ACOG PRACTICE BULLETIN

CLINICAL MANAGEMENT GUIDELINES FOR OBSTETRICIANGYNECOLOGISTS NUMBER 34, FEBRUARY 2002

This Practice Bulletin was developed by the ACOG Committee on Practice Bulletins Gynecology with the assistance of Robert Barbieri, MD. The information is designed to aid practitioners in making decisions about appropriate obstetric and gynecologic care. These guidelines should not be construed as dictating an exclusive course of treatment or procedure. Variations in practice may be warranted based on the needs of the individual patient, resources, and limitations unique to the institution or type of practice.

Management of Infertility Caused by Ovulatory Dysfunction

Approximately 20% of infertile women have ovulatory disorders (1, 2). In infertile women with ovulatory disorders, the cause of anovulation will guide the selection of an appropriate treatment plan. Advances in reproductive endocrinology allow the generalist obstetriciangynecologist to provide treatment that results in successful ovulatory stimulation and pregnancy in most women with ovulatory disorders.

Background
Etiology
Ovulatory dysfunction is likely to be present in women with polymenorrhea or oligomenorrhea and is almost always present in women with amenorrhea (except in patients with uterine disease, such as uterine synechiae or Ashermans syndrome). Regular menstrual cycles, with a cycle length between 22 and 35 days, and the presence of premenstrual bloating, dysmenorrhea, and breast tenderness suggest the presence of ovulatory cycles. Laboratory methods for determining ovulation include the basal body temperature chart, urine testing for the luteinizing hormone (LH) surge, properly timed measurement of serum progesterone, and endometrial biopsy. Serial pelvic ultrasonography also may be able to identify the growth and rupture of a follicle, suggesting that ovulation has occurred. Basal body temperature charts are inexpensive but may be a burden to the patient to complete and only document ovulation retrospectively. The pulsatile ovarian secretion of progesterone in the luteal phase may decrease the sensitivity of a single measurement of progesterone, but a serum progesterone level higher than 3 ng/mL is highly specific for detecting ovulation. (These tests also can detect ovulation in induced cycles.)

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If anovulation or clinically significant oligo-ovulation has been documented, a complete physical examination and selected laboratory testing are important to identify the etiology of the ovulatory dysfunction. The most common causes of ovulatory dysfunction are 1) polycystic ovary syndrome (PCOS) (approximately 70% of cases of ovulatory dysfunction) (3), 2) hypothalamic amenorrhea, also known as hypogonadotropic hypogonadism (approximately 10% of cases), 3) hyperprolactinemia (approximately 10% of cases), and 4) premature ovarian failure, also known as hypergonadotropic hypoestrogenic anovulation (approximately 10% of cases) (4). During the physical examination, the practitioner should note the presence of galactorrhea, thyromegaly or other evidence of hypothyroidism or hyperthyroidism, acanthosis nigricans, hirsutism, acne, or signs of virilization. In addition, the patients body mass index (BMI) should be calculated. A BMI less than 20 may indicate hypothalamic ovulatory dysfunction (low gonadotropinreleasing hormone [GnRH] secretion, low LH and follicle-stimulating hormone [FSH] secretion, low endogenous estrogen secretion) (5). The combination of amenorrhea and galactorrhea strongly correlates with hyperprolactinemia. The presence of acanthosis nigricans suggests the patient has a marked degree of insulin resistance. In general, clinicians should first recommend the least resource-intensive ovulation induction regimens that are appropriate for each cause of ovulatory dysfunction. For example, for women with hypogonadotropic hypogonadism and a BMI less than 20, weight gain may be associated with the resumption of normal menses.

In women with PCOS, many therapies are available to treat anovulatory infertility, including weight loss, clomiphene, clomiphene plus metformin, clomiphene plus glucocorticoid, gonadotropin injections, ovarian surgery, and in vitro fertilization-embryo transfer (IVF-ET). Using the principle of progressing from the least resource-intensive treatments to the most resource-intensive treatments, one potential strategy for organizing the care of women with PCOS is presented in the box.

