Infertility and Assisted Reproductive Technologies

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Chapter 34 Infertility and Assisted Reproductive Technologies

It is estimated that 10% to 15% of couples in the United States are involuntarily infertile. Newer reproductive technologies such as in vitro fertilization (IVF) and embryo transfer are increasing the success of treatment for this condition.

A couple is considered infertile after unsuccessfully attempting to achieve pregnancy for 1 year. Infertility is termed primary when it occurs without any prior pregnancy and secondary when it follows a previous conception. Some conditions, such as azoospermia, endometriosis, and tubal occlusion, are more common in women with primary infertility, but virtually all conditions occur in both settings, making the distinction of little clinical significance.

Physiology of Conception

Conception requires the juxtaposition of the male and female gametes at the optimal stage of maturation, followed by transportation of the conceptus to the uterine cavity at a time when the endometrium is supportive of its continued development and implantation (see Chapter 4). For these events to occur, the male and female reproductive systems must be both anatomically and physiologically intact, and coitus must occur with sufficient frequency and at the proper time (preferably a few hours before) to the release of the oocyte from the follicle. Even when fertilization occurs, it is estimated that more than 70% of resulting embryos are abnormal and fail to develop or become nonviable shortly after implantation.

Considering the vast complexity of the reproductive process, it is remarkable that 80% of couples achieve conception within 1 year. More precisely, 25% conceive within the first month, 60% within 6 months, 75% by 9 months, and 90% by 18 months. The steadily decreasing rate of monthly conception demonstrated by these figures most likely reflects a spectrum of fertility extending from highly fertile couples to those with relative infertility. After 18 months of unprotected sexual intercourse, the remaining couples have a low monthly conception rate without treatment, and many may have absolute defects preventing fertility (sterility).

General Principles of Evaluation

Conception requires adequate function of multiple physiologic systems in both partners. Infertility may result from either one major deficiency (e.g., tubal occlusion) or multiple minor deficiencies. Failure to realize this important dictum may lead the inexperienced practitioner to overlook additional factors that might be more amenable to treatment than the one that has been identified. Infertility in about 40% of infertile couples has multiple causes. Therefore, in general, a complete infertility evaluation should be performed on each couple.

Age substantially decreases the rate of conception because of lower embryo quality, reduced ovulation, and possibly decreased coital frequency. From a large study of donor insemination, the strictly age-related reduction appears to be about one third for women aged 35 to 45 years. It is reasonable to begin the basic evaluation at 6 months in older patients and to consider starting treatment for unexplained infertility earlier in women older than 35 years of age.

Basic Evaluations

Evaluation and therapy may be started earlier when obvious defects are identified, or they may be delayed, for instance, when a correctable factor, such as infrequent intercourse, is identified.

In general, the first 6 to 8 months of evaluation involve relatively simple and noninvasive tests and the performance of a radiologic evaluation of tubal patency (hysterosalpingography, or HSG), which can sometimes have a therapeutic effect. In some studies, use of an oil-based dye about doubled the success rate after HSG. Operative evaluation by laparoscopy is thus reserved for the small proportion of couples who have not conceived after 18 to 24 months or who have specific abnormalities or indications of a probable pelvic factor.

To keep the status of the evaluation in mind, it is helpful to arrange the workup under a series of five categories that can be mentally reviewed at each visit. Table 34-1 shows the approximate incidence and the tests involved in the evaluation of each category. Box 34-1 summarizes the treatment options for infertility. In 5% to 10% of couples, no explanation can be found (idiopathic infertility).

TABLE 34-1 COMMON INFERTILITY FACTORS

Factor	Incidence (%)	Basic Investigations
Male, coital	40	Semen analysis
		Postcoital test
Ovulatory	15-20	Urinary luteinizing hormone self-test^∗; serum progesterone^∗
Cervical	5	Postcoital test
Uterine, tubal	30	Hysterosalpingogram
		Laparoscopy
Peritoneal	40	Laparoscopy

∗ Investigations only when menses are regular (every 22 to 35 days); oligomenorrhea generally requires treatment.

