antral follicles, high AMH level, or prior high response to ovulation induction) should be stimulated with a GnRH antagonist protocol. This allows a single GnRH agonist dose to be used for the “trigger” in place of hCG. The resulting endogenous LH surge can bring about the final stages of follicle and oocyte maturation without significant OHSS risk. Moreover, prevention of pregnancy does not completely eliminate the risk of OHSS but certainly serves to limit symptom duration. Thus, an additional option in ART cycles is to freeze all embryos and forgo embryo transfer that cycle.

Multifetal Gestation

From 1980 through 1997, the number of twin births rose by more than 50 percent, and the number of higher-order multifetal births increased by more than 400 percent (Fig. 20-5) (Martin, 1999). Using data from these years, the Centers for Disease Control and Prevention (CDC) (2000) estimated that approximately 20 percent of triplets and higher-order multifetal births were attributable to spontaneous events; 40 percent were related to ovulation-inducing drugs without ART; and 40 percent resulted from ART. However, further analysis of the same data indicates that the overwhelming majority of all multifetal births result from spontaneously conceived twin gestations and that only approximately 10 percent result from IVF and related procedures.

Higher-order multifetal pregnancy is an adverse outcome of infertility treatment. In general, increased fetal number leads to greater risk of perinatal and maternal morbidity and mortality. Prematurity leads to most adverse events in these cases, but fetal-growth restriction and discordance are other potential factors.

Monozygotic gestation is also increased in ovulation induction and ART and is associated with greater fetal risks. These include a three- to fivefold higher perinatal mortality rate compared with that of dizygotic twins. Abnormal placentation also develops at higher rates. Additionally, congenital anomalies are increased two- to threefold in monozygotic twins versus singleton neonates, with an estimated incidence of 10 percent. Initially, extended embryo culture and zona manipulation were postulated to increase the risk of monozygosity. More recent, well-designed trials have refuted this contention (Franasiak, 2015; Papanikolaou, 2010).

Patients with higher-order multifetal gestations are faced with options of continuing their pregnancy with all the risks previously described, terminating the entire pregnancy, or selecting multifetal pregnancy reduction (MFPR). MFPR reduces the number of fetuses to decrease the risk of maternal and perinatal morbidity and mortality. Although MFPR lowers the risks associated with preterm delivery, it often creates profound ethical dilemmas. Moreover, multifetal reduction lowers, but does not eliminate, the risk of fetal-growth restriction in remaining fetuses. With MFPR, pregnancy loss and prematurity are primary risks. However, current data suggest that such complications have decreased as experience with the procedure has grown (Evans, 2008).

Several issues in infertility care contribute to the increased incidence of higher-order multifetal pregnancies. An infertile couple’s sense of urgency may lead to a preference for more aggressive strategies involving gonadotropin treatment or for more embryos to be transferred in IVF cycles. Clinicians may feel competitive pressures to achieve higher pregnancy rates and may be inclined to turn to superovulation or IVF earlier in treatment or to transfer a greater number of embryos.

There have been efforts to lower the rates of multifetal gestation in patients undergoing ovulation induction or superovulation by using serum estradiol limits and arbitrary sonographic criteria of follicular size. These, however, have been ineffective. In a multicenter randomized clinical trial involving 1255 ovulation induction cycles, hCG was withheld if the estradiol concentration rose above 3000 pg/mL or if more than six follicles greater than 18 millimeters in diameter were present (Guzick, 1999). Despite these limits on hCG administration, the multifetal gestation rate was still 30 percent. Although sonography and serum estradiol monitoring have not reduced the incidence of multifetal gestation or OHSS, the risk of multifetal pregnancy does correlate with the magnitude of follicular response as indicated by follicle number and serum estradiol levels. However, there is no consensus among centers regarding specific sonographic criteria or estradiol levels beyond which hCG should not be administered.

When the likelihood of multifetal gestation is felt to be excessive, IVF can be undertaken to reduce the risk. Because the number of embryos transferred can be strictly controlled, this strategy can minimize the risk of higher-order multifetal gestations. Guidelines set forth by the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology (2013a) have led to a significant reduction in triplet (and higher-order) gestations (Table 20-3). Efforts to reduce twin pregnancies through the increased use of elective single embryo transfer (eSET) are currently ongoing (American Society for Reproductive Medicine, 2012c).

Ovarian Drilling

Surgical ovarian wedge resection was the first established treatment for anovulatory PCOS patients. It was largely abandoned because of postsurgical adhesion formation, which converted endocrinologic subfertility to mechanical subfertility (Adashi, 1981; Buttram, 1975; Stein, 1939). As a result, it was replaced by medical ovulation induction with CC and gonadotropins (Franks, 1985). However, medical ovulation induction, as discussed earlier, has limitations. Accordingly, surgical therapy using laparoscopic techniques and termed laparoscopic ovarian drilling is an alternative in women resistant to medical therapies.

During laparoscopic ovarian drilling, electrosurgical coagulation, laser vaporization, or Harmonic scalpel may be used to create multiple perforations into the ovarian surface and stroma (Section 44-7). In many uncontrolled observational studies, drilling has led to temporary, higher rates of spontaneous postoperative ovulation and conception or to improved medical ovulation induction (Armar, 1990, 1993; Farhi, 1995; Greenblatt, 1987; Kovacs, 1991).