Hypothalamic Anovulation
Hypothalamic anovulation (hypogonadotropic hypogonadism) usually is associated with low levels of GnRH secretion, low or normal levels of LH and FSH secretion, and low levels of endogenous estrogen secretion. Diseases associated with hypothalamic anovulation include anorexia nervosa, Kallmanns syndrome, and hypothalamic tumors and cysts. Factors associated with hypogonadotropic hypogonadism include a low BMI (<20); high-intensity exercise; certain dietary patterns, including high-fiber, low-fat diets; and excessive stress. One approach to treating this condition is to reverse the lifestyle factors that contribute to the anovulation. For example, in one study of 26 underweight women who practiced strict dieting and were infertile, the subjects were counseled by a dietitian and given physician-directed advice to increase their BMI (5). After the intervention, the women gained a mean 3.7 kg, and 73% of the women became pregnant. Decreasing the intensity of

A Step-by-Step Approach to Ovulation Induction in Women with PCOS The least resource-intensive interventions are recommended in the early steps in the protocol, while the most resource-intensive interventions are reserved for later treatment. Step 1. If the BMI is higher than 30, recommend weight loss of at least 10% of body weight. Step 2. Prescribe clomiphene to induce ovulation. Step 3. If DHEAS is higher than 2 g/mL, consider combining clomiphene with a glucocorticoid to induce ovulation. Step 4. If clomiphene does not result in ovulation, consider a combination of metformin plus clomiphene. Step 5. Initiate low-dose FSH injections. Step 6. Initiate low-dose FSH injections plus metformin. Step 7. Consider laparoscopic ovarian surgery or in vitro fertilization.

Polycystic Ovary Syndrome

Polycystic ovary syndrome is defined as the presence of oligomenorrhea or amenorrhea and hyperandrogenism in the absence of other hyperandrogenic disorders, such as androgen-secreting tumors or nonclassical adrenal hyperplasia. Clinical evidence of hyperandrogenism includes hirsutism and acne. Laboratory evidence of hyperandrogenism includes an elevated total, bioavailable, or free testosterone concentration. Elevated serum dehydroepiandrosterone sulfate (DHEAS) or androstenedione levels also are evidence of hyperandrogenism. The morphologic characteristics of polycystic ovaries as demonstrated on pelvic ultrasonography are not essential for the diagnosis of PCOS but support the diagnosis. In women of reproductive age, the prevalence of PCOS is approximately 5%, making it one of the most common reproductive disorders (3). Among women with ovulatory dysfunction, about 70% have PCOS (3).

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exercise and stress also may help improve the rate of ovulation in some of these women. However, no welldesigned clinical trials testing these recommendations have been reported. In the past, one option for ovulation induction for hypogonadotropic hypogonadism was the parenteral administration of GnRH in pulses using a portable programmable pump. It was associated with monofollicular ovulation and a high rate of singleton pregnancy but the pump is not commercially available in the United States (6, 7).

Hyperprolactinemia
The most common causes of hyperprolactinemia are a prolactin-secreting pituitary gland tumor and the use of psychiatric medications. The presence of hyperprolactinemia should be confirmed if there is any question about the timing of the blood test or the quality of the assay; blood should be drawn after the patient has fasted and preferably not after a breast examination or breast stimulation (8). All women with hyperprolactinemia should be tested for hypothyroidism (a thyroid-stimulating hormone screening or additional thyroid hormone testing as clinically indicated) and pregnancy (9). An imaging study (magnetic resonance imaging or computed tomography) of the central nervous system and the pituitary gland should be obtained in all women with hyperprolactinemia unless there is an obvious cause, such as hypothyroidism, that makes a pituitary gland tumor unlikely (10). If the imaging study reveals a macroadenoma of the pituitary gland (tumor diameter 10 mm), the patient should be referred to a physician with expertise in endocrinology or pituitary gland disease for consultation. Induction of ovulation in women with large pituitary gland tumors is associated with a high risk of neurosurgical complications during pregnancy (1113). In addition, women with large pituitary gland tumors may have undiagnosed adrenal insufficiency, a condition that poses significant health risks. For women with microadenomas (tumor diameter <10 mm) that secrete prolactin, the risk of pituitary insufficiency and neurosurgical complications during pregnancy is very low (<1%) (1113). Observational studies indicate that during 4 6 years of observation, 95% of microadenomas do not increase in size (14, 15).

pituitary gland secretion of FSH increases. An elevated random FSH level in amenorrheic or severely oligomenorrheic women or an elevated day-3 FSH level in women with menses is highly sensitive and specific for identifying women with a depleted ovarian follicular pool (16). If initial attempts at ovulation induction do not result in a pregnancy in women older than 37 years, consultation with an infertility specialist may be advisable to develop a plan for when assisted reproductive procedures, such as IVF-ET or oocyte donation should be pursued. Treatments proposed to induce ovulation in women with premature ovarian failure include 1) oral contraceptive suppression of gonadotropins followed by discontinuation of the oral contraceptive to allow a rebound in gonadotropin secretion and ovarian function, 2) GnRHagonist suppression of gonadotropin secretion followed by high-dose gonadotropin injections, and 3) glucocorticoid suppression of the immune system. None of these treatments has demonstrated efficacy in randomized clinical trials for inducing ovulation in women with premature ovarian failure (17). Women with infertility, ovulatory dysfunction, and an elevated FSH level should be referred to a physician with specialized expertise in treating infertility.