BOX 34-1 Treatment Options for Infertility

Male Factor Problems

Avoidance of alcohol and

Scheduled intercourse without toxic lubricants

Ligation of venous plexus for significant varicocele and low semen quality

IUI with washed sperm

Intracytoplasmic sperm injection combined with IVF

Donor sperm insemination (frozen and thawed from tested donor)

Ovulatory Factor Problems

Clomiphene citrate without or with hCG to trigger ovulation

Gonadotropins (hMG)—combination of LH and FSH, or pure FSH; low-dose regimen decreases risk for multiple pregnancies

IVF and embryo transfer

Donor egg IVF and embryo transfer for unresponsive age-related infertility

Cervical Factor Problems

Treatment of any lower reproductive tract infection

IUI with washed sperm

Uterine-Tubal Factor Problems

Tuboplasty (microsurgical technique more effective)

Tubal anastomosis for sterilization reversal; good results with laparoscopic technique

IVF

Peritoneal Factor Problems

Laparoscopic treatment of endometriosis or adhesions (see Chapter 25)

Medical treatment for endometriosis (see Chapter 25)

IVF

Unexplained Infertility

Trial of COS with or without IUI

IVF

COS, controlled ovarian hyperstimulation; FSH, follicle-stimulating hormone; hCG, human chorionic gonadotropin; hMG, human menopausal gonadotropin; IUI, intrauterine insemination; IVF, in vitro fertilization.

Etiologic Factors

MALE COITAL FACTOR

Characteristics	Quantity
Semen volume	2-5 mL
Sperm count	Greater than 20 million/mL
Sperm motility	Greater than 50%^∗
Normal forms	Greater than 30% standard morphology or greater than 14% “strict” morphology
White blood cells	Fewer than 10 per high-power field or 1 × 10⁶/mL

∗ At least 25% A motility or 40% A plus B motility.

An excessive number of leukocytes (more than 10 per high-power field) may indicate infection, but special stains are required to differentiate polymorphonuclear leukocytes from immature germ cells. Semen quality varies greatly with repeated samples. An accurate appraisal of abnormal semen requires at least three analyses. Periodic reassessment is necessary.

Endocrine evaluation of the male with subnormal semen quality may uncover a specific cause. Hypothyroidism can cause infertility, but there is no place for the empirical use of thyroxine. Low levels of gonadotropins and testosterone may indicate hypothalamic-pituitary failure. An elevated prolactin concentration may indicate the presence of a prolactin-producing pituitary tumor. An elevated level of follicle-stimulating hormone (FSH) generally indicates substantial parenchymal damage to the testes, as inhibin, produced by the Sertoli cells of the seminiferous tubules, provides the principal feedback control of FSH secretion. A response to any treatment is unlikely in the presence of an elevated level of FSH. However, the level of FSH is not helpful in predicting whether sperm will be recovered with testicular sperm extraction.

Treatment

The couple should be advised to have intercourse about every 1 to 2 days during the periovulatory period (e.g., days 12 through 16 of a 28-day cycle). Because infrequent coitus is a common contributing factor, firm advice in this regard can be beneficial. This “scheduled intercourse” can be disruptive and stressful, however, and insemination using husband or partner sperm may relieve considerable pressure on a couple.

The woman should be advised to lie on her back for at least 15 minutes after coitus to prevent rapid loss of semen from the vagina. Lubricants may be toxic to sperm. A nontoxic lubricant, Preseed, has been developed for infertile couples.

Smoking should be reduced or stopped, as should intake of alcohol. The use of saunas, hot tubs, or tight underwear should be discouraged, as should exposure to other environments that raise scrotal temperature, because these factors may affect spermatogenesis.