The mechanism of action with laparoscopic ovarian drilling is thought to be similar to that of ovarian wedge resection. Both procedures destroy ovarian androgen-producing tissue and reduce peripheral conversion of androgens to estrogens. Specifically, a fall in serum levels of androgens and LH and an increase in FSH levels have been demonstrated after ovarian drilling (Armar, 1990; Greenblatt, 1987). The endocrine changes following surgery are thought to convert the adverse androgen-dominant intrafollicular environment to an estrogenic one and to restore the hormonal environment to normal by correcting ovarian-pituitary feedback disturbances (Aakvaag, 1985; Balen, 1993). Thus, both local and systemic effects are thought to promote follicular recruitment and maturation and subsequent ovulation.

Risks of ovarian drilling include postoperative adhesion formation and the other risks of laparoscopic surgery (Chap. 41). Additionally, theoretical risks of diminished ovarian reserve and premature ovarian failure remain to be well investigated. As surgery is more invasive, ovarian drilling is generally not offered prior to consideration of medical therapies.

Ovarian dysfunction may result from ovarian failure or from a diminished ovarian reserve, either of which may follow normal aging, disease, cancer treatment, or ovarian surgery. Even if a woman is spontaneously menstruating, a basal (cycle day 2 or 3) FSH level above 15 IU/L predicts that medical therapies including exogenous gonadotropins will be of little benefit. For these women, the option of using donor eggs should be considered. Expectant management may also be considered, although the likelihood of pregnancy is low. AMH can identify patients with diminished ovarian reserve prior to the elevation of basal FSH. Although patients with low AMH (<1 ng/mL) generally respond poorly to gonadotropins, some may benefit from ART.

Anatomic distortions of the female reproductive tract are a major cause of infertility and may prevent ovum entry into the fallopian tube; impair transport of ova, sperm, or embryos; or interfere with implantation. The three primary types of anatomic abnormalities include tubal factors, peritoneal factors, and uterine factors. Each has differing effects and therefore may require different therapies.

Tubal Factors

Tubal occlusion can arise from congenital abnormality, infection, or iatrogenic causes. Additionally, a small subset of tubal infertility is idiopathic. Not only the cause of tubal damage but also the anatomic abnormality is important. For example, proximal tubal occlusion, distal tubal occlusion, and tubal absence differ markedly in their treatment.

Proximal tubal occlusion describes obstruction proximal to the fimbria and may develop at the tubal ostium, isthmus, or ampulla. Midtubal occlusion is considered a subset of proximal occlusion. Proximal tubal occlusion may be secondary to tubal resection, luminal obliteration, or simple plugging with mucus or debris. In contrast, distal tubal occlusion describes obstruction at the tube’s fimbria. It typically results from prior pelvic infection and may be associated with concomitant adnexal adhesions.

Tubal Cannulation

Proximal tubal occlusion is often amenable to direct techniques. If diagnosed at the time of hysterosalpingography (HSG), consideration is given to performing concurrent selective salpingography. A catheter is placed such that it wedges within the tubal ostium. This allows significant hydrostatic pressure to be applied to the tube. Such pressure will likely overcome most instances of tubal spasm or plugging by mucus or debris. If tubal patency cannot be reestablished, an inner catheter with guide wire is used to cannulate the tube. This creates patency of isolated short segmental scarring in most instances. Scarring of a longer segment or luminal obliteration, however, is not amenable to correction with tubal cannulation. In these women, surgical segmental resection with reanastomosis or IVF may be considered.

Tubal Reconstruction

Proximal Tubal Obstruction

Tubal obstruction not amenable to treatment with selective salpingography has traditionally been treated surgically, and options include hysteroscopic cannulation, surgical reanastomosis, and neosalpingostomy. Although success rates of ART have risen considerably, reproductive surgery remains an important option or complement to ART for many couples.

Some types of tubal blockage have a much better prognosis with surgical therapy than others. For example, hysteroscopic cannulation of fallopian tubes can treat some types of proximal obstruction in a fashion similar to selective salpingography (Section 44-18). Hysteroscopic cannulation is best performed with concurrent laparoscopy to verify distal tubal patency.

Proximal obstruction not amenable to cannulation techniques can be treated with segmental resection and reanastomosis (Fig. 20-6). In most cases, this can be done as an outpatient procedure through a minilaparotomy incision. However, obstruction extending into the interstitial portion of the tube is more technically challenging to repair and more prone to repeated obstruction postoperatively. Therefore, proximal occlusion extending to the interstitial segment that cannot be treated with cannulation is best treated in most instances with IVF.

Options for proximal and midtubal occlusion resulting from prior sterilization are either tubal reanastomosis or IVF. From a patient perspective, outpatient tubal reanastomosis avoids ovarian stimulation and increased risk for multifetal gestation and provides an ability to conceive normally. In general, although the monthly probability of pregnancy following tubal reversal is likely lower than that for age-matched controls without prior sterilization, the cumulative chance of pregnancy is high. However, IVF is strongly considered if other fertility factors are present or the type of sterilization performed does not permit reconstruction. For example, in cases of sterilization completed by fimbriectomy, neosalpingostomy can be corrective. However, the probability of pregnancy is lower, and IVF is considered. Importantly, the risk of subsequent ectopic pregnancy following reanastomosis for midtubal occlusion is 3 to 5 percent (Gordts, 2009).

The “reversibility” of sterilization can generally be determined by review of the operative report and also the pathology report if the procedure involved segmental resection. If operative records are unavailable or suggest that reanastomosis may not be feasible, laparoscopy is performed prior to laparotomy to assess chances of surgical success.