Luteal Phase Deficiency

Luteal phase deficiency is a theoretical disorder in which ovulation occurs, but there is insufficient progesterone production by the corpus luteum to allow for successful implantation. Luteal phase deficiency is thought to cause recurrent pregnancy loss, especially in the first trimester, and is believed to be responsible for a subset of cases of infertility. Studies that have attempted to establish luteal phase deficiency as a cause of infertility have not included control groups of fertile women. However, women who have regular menstrual cycles may have luteal phase abnormalities in as many as 31% of their cycles (18). Methods to diagnose and treat luteal phase deficiencies, therefore, are largely speculative. Because current infertility treatment often includes empiric treatment for unexplained infertility, most women who have luteal phase deficiencies and are infertile will receive treatment that includes controlled ovarian hyperstimulation. Therefore, a therapy specific to luteal phase deficiency is not being aggressively pursued.

Age-Related Ovulation Dysfunction and Premature Ovarian Failure

As the ovarian follicular pool depletes with age, the remaining follicles appear to be less capable of fertilization and establishing a successful pregnancy. Inhibin B production by the small follicles decreases with age, the inhibin suppression of FSH secretion decreases, and

Treatment Options
Clomiphene Citrate
The precise mechanism of action of clomiphene citrate is not completely understood. The administration of clomiphene to anovulatory women with endogenous

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estrogen secretion often is followed by an increase in both hypothalamic GnRH secretion and pituitary LH and FSH secretion, which causes follicle growth, triggering the LH surge and ovulation. Clomiphene treatment is most effective in women with normal FSH levels and adequate endogenous production of estrogen and is least effective in women with hypothalamic amenorrhea or in women with an elevated basal FSH concentration (19). In women with PCOS, the presence of obesity, elevated testosterone concentration, and severe insulin resistance decreases the efficacy of clomiphene citrate (20). Most women with hypogonadotropic hypogonadism do not ovulate in response to treatment with clomiphene. Most clomiphene-induced pregnancies occur within the first three menstrual cycles, and the vast majority occur within 6 months. There is no benefit to increasing the dosage once ovulation has occurred or to continuing beyond 6 months of treatment (21). Clomiphene administration in anovulatory women differs from superovulation, or controlled ovarian hyperstimulation, which is frequently attempted in couples with unexplained infertility. With clomiphene, monofolliculogenesis is the goal, and adjunctive treatments, such as intensive follicle monitoring and intrauterine insemination, do not have a defined role. With superovulation, women are already ovulatory; clomiphene, if administered, is typically given with human chorionic gonadotropin (hCG) to ensure ovulation, and intrauterine insemination also is appropriate.

Metformin
Metformin is an oral biguanide antihyperglycemic agent approved for the treatment of adult-onset diabetes mellitus. It is a category-B drug used by some clinicians to treat diabetes mellitus in pregnant women. Metformin decreases blood glucose levels by inhibiting hepatic glucose production and by enhancing peripheral glucose uptake. Metformin increases insulin sensitivity at the postreceptor level and stimulates insulin-mediated glucose disposal. Unlike sulfonylureas, metformin does not cause hypoglycemia because it does not increase insulin secretion. Unlike phenformin, metformin does not block mitochondrial metabolism of lactate unless the patient has renal failure (renal failure will cause lactate to accumulate to very high concentrations) or severe hypoxia (mitochondrial dysfunction). Metformin is not approved by the U.S. Food and Drug Administration (FDA) for ovulation induction.

Dopamine Agonists
Dopamine-agonist drugs (bromocriptine, pergolide, cabergoline) are the treatment of choice for ovulation induction in women with hyperprolactinemia (23). Dopamine-agonist drugs directly suppress prolactin production by the tumor and cause an increase in endogenous GnRH secretion, which stimulates pituitary gland secretion of LH and FSH and consequently induces follicle development and ovulation. In addition, dopamine agonists decrease the size of prolactin-secreting pituitary gland tumors. With dopamine-agonist therapy, a near-maximal decrease in serum prolactin levels should be achieved after 4 weeks of treatment. Serum prolactin levels should be measured approximately 1 month after initiating therapy and about 1 month after a change in the dosage or drug. Normalization of prolactin levels is the therapeutic goal, as well as assuring that the tumor is responding to the dopamine agonists. If the serum prolactin concentration is normal and no side effects have occurred, the initial dosage should be continued. If the serum prolactin level has not decreased to normal and no side effects are present, the dosage should be gradually increased. The maximal dosage of bromocriptine is 5 mg twice daily; pergolide, 0.25 mg once daily. Cabergoline is the newest of these agents; it can be administered less frequently and may induce nausea less often. However, as a result of FDA approval, its use in pregnancy is extremely limited. Women who do not tolerate the side effects of bromocriptine may need to be referred to a practitioner with additional expertise in the field to discuss in detail the risks and benefits of newer therapies that have not been tested as thoroughly.