Low semen volume may provide insufficient contact with the cervical mucus for adequate sperm migration to occur. When a high semen volume coexists with a low count, infertility may result because a lower density of sperm contacts the cervical mucus. At present, these abnormalities of volume are most commonly treated with sperm washing and intrauterine insemination (IUI).

If low sperm density (oligospermia) or low motility (asthenospermia) is caused by hypothalamic-pituitary failure, injections of human menopausal gonadotropin (hMG) may be effective. The suppressive effects of hyperprolactinemia on hypothalamic function can be reversed by the administration of bromocriptine, a dopamine agonist. When low semen quality coexists with a varicocele (dilation and incompetence of the spermatic veins), improved semen quality, particularly motility, may occur with ligation of this venous plexus. Various medications (clomiphene, human chorionic gonadotropin [hCG], testosterone, and hMG) have been tried when no cause is apparent (idiopathic oligoasthenospermia), but none has proved effective. Because about 3 months is required for spermatogenesis and sperm transport to occur, frequent semen checks during treatment are unnecessary and serve only to discourage the patient.

If semen quality cannot be improved, IUI with close timing of the insemination to the precise point of ovulation is effective. By washing and concentrating the sperm into a small volume by centrifugation, large numbers of sperm can be placed into the uterus. Without washing, IUI must be limited to small amounts of semen, owing to marked cramping. Accurate timing may be accomplished either by measurement of daily luteinizing hormone (LH) concentrations or by controlled stimulation of the cycle with clomiphene or hMG, followed by administration of hCG when follicular diameter, as seen by ultrasonography, indicates maturity. Insemination may then be carried out within a few hours of ovulation, which occurs about 36 hours following the onset of the LH surge or hCG injection. When urinary LH testing is used, there is a delay of several hours between the onset of the surge and the positive urine test. It is advisable to test in the afternoon or evening, with insemination the following morning.

IVF is an effective treatment for the male factor because with intracytoplasmic sperm injection (ICSI), only one motile sperm for each egg is required. Finally, insemination with donor sperm is effective when the male factor is refractory to treatment.

OVULATORY FACTOR

History

Most women with regular cycles (every 22 to 35 days) are ovulating, particularly if they have premenstrual molimina (e.g., breast changes, bloating, and mood change). Recent studies indicate reduced fecundity associated with very irregular cycles.

Investigations

The simplest screening tests to confirm reasonably normal ovulation are serial measurement of urinary LH, which assesses the duration of luteal function, and the mid-luteal level of serum progesterone, which assesses the level of luteal function. The interval from the urinary LH surge to the onset of menses should be at least 12 days. An older test of ovulation, the basal body temperature, is now seldom used. A luteal progesterone level of greater than 5 ng/mL indicates ovulatory activity, but mid-luteal concentrations usually exceed 10 ng/mL in cycles in which conception can take place. Because of the marked pulsatile secretion of progesterone, a level between 5 and 40 ng/mL can be found in the normal luteal phase.

Despite ovulation, an inadequate luteal phase may be responsible for infertility. Endometrial biopsy, considered for many years to accurately reflect luteal function, has been recently shown to be a very imprecise test, causing most practitioners to abandon it as a tool to assess ovulation.

Treatment

Use of fertility drugs such as clomiphene citrate or gonadotropins will correct any luteal insufficiency in women with unexplained infertility.

In women whose menses are less frequent than every 35 days (oligomenorrhea), it is helpful to induce more frequent ovulation, thus increasing the opportunity for pregnancy and improving the ability to time coitus. Ovulation induction should always be preceded by a thorough workup, as discussed in Chapter 32, because conditions causing anovulation may be worsened by pregnancy or may complicate it. In addition, ovarian failure seldom responds to attempts to induce ovulation.

The choice of the most appropriate technique for ovulation induction is determined by the patient’s specific diagnosis. With this approach, regular ovulation can be restored in more than 90% of anovulatory women. Provided that these patients persevere with treatment for an adequate period of time, and no other infertility factors are present, their fertility should approximate that of normal women.