Outpatient reversal of sterilization is most commonly done by minilaparotomy. Incision size typically varies from 3 to 6 cm depending on a patient’s weight and anatomy. Some surgeons are able to complete some of these procedures by laparoscopy. Robotic control may be helpful for this but may increase operating time and expense.

Distal Tubal Obstruction

Following pelvic inflammatory disorders, normal fimbrial anatomy may be destroyed, or fimbria may be encased by adnexal adhesions. In these cases, neosalpingostomy can be performed at minilaparotomy or laparoscopy (Fig. 20-7). However, women desiring neosalpingostomy for treatment of distal occlusion are counseled that the risk of ectopic pregnancy is high, the likelihood of pregnancy is 50 percent or lower, and postoperative reocclusion is common (Bayrak, 2006). Moreover, hydrosalpinges that are dilated more than 3 cm in diameter, that are associated with significant adnexal adhesions, or that display an obviously attenuated endosalpinx yield a poor prognosis. These tubes are best treated by salpingectomy. If both tubes are affected, bilateral salpingectomy is recommended prior to proceeding with IVF. This stems from data showing women with hydrosalpinges undergoing IVF have approximately half the pregnancy rate of other women with unaffected tubes (American Society for Reproductive Medicine, 2012a).

Uterine Factors

Three types of uterine factors have been implicated in infertility and include leiomyomas, endometrial polyps, and intrauterine adhesions. Müllerian anomalies, especially intrauterine septum or segmental agenesis, can increase infertility or pregnancy complication rates. These congenital abnormalities are described fully in Chapter 18. Mechanisms of infertility with these factors have not been clearly elucidated. However, the end result is decreased endometrial receptivity and reduced likelihood of embryo implantation.

Leiomyomas

Leiomyomas are common benign tumors of the uterus and have been associated with infertility in some women (Chap. 9). Retrospective studies have suggested a benefit from surgically removing certain tumors to increase efficacy of both natural and assisted conception (Griffiths, 2006).

There are no randomized controlled trials to clearly demonstrate that myomectomy improves fertility. However, in view of the many retrospective observational studies that suggest this, it is reasonable to offer myomectomy to well-selected infertile women, especially if tumors are large or impinge on the endometrial cavity. Myomectomy can be performed using hysteroscopy, laparoscopy, or laparotomy, and selection of the approach is discussed in Chapter 9. Currently, no studies validate one method compared with another in terms of efficacy. Therefore, clinical judgment should determine the most appropriate technique from the standpoint of safety, restoration of normal uterine anatomy, and speed of recovery.

Endometrial Polyps

These soft, fleshy endometrial growths are commonly diagnosed during infertility evaluation. Several studies suggest good pregnancy rates following polypectomy, although the mechanism by which polyps impair fertility has not been established. The requirement to remove even small polyps in infertile women has been previously debated. However, one prospective trial of 204 women with polyps and with an additionally diagnosed cervical factor, male factor, or unexplained infertility appears to give some clear guidance.

In this trial, women were randomized to one of two groups prior to treatment with intrauterine insemination (IUI) (Pérez-Medina, 2005). The first group underwent polypectomy. The second underwent only hysteroscopic biopsy of the polyp to obtain histologic confirmation. All patients were managed expectantly for three cycles prior to proceeding with up to four cycles of IUI. The pregnancy rate in the polypectomy group was more than twice as high regardless of initial polyp size (Table 20-4). These data suggest that endometrial polyps can significantly impair infertility treatment outcome. Thus, it would seem prudent to perform hysteroscopic polypectomy in all infertile patients if a polyp is identified (Section 44-13).

Intrauterine Adhesions

Adhesions within the endometrial cavity, also called synechiae, can range from asymptomatic small bands to complete or near complete obliteration of the endometrial cavity. If amenorrhea or hypomenorrhea result, the condition is termed Asherman syndrome (Chap. 16).

Treatment involves surgical adhesiolysis to restore normal uterine cavity size and configuration. Dilatation and curettage (D & C) and abdominal approaches have previously been used. However, with the advantages of hysteroscopy, the role of these other techniques has been minimized.

Hysteroscopic adhesion resection may range from simple lysis of a small band to extensive adhesiolysis of dense intrauterine adhesions using scissors, electrosurgical cutting, or laser energy (Section 44-19). However, women whose uterine fundus is completely obscured and those with a markedly narrowed, fibrotic cavity present the greatest therapeutic challenge. Several techniques have been described for these difficult cases, but outcome is far worse than in patients with small band adhesions. In those women with severe Asherman syndrome that is not amenable to reconstructive surgery, gestational carrier surrogacy is a valuable option.

Peritoneal Disease

Endometriosis

This condition and its effects on infertility are extensively discussed in Chapter 10. In women with minimal or mild disease, evidence supporting lesion ablation is limited and use of empiric general fertility boosting procedures such as ART or superovulation combined with IUI is reasonable. These treatments have been validated to increase fecundity in women with stage I and II disease (Table 20-5) (Guzick, 1999).

Moderate and severe endometriosis results in distortion of anatomic relationships of reproductive organs. In many cases, surgical treatment may improve anatomy, and pregnancy can result (American Society for Reproductive Medicine, 2006). Unfortunately, advanced disease may prevent adequate restoration of pelvic anatomy. Therefore, a surgeon’s operative findings and anticipated surgical results guide postoperative strategy. If satisfactory surgical outcome is achieved, it is reasonable to attempt pregnancy for 6 to 12 months prior to considering other options such as IVF. It should be remembered that endometriosis in some cases may recur quickly, and unnecessary delay in attempting pregnancy postoperatively is not advised.