Gonadotropin Injection
Gonadotropins can be administered using human urinary menopausal gonadotropins, which contain both LH and FSH, or by using recombinant FSH. Both types of gonadotropins are effective in treating anovulation in women with PCOS. The use of gonadotropin injections to induce ovulation in women with PCOS is resource intensive and is associated with a high risk of adverse outcomes, such as ovarian hyperstimulation and highorder multiple pregnancy. Gonadotropin injections are effective in the treatment of hypothalamic anovulation. Women with hypothalamic anovulation who have a baseline serum LH level lower than 0.5 IU/L should be treated with both FSH and LH because they have a deficiency in both gonadotropins. Women with hypothalamic amenorrhea and a baseline LH level higher than 0.5 IU/L can be successfully treated with FSH alone (22). In most circumstances, the use of FSH injections to induce ovulation should be performed by physicians with advanced training in treating infertility.

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If the serum prolactin level does not decrease to normal, switching to a different dopamine agonist may be effective. If the patient cannot tolerate the dopamine agonist initially prescribed, a different dopamine agonist may be associated with fewer side effects. If the patient experiences side effects with all dopamine agonists, vaginal administration can be tried. If the patient cannot tolerate any of the dopamine agonists, transsphenoidal surgery may be effective in removing the tumor, returning prolactin secretion to normal, and causing the resumption of ovulatory menses. Following correction of hyperprolactinemia, about 80% of women will ovulate, and cumulative pregnancy rates of 80% are commonly observed (24). Treatment usually is discontinued once pregnancy is diagnosed. However, in women with a macroprolactinoma, therapy should be continued throughout pregnancy to decrease the risk of tumor growth and neurosurgical complications, such as compression of the optic nerve. In the small percentage of women with hyperprolactinemia who do not respond to dopamine-agonist therapy, standard ovulation induction therapy with clomiphene citrate may be considered. In rare cases, gonadotropin therapy may be considered.

Before using ovulation-inducing medications, it is useful to consider evaluating the couple for male factor infertility by performing a semen analysis. Routinely performing hysterosalpingography is unnecessary. However, if the woman has a history of sexually transmitted diseases, pelvic inflammatory disease, appendicitis with rupture, in utero exposure to diethylstilbestrol, or previous pelvic surgery, hysterosalpingography should be considered to establish tubal patency. Laparoscopy is not routinely necessary before ovulation induction. The age of the woman strongly influences the pregnancy rate with ovulation induction (see Fig. 1). In older women, this may lead to a greater sense of urgency and a rapid progression to more intensive treatments, with their greater associated risks (26, 27).

Does weight loss improve fertility in obese women?

Clinical Considerations and Recommendations

v How is the diagnosis of ovulatory dysfunction established?

In women with a high BMI, abnormal hypothalamic GnRH secretion, pituitary gland LH and FSH secretion, insulin resistance, and anovulation are common (28). Women with a BMI greater than 30 and oligo-ovulation often have PCOS. Epidemiologic studies have demonstrated that a BMI greater than 27 is associated with an increased risk of ovulatory infertility. For example, in one study of 597

cumulative pregnancy rate in women younger than 35 years cumulative pregnancy rate in women older than 35 years

If the patient is amenorrheic, the minimal laboratory evaluation should include measurement of serum levels of FSH, thyroid-stimulating hormone, and prolactin. If the patient has evidence of hyperandrogenism (eg, hirsutism, acne, signs of virilization), measurement of testosterone and DHEAS may have clinical value if ovulation induction is planned. Clinical evaluation may be used to determine if testing for Cushings syndrome or Addisons disease should be performed. If the patient has a BMI higher than 30, testing for diabetes mellitus may be indicated before inducing ovulation (25). To decrease the risk of congenital malformations, diabetes mellitus should be treated before inducing pregnancy. In women with irregular menses, attempting to obtain a luteal-phase progesterone measurement may be cumbersome and unnecessary if menses are relatively infrequent. Documenting ovulation by basal body temperature evaluation or LH surge testing may be helpful. Women with regular menses can be assessed for ovulatory status by any of the techniques described previously.