Pituitary insufficiency requires the injection of hMG (follicle-stimulating hormone [FSH] and LH). Hypothalamic amenorrhea is caused by infrequent or absent pulsatile release of gonadotropin-releasing hormone (GnRH). GnRH is highly effective when administered in small pulses subcutaneously or intravenously in these patients every 90 to 120 minutes by a small portable infusion pump. Because this treatment is not currently as available in the United States, hMG is used, but with a much higher risk for multiple pregnancy. Hyperprolactinemia and its suppressive effect on the hypothalamus are specifically treated by use of the dopamine agonists bromocriptine (Parlodel) and cabergoline (Dostinex).

Most of the remaining patients with anovulation have some form of polycystic ovarian syndrome (PCOS) and generally respond to clomiphene, an orally active antiestrogen. Anovulation occurs in patients with polycystic ovaries because of chronic, mild suppression of FSH release. These women often have both increased ovarian and increased adrenal androgen production. Clomiphene, by inhibiting the negative feedback effect of endogenous estrogen, causes a rise of FSH and stimulation of follicular maturation. One of the principal causes of excessive ovarian androgen production is higher circulating insulin concentrations because of insulin resistance. Metformin, which reduces glucose mobilization and increases insulin sensitivity, is currently being used together with clomiphene or gonadotropins to improve response as well as to reduce an excessive response to ovulation induction. Metformin can also be used alone and may result in ovulation and pregnancy.

Other treatments used to induce ovulation in PCOS are laparoscopic “ovarian drilling,” in which multiple small craters are created with laser or cautery, and dexamethasone, which increases the ovarian response to clomiphene. Surgery is not often recommended because of the possibility of causing scarring around the ovaries and tubes.

If ovulation does not occur with clomiphene, follicular development may be occurring, but the normal LH surge may fail to occur. This results in lack of follicular rupture. Assessment by serial pelvic ultrasonography and carefully timed hCG administration may lead to normal ovulation. If follicular maturation is not occurring, ovulation induction will require low-dose FSH or hMG.

The main complications of ovulation induction are related to excessive stimulation of the ovaries. Substantial enlargement of the ovary with clomiphene citrate can generally be avoided by examining the ovaries before each treatment course and by using the lowest effective dose. Cystic ovarian enlargement is not an uncommon complication of hMG treatment but almost always regresses spontaneously. The hyperstimulation syndrome is a critical illness associated with marked ovarian enlargement and exudation of fluid and protein into the peritoneal cavity. The use of serum estradiol measurements, transvaginal ultrasonic scanning, and low-dose gonadotropin has greatly reduced the incidence of hyperstimulation syndrome. When starting at 50 to 75 units and increasing the dose by 25 to 50 units every 7 days if follicular maturation is not detected, there is a marked reduction in the incidence of multifollicular development, hyperstimulation, and multiple pregnancy. Multiple pregnancy occurs in 6% to 8% of clomiphene citrate conceptions, with less than 1% of cases exceeding twins. Multiple gestation occurs in 20% to 30% of hMG conceptions, and 5% of these conceptions are multiple births of more than two. Ultrasonic monitoring reduces this risk if the hCG is withheld in the presence of an excessive number of mature follicles. Current use of a low-dose regimen of hMG or pure FSH reduces the overall risk for multiple pregnancy to about 5%.

CERVICAL FACTOR

During the few days before ovulation, the cervix produces profuse watery mucus (spinnbarkeit) that exudes out of the cervix to contact the seminal ejaculate. To assess its quality, the patient must be seen during the immediate preovulatory phase (days 12 to 14 of a 28-day cycle). Spuriously abnormal results can be reduced by timing the test to the morning after the urinary LH surge.