In women with advanced endometriosis, several studies suggest that long-term treatment with GnRH agonists before initiation of a cycle may improve fecundity (Dicker, 1992; Surrey, 2002). Currently, however, this treatment strategy is not universally accepted.

If endometriomas are noted, surgical options include cyst drainage, drainage followed by cyst wall ablation, or cyst excision. These three procedures can be performed laparoscopically in nearly all circumstances given adequate surgeon experience. Simple drainage minimizes ovarian destruction but commonly results in rapid cyst recurrence. One histologic study demonstrated that a mean of 60 percent of the cyst wall (range of 10 to 98 percent) was lined by endometrium to a depth of 0.6 mm (Muzii, 2007). Thus, drainage and ablation may not destroy all endometrium to this depth. Moreover, this approach is associated with significant risk of cyst recurrence and thermal damage to the ovary. For these reasons, laparoscopic excision of the cyst wall by a stripping technique should be considered optimal treatment for most endometriomas (Section 44-5). Hart and coworkers (2008) compared ablative surgery and cyst excision. With excision, they noted more favorable rates of diminished pain, cyst recurrence, and spontaneous pregnancy. However, excision is inevitably accompanied by removal of normal ovarian tissue and often leads to decreased ovarian volume and diminished ovarian reserve (Almog, 2010; Exacoustos, 2004; Ragni, 2005).

Endometrioma recurrence is common. But, surgery for a recurrent endometrioma appears to be even more harmful to the ovarian reserve than primary surgery (Muzii, 2015). Thus, further ovarian surgery is individualized (American College of Obstetricians and Gynecologists, 2014a). If there is confidence in the diagnosis, it may be prudent in some cases to avoid surgery entirely when future fertility is desired.

Pelvic Adhesions

Pelvic adhesions may result from endometriosis, prior surgery, or pelvic infection and often vary in their density and vascularity. Adhesions may impair fertility by distorting adnexal anatomy and by interfering with gamete and embryo transport, even in the absence of tubal disease.

Surgical lysis may restore pelvic anatomy in some cases, but adhesions may recur, especially if they are dense and vascular. Adherence to microsurgical principles and minimally invasive surgery may help decrease adhesion formation. Although numerous adjuvants, such as adhesion barriers, have been used to reduce the risk of postoperative adhesion formation, currently none have been validated to improve fecundity (American Society for Reproductive Medicine, 2013c).

Among infertile women with adnexal adhesions, pregnancy rates after adhesiolysis are 32 percent at 12 months and 45 percent at 24 months of surveillance. These rates can be compared with 11 percent at 12 months and 16 percent at 24 months in those left untreated (Tulandi, 1990). As with severe endometriosis, clinical judgment regarding operative findings and results of surgery should guide the strategy postoperatively. IVF is the best option for those with a poor prognosis for normal anatomy restoration.

In response to follicular estradiol production, the cervix should produce abundant thin mucus. If present, this mucus acts as a conduit and functional reservoir for sperm. Accordingly, inadequate cervical mucus impairs sperm transport to the upper female reproductive tract.

Causes of abnormal or deficient mucus include infection, prior cervical surgery, use of antiestrogens (e.g., clomiphene citrate) for ovulation induction, and sperm antibodies. However, many women with decreased or hostile mucus have no history of predisposing factors.

Examination of cervical mucus may reveal gross evidence of chronic cervicitis that deserves treatment. Doxycycline, 100 mg orally twice daily for 10 days, is an appropriate therapy. In those with decreased mucus volume, treatments include short-term supplementation with exogenous estrogen, such as ethinyl estradiol, and the use of the mucolytic expectorant guaifenesin. However, the value of estrogen and guaifenesin has not been confirmed. Moreover, exogenous estrogens could have a negative effect on follicular development and ovarian function.

For these reason, most clinicians treat noninfectious, suspected cervical mucus abnormalities with IUI (Fig. 20-8). Although this approach also has not been validated with randomized prospective trials, the theoretical basis for this approach seems sound (Helmerhorst, 2005). Additionally, IUI has been demonstrated to be effective for treatment of unexplained infertility. As a result, many clinicians forgo cervical mucus testing and proceed directly with IUI treatments in the absence of tubal disease.

Male infertility has numerous causes and may include various sperm or semen volume abnormalities that are described subsequently. Accordingly, therapy should be planned only after thorough evaluation (Chap. 19). In the absence of identifiable correctable cause, it is appropriate to offer IUI or ART as treatment options. The choice of whether to proceed initially with IUI therapies as opposed to the more intensive and expensive ART treatments is dependent on several factors. These include duration of infertility, age of the female, and history of prior treatments. If ART is considered for male factor, intracytoplasmic sperm injection (ICSI) is typically selected rather than traditional IVF (Fig. 20-9).

Abnormal Semen Volume

Aspermia is characterized by a complete lack of semen and results from failure to ejaculate. The physiology of normal ejaculation includes emission of sperm with accessory gland fluid into the urethra, simultaneous closure of the urethral sphincters, and forceful ejaculation of semen through the urethra. Emission and closure of the bladder neck are primarily alpha-adrenergically mediated thoracolumbar sympathetic reflex events with supraspinal modulation. Ejaculation is a sacral spinal reflex mediated by the pudendal nerve.