Figure 1. Cumulative pregnancy rates for hypogonadotropic anovulatory women treated with gonadotropins. (From Lunenfeld B, Insler V. Human gonadotropins. In: Wallach EE, Zacur HA, eds. Reproductive medicine and surgery. St. Louis: Mosby-Year Book, 1995:617)

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women with ovulatory infertility and 1,695 controls, the women with a BMI higher than 27 had a relative risk of ovulatory infertility of 3.1 (95% confidence interval, 2.2 4.4) when compared with the control group with a BMI of 2024.9 (29). Many studies (most without a control group) have demonstrated that in women who have PCOS and are obese, weight loss often is associated with a decrease in serum testosterone concentration, resumption of ovulation, and, for infertile women, pregnancy. For example, in one study, 18 obese women with PCOS were treated with a hypocaloric diet (30). Before the diet, the mean weight of the women was 77 kg; after the diet, it was 57 kg. The plasma testosterone concentration was 0.75 ng/mL before the diet and 0.39 ng/mL after (P <0.001). Many of the women resumed ovulation after weight loss. Another study evaluated the effects of weight loss on 20 obese women with PCOS (31). Before the diet, the women had a mean BMI of 32, amenorrhea for more than 3 months, and increased plasma concentrations of androstenedione, testosterone, or DHEAS. Following a hypocaloric diet of 1,0001,500 kcal per day, weight loss ranged from 4.8 kg to 15.2 kg. After weight loss, significant reductions in the concentration of LH (45% decrease), fasting insulin (40% decrease), and testosterone (35% decrease) were observed. After weight loss, most of the women ovulated, and many of the infertile women became pregnant. In a small trial that examined the effect of weight loss on reproductive function in 12 obese women with PCOS, the women were randomized to either a weight reduction program or a waiting list observation control group (32). The six women randomized to the weight reduction program had a mean weight decrease of 16 kg, a significant decrease in circulating testosterone concentration, and a decrease in fasting insulin; four of the six women resumed ovulating. The women randomized to the observational control group had no weight change during the study. All of the women in the control group who were anovulatory before the study (five) remained anovulatory during the study. Weight reduction is best achieved by a combination of diet and exercise. However, exercise at levels greater than 60 minutes per day has been associated with an increase in ovulatory infertility (33).

How is clomiphene citrate administered?

The FDA has approved clomiphene dosages of 50 mg or 100 mg daily for a maximum of 5 days per cycle. After spontaneous menses or the induction of menses with a progestin withdrawal, clomiphene is started on cycle day 3, 4, or 5 at 50 mg daily for 5 days. Starting clomiphene on cycle day 3 or 5 does not appear to influence the preg-

nancy rate (34). It is important to give clomiphene only after menstrual bleeding to help ensure that the patient is not pregnant. In properly selected women, approximately 50% will ovulate using the 50-mg daily dosage, and another 25% will ovulate if the dosage is increased to 100 mg daily (35). If lower dosages are not successful in inducing ovulation, many clinicians will prescribe 150 mg daily for 5 days; a few have used dosages as high as 250 mg daily for 5 days. However, the pregnancy rates associated with the use of clomiphene at dosages higher than 150 mg daily for 5 days are very low (21). In general, if the 150-mg dosage is not successful, alternative approaches to ovulation induction should be considered. Of those women who ovulate while taking clomiphene, between 40% and 80% will become pregnant. In one study of 3,022 women taking clomiphene, the pregnancy rate per ovulatory cycle was 20% (36). The pregnancy rate decreases substantially after six cycles of clomiphene therapy (37). Patients taking clomiphene should be monitored for ovulation, pregnancy, and ovarian enlargement, as clinically indicated. Ovulation can be determined by measuring serum progesterone levels (about 14 days after the last dose of clomiphene), basal body temperature charting, or properly timed endometrial biopsy. Detection of an LH surge in the urine suggests a preovulatory follicle has triggered the surge. Intense cycle monitoring with frequent measurement of serum estradiol levels and pelvic ultrasonography is generally not necessary with the use of clomiphene but is required for gonadotropin therapy. Clomiphene treatment can be associated with luteal phase defects and the suboptimal production of cervical mucus. Some clinicians recommend an endometrial biopsy in a test cycle of clomiphene treatment to assess whether clomiphene-induced ovulation is associated with luteal phase defect (38). A few authorities recommend a postcoital test be performed during the first clomiphene cycle to assess cervical mucus quality and quantity. However, little evidence exists to support either practice. Of clomiphene-induced pregnancies, 7% are twin gestations and 0.3% are triplet gestations (39). The rate of spontaneous abortion after clomiphene-induced pregnancy is approximately 15%. The incidence of birth defects is similar to that seen in spontaneous pregnancy (40). The most common symptoms experienced by women taking clomiphene include vasomotor symptoms (20%), adnexal tenderness (5%), nausea (3%), headache (1%), and, rarely, blurring of vision or scotomata (21, 41). Many clinicians permanently discontinue clomiphene treatment in women with clomiphene-induced visual changes. The main contraindications to the use of clomiphene are pregnancy, hypersensitivity to the medication, and ovarian cysts.