Investigations

The amount and clarity of the mucus is recorded. The spinnbarkeit may be tested by touching the mucus with a piece of pH paper and lifting vertically. The mucus should extend in a thread to at least 6 cm. The pH should be 6.5 or greater. A postcoital (Sims-Huhner) test is performed 2 to 12 hours after intercourse to assess the number and motility of spermatozoa that have entered the cervical canal. The number of sperm, however, does not correlate well with semen quality, recovery of sperm from the cul-de-sac, or subsequent fertility. Consequently, the predictive value of this test for fertility is low. Although many practitioners have abandoned this test, treatment for poor mucus may avoid the morbidity and expense of fertility drugs.

Treatment

Any cervical infection is treated by prescribing a 10-day course of doxycycline, 100 mg twice daily, for both partners. Persistent chronic cervicitis may be treated with cryotherapy if antibiotic treatment fails. Poor mucus quality can be treated (bypassed) with IUI.

Abnormalities of the uterine cavity are seldom the cause of infertility. Large submucosal myomas or endometrial polyps, as seen in Figure 34-1, may be associated with infertility and first-trimester spontaneous abortions. The role of intramural myomas is not clear, although myomectomy has been associated with conception in 40% to 50% of couples in uncontrolled series, and some studies with IVF have shown reduced conception with intramural myomas. Subserous fibroids do not affect fecundity.

FIGURE 34-1 Photograph of a significant submucous polyp (bottom center) seen at the time of hysteroscopy.

Tubal occlusion may occur at three locations: the fimbrial end, the mid-segment, or the isthmus-cornu. Fimbrial occlusion is by far the most common. Prior salpingitis is a common cause of tubal occlusion, although about half of cases are not associated with any such history. Isthmic-cornual occlusion can be congenital or caused by mucus plugs, endometriosis, tubal adenomyosis, or prior infection. Mid-segment occlusion can be seen after surgery or infection with tuberculosis.

Investigations

Tubal abnormalities may be diagnosed by HSG or laparoscopy. To perform HSG, an occlusive cannula is placed in the cervix, and the instillation of a radiopaque dye is followed with image intensification under fluoroscopy. Selected radiographs are taken for permanent documentation (Figure 34-2). Anesthesia generally is not required. A water-soluble dye is used initially to confirm tubal patency because of the adverse effects of sequestration of an oil-based dye within the lumen of an occluded tube. If patency is confirmed, an oil-based dye may then be instilled because of its prominent therapeutic effect in women with unexplained infertility. If only one tube fills with dye, the hysterosalpingogram should be considered normal because this finding is usually, although not invariably, caused by the dye following the path of least resistance.

FIGURE 34-2 Normal hysterosalpingogram showing free spill of contrast material (A) and bilateral hydrosalpinges (B).

Serious infections can result from HSG. Confirmation of a normal pelvic examination and prophylactic doxycycline should reduce this risk to a minimum.

Treatment

In most circumstances, microsurgical tuboplasty is more effective than conventional surgical techniques for reversal of tubal occlusion. About 60% to 80% of patients achieve pregnancy after reversal of sterilization using microsurgical techniques. Tubal anastomosis may be carried out laparoscopically, with good results in experienced hands.

When performed for fimbrial occlusion, neosalpingostomy is associated with a success rate of 20% to 30%, although it has reached 40% with long-term follow-up. Most often this is done by laparoscopy. Because a hydrosalpinx reduces the success rate of IVF by about 50%, any hydrosalpinx not repaired should be removed or its communication with the uterus interrupted by cautery or clips.

For an isthmic-cornual occlusion caused by disease, clearing the obstruction with oral danazol has been reported when the occlusion coexists with peritoneal endometriosis. Selective catheterization has restored patency in most proximal occlusions and should be the first line of therapy. Microsurgical resection and reanastomosis are associated with a 50% to 60% pregnancy rate. If the intramural portion of the tube is occluded, reimplantation is required, with a new opening being made into the endometrial cavity. A substantially lower rate of success is achieved in this circumstance, a laparotomy is required, and similar success can be achieved with a single cycle of IVF.