Anejaculation or anorgasmia is not rare and may stem from psychogenic factors, organic erectile dysfunction, or impaired parasympathetic sacral spinal reflex. Appropriate treatments depend on the cause and can include psychologic counseling or erectile dysfunction treatment with sildenafil citrate (Viagra) or other similar medication. Vibratory stimulation may also be effective in some instances. Electroejaculation is an invasive procedure and is generally used for men with spinal cord injuries who are unresponsive to the therapies above.

Men who always achieve orgasm but never experience prograde ejaculation or have a greatly reduced prograde volume typically have retrograde ejaculation. Therefore, administration of oral pseudoephedrine or another alpha-adrenergic agent to aid bladder neck closure is warranted. However, for many, pharmacologic methods are ineffective, and IUI may be performed using sperm processed from a voided urine specimen collected after ejaculation.

A minority of men who achieve orgasm, but not prograde ejaculation, have failure of emission. A trial of sympathomimetic agents is reasonable in these individuals as well, although pharmacologic therapies have generally provided limited success. Alternatively, testicular or epididymal extraction of sperm via aspiration or biopsy may be used in cases refractory to medication. As with electroejaculation, this technique recovers a limited number of viable sperm and is best suited for use with ICSI.

Hypospermia, that is, low semen volume (<2 mL), impairs sperm transport into cervical mucus and can be associated with decreased sperm density or motility. Retrograde ejaculation may underlie this condition, and treatment follows that just described for aspermia.

Alternatively, hypospermia may follow partial or complete ejaculatory duct obstruction. In these cases, transurethral excision of the obstruction and reanastomosis of the ejaculatory ducts has resulted in marked semen parameter improvement, and pregnancies have been achieved. However, couples are counseled that postoperative complete obstruction of the ejaculatory ducts is not rare. Thus, consideration is given to cryopreservation of sperm prior to surgical attempts in those individuals with partial obstruction.

Abnormal Sperm Count

Azoospermia is characterized by the total absence of sperm in semen. This may result from male reproductive tract obstruction or from nonobstructive causes.

Obstructive azoospermia, especially resulting from prior vasectomy or ejaculatory duct obstruction, may be amenable to surgical treatment. However, congenital bilateral absence of the vas deferens (CBAVD) is a common cause of azoospermia and unfortunately is not treatable surgically. In such candidates, testicular sperm extraction (TESE) may be performed in conjunction with ICSI.

Nonobstructive azoospermia may be caused by a karyotypic abnormality such as Klinefelter syndrome (47,XXY) or balanced translocation; deletion of a small portion of the Y chromosome; testicular failure; or by unexplained causes. In many cases, TESE may be combined effectively with ICSI in those with Klinefelter syndrome and Y microdeletion of the AZFc region. However, in men with Y microdeletion in the AZFa or AZFb region, this ART combination has been ineffective (Choi, 2004).

Oligospermia is diagnosed if fewer than 15 million sperm are present per milliliter of semen. Causes are varied and include hormonal, genetic, environmental (including medications), and unexplained causes. Additionally, an obstructive cause, especially ejaculatory duct obstruction, should be considered if oligospermia is seen in conjunction with low semen volume. If severe oligospermia (<5 to 10 million sperm per mL) is noted, then an evaluation similar to that for azoospermia is warranted.

Oligospermia in the absence of decreased sperm motility not uncommonly reflects hypogonadotropic hypogonadism. In general, hypogonadotropic hypogonadism is best treated with FSH and hCG administered to the male. Alternatively, clomiphene citrate and aromatase inhibitors, although not FDA-approved treatment for this indication, may be considered for some males, especially if obesity and elevated serum estradiol levels are present. Spermatogenesis is a long process lasting approximately 100 days. Thus, several months may be required to identify significant improvements in sperm density with either treatment.

Environmental factors such as excessive exposure to high temperatures should be investigated. Drug and medication history is also obtained. If an environmental factor is identified, correction may improve sperm numbers.

Abnormal Sperm Motility or Morphology

Asthenospermia, that is, decreased sperm motility, may be seen alone or in combination with oligospermia or other abnormal semen parameters. In general, asthenospermia does not respond to directed treatments. Expectant management may be considered especially if the duration of infertility is short and maternal age is less than 35 years. For treatment, IUI and ICSI are preferred, although IUI is generally not successful in severe cases (Centola, 1997). If fewer than 1 million motile sperm are available for insemination following semen processing or the couple has experienced more than 5 years of infertility, then ICSI is considered as initial therapy (Ludwig, 2005).

Teratozoospermia or abnormal sperm morphology is most often seen in conjunction with oligospermia, asthenospermia, and oligoasthenospermia. Directed treatments for teratozoospermia are not available, and therapy options include IUI and ART. Because teratozoospermia may commonly be accompanied by sperm function defects that may impair fertilization, ICSI is considered if ART is selected.

Varicocele

This results from dilatation of the pampiniform plexus of the spermatic vein and is usually left-sided (Fig. 19-3). Traditional treatment is surgical ligation of the internal spermatic vein. With ligation, several surgical techniques have been employed, but retroperitoneal high ligation and transinguinal ligation are the most frequently performed. More recently, interventional radiographic techniques that selectively catheterize and embolize the internal spermatic vein with sclerosing solutions, tissue adhesives, or detachable balloons or coils have been used as alternatives. Despite the widespread application of varicocele treatments, there is insufficient evidence to conclude that treatment of a clinical varicocele in couples with male subfertility improves the likelihood of conception (Evers, 2003).