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v v

In women who do not ovulate using clomiphene alone, can the chances of ovulation be improved by adding glucocorticoids?

Women with PCOS and a serum DHEAS concentration higher than the middle of the normal range (>2 g/mL) appear to have decreased ovulation and pregnancy rates when they are treated with clomiphene. Some studies suggest treatment with clomiphene plus a glucocorticoid improves pregnancy rates in these women. One study randomized 64 anovulatory infertile women to receive either clomiphene, 50 mg daily on cycle days 59, or clomiphene plus 0.5 mg dexamethasone daily (42). If ovulation did not occur, the dosage of clomiphene was increased by 50-mg increments up to 150 mg daily for 5 days each cycle. The investigators observed significantly higher rates of ovulation and conception in women treated with clomiphene plus dexamethasone than with clomiphene alone. The impact of combined therapy was especially marked in the women with a DHEAS concentration higher than 2 g/mL. Of the women with a DHEAS concentration higher than 2 g/mL, 12 were randomized to receive clomiphene alone, and 13 were randomized to receive clomiphene plus dexamethasone. Among the 12 women receiving clomiphene alone, six (50%) ovulated and four (33%) became pregnant. Among the 13 women who received clomiphene plus dexamethasone, 13 (100%) ovulated and 11 (85%) became pregnant.

hCG injection was an inexpensive and potentially effective approach to treating women with PCOS who had failed to ovulate and become pregnant with standard clomiphene therapy (44). In that study, 38 infertile women with PCOS who had failed to ovulate when treated with clomiphene (150 mg daily for 5 days) and who had a DHEAS concentration lower than 2 g/mL took oral contraceptives (ethinyl estradiol 0.03 mg, and desogestrel 0.15 mg daily) for 2 months followed by clomiphene. Instead of the usual 7-day pill-free interval between cycles, the investigators prescribed a regimen with a 3-day pill-free interval. On cycle days 59 after completion of the second month of oral contraceptives, clomiphene (100 mg daily for 5 days) was prescribed. Transvaginal ultrasonography was initiated on cycle day 12 and repeated every 12 days until hCG was administered. When the mean diameter of the lead follicle reached 20 mm, hCG (10,000 units) was administered. The 38 women completed 95 treatment cycles. Sixtynine of the 95 cycles were ovulatory (73%), and 29 of the 38 women (76%) ovulated. Twenty-two pregnancies occurred. Most of the pregnancies (82%) occurred in one of the first three treatment cycles.

v v

In women who do not respond to clomiphene, does ovarian diathermy increase the chances of ovulation more than FSH?

In women who do not ovulate using clomiphene alone, can the chances of ovulation be improved by adding an hCG injection?

The combination of clomiphene plus a single dose of hCG may increase the efficacy of clomiphene induction of ovulation when women fail to ovulate with standard dosages of clomiphene (43). After the last dose of clomiphene, pelvic ultrasonography can be used to monitor follicle size. When the mean diameter of the lead follicle reaches 18 mm, a single dose of hCG can be administered. Ovulation occurs approximately 3644 hours after the injection. There are no randomized controlled clinical trials that document the efficacy of this approach. It has been proposed that a regimen of 2 months of oral contraceptives before ovulation induction with clomiphene followed by an hCG injection when follicle ripening has occurred may improve the rate of ovulation and pregnancy. No randomized clinical trial supports this approach. However, a clinical trial without controls reported oral contraceptive treatment followed by clomiphene therapy (100 mg daily for 5 days) plus an

A number of surgical techniques have been described that may increase the rate of ovulation in women with PCOS. To date, no randomized, controlled clinical trial has demonstrated the efficacy of surgery in this setting, but case series totaling more than 1,000 subjects have been published. Although ovarian wedge resection was the initial surgical procedure reported to increase ovulation in women with PCOS, this procedure has been replaced by laparoscopic techniques that use electrosurgical or laser energy. Overall, the case series report ovulation rates of 80% and pregnancy rates of 50% (45). For women with PCOS, ovulation induction with FSH also is associated with pregnancy rates of 50% (46). Injections with FSH for ovulation induction are associated with a high rate of multiple gestations (approximately 20%), and it is not known if ovarian diathermy affects ovarian reserve. Thus, treatment should be individualized.

In women with hyperprolactinemia, which medical treatments stimulate the resumption of ovulation?