At least 10% of conceptions after repair of diseased tubes are ectopic pregnancies. Anastomosis of healthy tubes carries a risk for ectopic pregnancy of about 3% to 5%. This possibility must always be considered in the management of an early pregnancy following tuboplasty.

PERITONEAL FACTOR

Laparoscopy identifies previously unsuspected pathologic conditions in 30% to 50% of women with unexplained infertility. Endometriosis is the most common finding. Periadnexal adhesions may be found and may hold the fimbriae away from the ovarian surface or entrap the released oocyte.

Endometriosis may interfere with tubal motility, cause tubal obstruction, or cause adhesions that directly disturb the pick-up of the oocyte by the fimbriae. Other mechanisms of endometriosis-associated infertility must exist as well because even minimal endometriosis has some negative effect. In a randomized study of laparoscopic cautery versus no treatment for minimal endometriosis, treatment resulted in one of eight affected women conceiving. These same women, however, may conceive with other treatments used for unexplained infertility. There is a strong trend toward omitting laparoscopy in women who have no symptoms indicating pelvic disease and who have a normal pelvic examination, a normal HSG, and a normal pelvic ultrasound. A serum titer for antichlamydia antibodies may be helpful if this approach is taken, to avoid overlooking occult pelvic adhesions.

Treatment of endometriosis depends on its extent and is discussed further in Chapter 25. If substantial adhesions or endometriomas are present, laparoscopic surgery is preferable because these conditions generally do not respond to medical management. With advanced operative laparoscopic techniques, most endometriosis can be removed or ablated without laparotomy by using advanced instrumentation, lasers, or fulguration.

Danazol, GnRH agonists, and oral medroxyprogesterone acetate are effective treatments for symptomatic disease, with continuous oral contraception therapy being generally inferior. If minimal disease with scattered implants is found, simple cautery at the time of laparoscopy should suffice.

Periadnexal adhesions may be lysed by operative laparoscopy. Microsurgical techniques diminish adhesions. The most effective adjunct in preventing recurrent scarring is the placement of an artificial tissue barrier, separating the raw surfaces during the early period of healing.

Because of the current high success rate with IVF, that treatment is often done as an alternative to the above surgeries. It is particularly important to conserve ovarian function as much as possible. If ovarian reserve is low, IVF is preferable to removal of an endometrioma, because of the compromised ovarian function that often results from ovarian surgery.

Unexplained Infertility

No cause is found for infertility in 5% to 10% of patients who have documented ovulation, normal semen analyses, and a normal HSG. The problem may be primarily one of sperm transport because IUI with washed sperm appears to increase the rate of conception. Some studies have shown subtle abnormalities of follicular growth and ovulation, partly explaining the increased fecundity with fertility drugs.

In other cases, a defect in the ability of the sperm to fertilize the egg may be present because a lower rate of fertilization is noted in couples with unexplained infertility who undergo IVF compared with couples in whom there is a tubal cause for infertility. Another male problem that may not be detected by routine evaluation is the presence of antisperm antibodies.

Other possible mechanisms of unexplained infertility include minimal endometriosis and mildly reduced ovarian reserve (reduced number of normal oocytes without hormonal abnormalities such as elevated FSH levels).

Intrauterine insemination, usually with controlled ovarian stimulation (stimulation of multiple follicles with clomiphene, gonadotropins, or both and hCG timing of insemination), is employed next. The final therapy is IVF.

Assisted Reproductive Technologies

The last resort for infertile couples with any of the aforementioned factors and failure of lesser treatments is the procedure of IVF and embryo transfer (Figure 34-3). In most cases of tubal occlusion in which the rate of success with tubal repair is low (<30%), IVF is preferable to surgery because of the more rapid conception rate and the lower ectopic pregnancy rate. Even severe male factors can be effectively treated with IVF by using intracytoplasmic sperm injection, with high fertilization rates of injected oocytes and pregnancy rates similar to those of non–male-factor IVF (30% to 35%).