This may represent one of the most common infertility diagnoses, and its reported prevalence has reached as high as 30 percent (Dodson, 1987). The diagnosis of unexplained infertility is highly subjective and depends on the diagnostic tests performed or omitted and on their quality. Paradoxically, a diagnosis of unexplained infertility, therefore, will more often be reached if the evaluation is incomplete or poor quality (Gleicher, 2006). Nevertheless, an unexplained infertility diagnosis can, by definition, not be directly treated. Expectant management may be considered especially with infertility of short duration and with relatively young maternal age. However, if treatment is desired, then IUI, superovulation, and ART are empiric appropriate interventions to consider.

This technique uses a thin flexible catheter to place a prepared semen sample into the uterine cavity. First, motile, morphologically normal spermatozoa are separated from dead sperm, leukocytes, and seminal plasma. This highly motile fraction is then inserted transcervically near the anticipated time of ovulation. Intrauterine insemination can be performed with or without superovulation and is appropriate therapy for treatment of cervical factors, mild and moderate male factors, and unexplained infertility.

If performed for cervical factors, IUI timed by urine LH surge is an initial strategy that achieves reasonable pregnancy rates of up to 11 percent per cycle (Steures, 2004). Although this rate is lower than that seen with superovulation combined with IUI, the side effects and costs of superovulation are avoided.

In contrast, for unexplained infertility and for male factors, IUI is most commonly performed in conjunction with superovulation. A combination of clomiphene citrate and IUI was evaluated by Deaton and colleagues (1990) in one randomized trial. The treatment group had a significantly higher pregnancy rate (9.5 percent) compared with controls (3.3 percent). Gonadotropin treatment (FSH or hMG) alone has been shown to increase the likelihood of pregnancy, but the benefit is markedly improved with the addition of IUI.

Assisted reproductive technology describes clinical and laboratory techniques used to achieve pregnancy in infertile couples for whom direct corrections of underlying causes are not feasible. In principle, IUI meets this definition. By convention, however, ART procedures are those that at some point require extraction and isolation of an oocyte as described in the following paragraphs.

In Vitro Fertilization

During IVF, mature oocytes from stimulated ovaries are retrieved transvaginally with sonographic guidance (Fig. 20-10). Sperm and ova are then combined in vitro to prompt fertilization (Fig. 20-11). If successful, viable embryos are transferred transcervically into the endometrial cavity using sonographic guidance (Fig. 20-12). As discussed earlier, prior to proceeding with IVF, hydrosalpinges are removed or tubal interruption performed to increase implantation rates and decrease the risk of miscarriage.

Similar to IUI, substantial benefit is achieved using controlled ovarian hyperstimulation prior to egg retrieval. Many ova are genetically or functionally abnormal. Thus, exposure of several ova to sperm results in an increased chance of a healthy embryo. Most often, a GnRH agonist is used in conjunction with gonadotropins (FSH or hMG). These agonists prevent the possibility of spontaneous LH surge and ovulation prior to egg retrieval. Optimally, 10 to 20 ova are harvested, and from these, one healthy embryo is ideally transferred back to the uterus.

Unfortunately, methods to determine embryo health are imperfect. Therefore, to maximize the probability of pregnancy, more than one embryo is typically transferred, thus resulting in increased risk of multifetal gestation. However, advances in culture conditions now permit embryos to be cultured to the blastocyst stage. This allows transfer of fewer embryos yet maintains high pregnancy rates (Langley, 2001).

Intracytoplasmic Sperm Injection

This variation of IVF is most applicable to male factor infertility. During the micromanipulation technique of ICSI, cumulus cells surrounding an ovum are enzymatically digested, and a single sperm is directly injected through the zona pellucida and oocyte cell membrane. Pregnancy rates with ICSI are comparable with those achieved with IVF for other causes of infertility. For azoospermic men, ICSI has made pregnancy in their partners possible. In these cases, sperm are mechanically extracted from the testicle or epididymis.

Gestational Carrier Surrogacy

This variation of IVF places a fertilized egg into the uterus of a surrogate rather than into the “intended mother.” Indications are varied, and this approach may be appropriate for women with uncorrectable uterine factors, for those in whom pregnancy would pose significant health risks, and for those with repetitive unexplained miscarriage.

Gestational carrier surrogacy has legal and psychosocial issues. In most states, a surrogate is the legal parent and therefore, adoption must be completed after birth to give the intended mother her parental rights. However, a few states have adopted specific laws that extend protection to the intended parents.

Egg Donation

This may be employed in cases of infertility associated with ovarian failure or diminished ovarian reserve. Additionally, the technique may also be used to achieve pregnancy in fertile women when offspring would be at risk for maternally transmitted genetic disease. Egg donors may be known to the recipient couple or more commonly are anonymous young women recruited by an agency or IVF center.

Egg donation can be performed using “fresh” oocytes or cryopreserved eggs. Fresh egg donation cycles require synchronization of the recipient’s endometrium with egg development in the donor.

To accomplish this, the egg donor completes one of the superovulation protocols outlined in Figure 20-2. Concurrently, if a recipient is not menopausal, GnRH agonists are used to suppress gonadotropin production in the receiving woman. This allows a scheduled priming of her endometrium with estrogen and progesterone. Following gonadotropin suppression, exogenous estrogen is given to the recipient. This estrogen administration begins just prior to the start of gonadotropin administration to the egg donor. After a donor receives hCG to allow the final stages of follicle and egg maturation, the recipient begins progesterone to prepare her endometrium. In the recipient, estrogen and progesterone are typically continued until late in the first trimester when placental production of these hormones is deemed to be adequate.