Bromocriptine has been used for more than 25 years to induce ovulation in women with hyperprolactinemia. In one study of 280 women with hyperprolactinemia,

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bromocriptine normalized the circulating prolactin level in 82% of the women (47). The main side effects associated with bromocriptine are nausea, vomiting, and orthostatic hypotension. To minimize these potential side effects, it is recommended that bromocriptine be initiated at a dosage of 1.25 mg at bedtime. After 1 week, the dosage can be increased to 1.25 mg twice daily. The dosage can then be increased to 2.5 mg twice daily, a standard dosage that successfully decreases serum prolactin levels in most women with hyperprolactinemia (47). Pergolide, an ergot dopamine agonist, is approved by the FDA for the treatment of Parkinsons disease but is not approved for the treatment of hyperprolactinemia. Unlike bromocriptine, pergolide can be given once per day. Pergolide is the least expensive of the dopamine agonists.

In women with PCOS, what is the role of gonadotropins in inducing ovulation?

In one randomized clinical trial, low-dose FSH treatment appeared to improve outcomes and decrease adverse events when compared with standard-dose FSH treatment in women with PCOS (48). In this study, 50 infertile women with PCOS who had failed to conceive with clomiphene therapy were randomized to receive either conventional FSH treatment (75 IU daily, increasing by 75 IU every 56 days until follicular ripening occurred) or low-dose FSH treatment (75 IU daily for 14 days of treatment, increasing by 37.5 IU every 7 days thereafter until follicular ripening was complete). Compared with standard FSH treatment, women who received longterm, low-dose FSH treatment had more cycles with the development of a single dominant follicle (74% versus 27%), fewer high-order multiple gestations, and a higher pregnancy rate (40% versus 24%).

When should metformin be added for the treatment of ovulatory infertility?

Insulin sensitizers can be used alone or in combination with clomiphene to induce ovulation in infertile women with oligo-ovulation, hyperandrogenism, and insulin resistance (49). To date, no large-scale clinical trials have been published that demonstrate the impact of metformin on live birth rates in women with PCOS and insulin resistance. A few small clinical trials have been published demonstrating that in women with PCOS the combination of clomiphene plus metformin is associated with higher rates of ovulation and pregnancy than clomiphene plus a placebo (50, 51). In one study, women with PCOS who did not ovulate when treated with clomiphene (150 mg daily for 5 days) were randomized

to receive either metformin (1,500 mg daily) or placebo for 7 weeks (51). During the initial 7-week treatment period, one of the 12 women in the metformin group ovulated, and none of the 15 women in the placebo group ovulated. After this initial treatment period, all of the women received clomiphene citrate, beginning at a dosage of 50 mg daily for 5 days, with dosage escalation if ovulation did not occur. Nine of the 12 women in the metformin-plus-clomiphene group ovulated, compared with four of the 15 women in the placebo-plusclomiphene group (P < 0 .02). Of the women who completed the clinical trial, six (of 11) in the metforminplus-clomiphene group became pregnant, and one (of 14) in the placebo-plus-clomiphene group became pregnant (P <0.02). Of the six pregnancies in the metforminplus-clomiphene group, two resulted in spontaneous abortion and four resulted in live singleton births. The one pregnancy in the placebo-plus-clomiphene group resulted in a live singleton birth. A commonly used dosage of metformin is 500 mg three times daily. The most common side effects of metformin are gastrointestinal disturbances, including diarrhea, nausea, vomiting, and abdominal bloating. To minimize gastrointestinal side effects, many clinicians recommend starting metformin at 500 mg daily for 1 week, increasing to 500 mg twice daily for 1 week, and then increasing to 500 mg three times daily. Once the full dosage is achieved, some clinicians switch to a dosing regimen of 850 mg twice daily to improve patient compliance. Progesterone measurements can be periodically obtained to determine whether ovulation has occurred, or the patient can keep a basal body temperature chart. If ovulation has not occurred after 48 weeks of metformin therapy, clomiphene (50 mg daily for 5 days) can be administered after progestin-induced menstrual withdrawal bleeding. If the patient becomes pregnant, the metformin therapy can be discontinued. Ovulation, if it is going to occur, can be expected to occur within 68 weeks. In rare cases, metformin therapy has caused fatal lactic acidosis. In most of these cases, renal insufficiency or severe hypoxia (congestive heart failure, septic shock) was present. Before treatment with metformin is initiated, it is recommended that serum creatinine levels be demonstrated to be lower than 1.4 mg/dL. Women with liver dysfunction should not take metformin. Also, metformin should be discontinued 48 hours beforeand not restarted for 72 hours afterany radiologic test involving intravenous contrast or before surgery. Metformin appears to improve the ovulatory response in women with PCOS treated with FSH injections. A trial randomized 20 infertile women with PCOS and insulin resistance who had failed to ovulate when

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treated with clomiphene (150 mg daily for 5 days) to receive either FSH injections alone or FSH injections plus metformin (500 mg three times daily) (52). The mean BMI of the subjects was approximately 27. Compared with the women who received FSH alone, the women who received both FSH and metformin had fewer dominant follicles (2.4 versus 4.5, P <0.01), a lower peak estradiol concentration (450 pg/mL versus 720 pg/mL, P <0.001), and a lower cycle cancellation rate (0% versus 32%, P < 0.03). The investigators concluded a combination of FSH plus metformin is associated with an orderly follicular response that probably decreases the risk for ovarian hyperstimulation and multiple pregnancy.