Gamete or Zygote Intrafallopian Transfer

Gamete intrafallopian transfer (GIFT) is similar to IVF in that egg retrieval is performed after controlled ovarian hyperstimulation. Unlike IVF, however, fertilization and early embryo development do not take place in the laboratory. Eggs and sperm are placed via catheter through the fimbria and deposited directly into the oviduct. This transfer of gametes is most commonly performed at laparoscopy. Like IUI, GIFT is most applicable for unexplained infertility and should not be considered for tubal factor causes.

This technique was most popular in the late 1980s and early 1990s. However, as laboratory techniques have improved, IVF has largely replaced GIFT. In general, GIFT is more invasive, provides less diagnostic information, and requires transfer of more than two eggs for optimal pregnancy chances, which increases the risk of higher-order multifetal gestation. Thus, the major indication for GIFT at present is to avoid the religious or ethical concerns that some patients may have with fertilization taking place outside the body.

Zygote intrafallopian transfer (ZIFT) is a variant of IVF with similarities to GIFT. Zygote transfer is not performed directly into the uterine cavity but rather into the fallopian tube at laparoscopy. If the transfer is completed after a zygote has begun to divide, the procedure is more accurately termed tubal embryo transfer (TET). Although a normal fallopian tube may provide a superior environment for the early-stage embryo, this advantage has been lessened with improvements in laboratory culture methods. Accordingly, ZIFT currently is considered most appropriately in the rare case in which transcervical transfer during IVF is technically not feasible.

Embryo, Oocyte, or Ovarian Tissue Cryopreservation

With IVF, many eggs are retrieved to ultimately produce one to three healthy embryos for transfer. This frequently leads to extra embryos. Successful freezing and thawing of embryos has been possible for two decades. Moreover, advances in cryoprotectants and techniques have allowed improved survival rates of embryos frozen at various developmental stages. With cryopreservation, these supernumerary embryos can yield pregnancies later, obviating the need for ovarian stimulation and egg retrieval. For some patients, avoidance of fresh transfer and cryopreservation of all embryos may improve the chance of pregnancy. This may be due to improve synchrony between the embryo and the endometrium (Doody, 2014).

Cryopreservation of unfertilized eggs had previously posed significant technical hurdles. These challenges have been largely overcome by the development of ultrarapid freezing techniques (vitrification). Because of this advancement and preliminary data confirming its safety, oocyte cryopreservation is no longer considered experimental. Egg freezing is useful in preserving the fertility potential of women facing gonadotoxic chemotherapy. This technique also provides greater timing flexibility to circumvent cycle synchronization during egg donation. As success improves, oocyte cryopreservation may assist women desiring to delay childbearing, although data are lacking regarding its efficacy in this patient population. Careful counseling is needed with regard to age and clinic-specific success rates (American Society for Reproductive Medicine, 2013a).

Distinct from oocyte freezing, ovarian tissue cryopreservation is an option to preserve reproductive potential. Candidates are patients who must urgently undergo aggressive chemotherapy and/or radiotherapy or who have other medical conditions requiring treatment that may threaten ovarian function and subsequent fertility. This fertility preservation strategy may be well suited for prepubertal girls or women with hormone-sensitive malignancies. One or both ovaries or ovarian cortex tissue is removed during laparoscopy or minilaparotomy. Postoperatively, the ovarian cortex is cut into small tissue slivers measuring 0.3- to 2-mm thick and cryopreserved. Successful pregnancies have been achieved following autologous transplantation of thawed cortical tissue into a pelvic site such as a contralateral ovary or pelvic sidewall. Some pregnancies have been achieved without further intervention, while others have required ART. Safety concerns include the risk for reintroducing a malignancy following transplantation. This risk may be greatest with blood-borne cancers such as leukemia. Although promising, this procedure is currently considered experimental (American Society for Reproductive Medicine, 2014).

In Vitro Maturation

This technique has been used to achieve pregnancy by aspirating antral follicles from unstimulated ovaries and culturing these immature oocytes to allow resumption and completion of meiosis in vitro. In vitro maturation (IVM) may be useful in patients with PCOS in whom stimulation poses a significant risk of OHSS. Recent data suggest that success rates with standard IVF remain superior to those with IVM (Walls, 2015). Additionally, long-term outcomes are unknown, thus IVM is deemed experimental (American Society for Reproductive Medicine, 2013b). In the future, refinement of this technique may make possible maturation of ova from preantral follicles. This could potentially allow preservation of fertility potential but without the need for subsequent autologous transplantation for women in whom gonadotoxic chemotherapy is required.

Preimplantation Genetic Diagnosis or Screening

These laboratory techniques identify genetic abnormalities in eggs or embryos prior to their transfer. Thus, risk for transmission of hereditable disease is a well-established indication for preimplantation genetic diagnosis (PGD). In contrast, preimplantation genetic screening (PGS) aims to identify embryonic aneuploidy resulting from gamete meiotic errors. Its proposed indications include recurrent miscarriage, advanced maternal age, and multiple failed IVF cycles.

PGD is no longer considered experimental, and implementation of newly developed methods for genetic analysis will likely continue to broaden its application (Society for Assisted Reproductive Technology, 2008). During this technique, cells are removed from a developing embryo. Multiple options exist regarding biopsy timing and genetic material source. Biopsy of the first and second polar body has the advantage of avoiding cell removal from the developing embryo. However, two separate micromanipulation procedures are required, and genetic abnormalities of paternal origin are not detected. Biopsy of cleavage-stage embryos (6- to 8-cell stage) allows evaluation of both maternal and paternal contribution to the genome (Fig. 20-13). However, biopsy at this stage may only partially reflect the embryo’s genetic makeup if mitotic nondisjunction has occurred and embryonic mosaicism has been created. In addition, biopsied normal embryos may have a slightly decreased implantation rate. Most recently, biopsy of the trophectoderm at the blastocyst stage has been suggested to hold several advantages (Fig. 20-14). The trophectoderm is the layer from which trophoblasts and thus the placenta develop. Biopsy from this layer allows evaluation of several cells but avoids removal of fetal cells. However, biopsy of embryos at this late stage may require embryo cryopreservation following biopsy if genetic analysis cannot be performed rapidly.

Once cells are extracted, they are tested for structural aberrations and/or aneuploidy. Common testing options include single-nucleotide polymorphism (SNP) plus comparative genomic hybridization (CGH) microarrays or quantitative polymerase chain reaction. To analyze single cells for disease-specific DNA mutations, linkage analysis and DNA sequencing are generally used. Most recently, next-generation sequencing (NGS) has been used for both PGS and PGD. NGS has the potential to improve genetic diagnosis in embryos, especially in terms of high-throughput automation (Fiorentino, 2014).

Complications of Assisted Reproductive Technology

In most cases, ART leads to successful delivery of healthy singleton pregnancies. However, some pregnancy complications may develop more frequently in those conceived using ART. Of maternal risks, preeclampsia, placenta previa, and placental abruption are more common in IVF-conceived pregnancies (Table 20-6). Of fetal risks, multifetal gestation, discussed earlier, is the most common. In addition, perinatal mortality, preterm delivery, low birthweight, and fetal-growth restriction have been implicated in IVF singleton gestations. These trends persist even following adjustment for age and parity (Reddy, 2007). Other studies, however, have not confirmed this increased risk (Fujii, 2010). Additionally, congenital anomalies and epigenetic issues are concerns (Table 20-7).

Discussions regarding the risks for congenital anomalies began shortly after the initial success of IVF and intensified following the use of ICSI. Specifically, studies do suggest a higher incidence of congenital anomalies in infants conceived with ovulation induction, IUI, or IVF compared with those from the general population (El-Chaar, 2009; Reddy, 2007). Interpretation of most published studies, however, is complex. For example, the patient population undergoing IVF is very different from the general obstetric population with respect to age and other factors. If data are adjusted for maternal age or duration of subfertility, the risk of congenital anomalies does not appear to be increased with ART (Shevell, 2005; Zhu, 2006). This implies that much of the risk is intrinsic to the infertile couple and not related to the procedure itself.

An increase in the risk of epigenetic issues has also been reported. Although these conditions appear to be rare, their importance cannot be overstated. For review, each autosomal gene is represented by two copies, or alleles, and one copy is inherited from each parent. For most genes, both alleles are expressed simultaneously. However, approximately 150 human genes are imprinted, and with these genes, only one of the alleles is expressed. Imprinted genes are under control of an imprinting center that directs embryogenesis and viability. Alteration of the cellular environment can interfere with this regulation and may follow gamete manipulation or inadequate in vitro culture conditions. As a result, accelerated embryo growth, birth complications, placental abnormalities, and polyhydramnios have been observed in nonhuman mammalian ART pregnancies. In humans, imprinted genes may contribute to behavior and language development, alcohol dependency, schizophrenia, and bipolar affective disorders. Imprinting may also increase risks for obesity, cardiovascular disease, and for childhood and adult cancers. Of imprinting disorders, only rates of the rare Beckwith-Wiedemann syndrome are currently suggested to be increased in human ART. Additionally, causation has not been conclusively proven. However, in view of the above increased risks, it is reasonable to consider more intensive prenatal assessment in pregnancies conceived by IVF.

Studies assessing cognitive development after ART have for the most part been reassuring, although conflicting studies do exist. Many studies are suboptimal due to small sample size, choice of comparison group, and confounding and mediating factors (Carson, 2010). Fortunately, currently available data suggest that the psychomotor development of preschool children conceived by IVF does not differ from that of naturally conceived children. Similarly, the socioemotional development of children conceived by IVF appears comparable with that of naturally conceived children (Ludwig, 2006).

The treatment of infertility is typically initiated only after a thorough investigation as outlined in the previous chapter. The initial focus is to identify lifestyle or environmental issues that may contribute to or cause the reproductive impairment. Obesity, adequate nutrition, and associated stress should not be overlooked. In general, it is desirable to correct any identifiable contributors to subfertility. In many cases, no obvious cause can be detected. In other couples, the cause(s) may be identifiable but not amenable to directed corrective therapies. In these circumstances, generalized fertility boosting strategies may be recommended. These treatments include IUI (with or without superovulation) and ART. Importantly, superovulation and ART are not without risks, and couples should be appropriately counseled. Additionally, these techniques may involve third parties (egg, sperm, or embryo donors or gestational carriers). These procedures are associated with unique psychosocial, legal, and ethical considerations. Emerging technologies such as preimplantation genetic testing bring additional ethical issues that must be confronted and resolved by both patient and practitioner.