Is the risk of ovarian cancer increased with the use of induction agents, such as clomiphene or gonadotropin injections?

Is a postcoital test useful in a patient taking clomiphene citrate?

The postcoital test has low reproducibility and low interobserver reliability and has not been proved to help guide treatment recommendations (5355). In addition, there is little consensus on what constitutes an abnormal postcoital test result. Given these limitations, there is little scientific rationale for performing a postcoital test. However, clinical experience suggests that clomiphene, acting as an antiestrogen in the cervix, can cause cervical mucus production that is abnormal in quantity and quality. Therefore, some clinicians recommend performing a postcoital test to assess the impact of clomiphene on cervical mucus production.

Can the risk of multiple gestation be minimized?

Multiple gestation is a growing problem. Public awareness is increasing about the hazards associated with multiple births, as well as the long-term costs and consequences (56). Monofolliculogenesis is the goal of therapy in infertile patients. To decrease the risk of multiple gestation, treatments associated with low rates of multiple gestation should be used. For example, in women with PCOS, ovulation induction with weight loss, clomiphene, clomiphene plus metformin, clomiphene plus glucocorticoid, and ovarian surgery are associated with low rates of triplet pregnancy. Gonadotropin injections and in vitro fertilization are associated with higher rates of multiple gestation (48). When using gonadotropin injections, the use of low-dose regimens appears to be associated with lower rates of multiple gestation than the use of standard dose regimens. In addition, the risk of multiple gestation with FSH injections can probably be decreased by withholding hCG and prescribing a barrier contraceptive whenever more than three follicles greater than 15 mm in diameter are detected with pelvic ultrasonography.

The risk of ovarian cancer is increased in women who are nulligravid (voluntarily and involuntarily) and women with a strong family history of ovarian cancer. The risk of ovarian cancer is decreased by pregnancy, use of oral contraceptives for more than 6 months, surgical tubal ligation, and hysterectomy. Preliminary studies reported ovulationinducing medications may be associated with a small increase in the risk of ovarian tumors (borderline tumors and cancer) and that the risk may increase with the extended use of ovulation-inducing agents for many months (57, 58). In one of these studies, the strongest risk occurred among 13 nulligravid women who had used infertility drugs and had never become pregnant. In this subset, the association was statistically significant, but the confidence interval was wide, suggesting a great deal of variation, and the sample size was small (n=13). Some practitioners believe infertility (involuntary childlessness) is a more powerful risk factor for ovarian tumors than treatment with an ovulation-inducing medication. However, given the low pregnancy rates observed after six cycles of ovulation induction with an induction agent (such as clomiphene) and the potential (although low) risk that 12 or more cycles of clomiphene may be associated with an increased risk of ovarian tumors, it is reasonable to limit clomiphene treatment to fewer than 12 cycles. There are no evidence-based guidelines about the appropriate duration of gonadotropin administration; however, given the possibility that such agents can cause harm, it seems appropriate to use them sparingly and only with clear-cut indications.

v v

Summary of Recommendations
The following recommendations are based on limited or inconsistent scientific evidence (Level B): v v
In obese women with PCOS, weight loss should be considered because it is associated with a decrease in circulating testosterone concentration, an increase in the frequency of ovulation, and in some women, pregnancy. In obese women with PCOS who did not ovulate when treated with clomiphene, the combination of clomiphene plus metformin may be considered because the rate of ovulation is greater than it is with clomiphene alone.

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v v v
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In women with PCOS and a serum DHEAS level higher than 2 g/mL, the combination of clomiphene plus glucocorticoid may be considered because the rate of ovulation is greater than it is with clomiphene alone. In women with hypothalamic amenorrhea and a BMI lower than 20, weight gain should be considered because it may be associated with the resumption of ovulation and pregnancy. In women with PCOS receiving gonadotropin injections for ovulation induction, low-dose FSH may be considered because it is associated with a higher rate of cycles with the development of a single dominant follicle and fewer high-order multiple gestations.

of pituitary tumors and other abnormal intrasellar masses. Retrospective analysis of 353 patients. Medicine (Baltimore) 1999;78:236269 (Level II-2) 11. Gemzell C, Wang CF. Outcome of pregnancy in women with pituitary adenoma. Fertil Steril 1979;31:363372 (Level III) 12. Lamberts SW, Klijn JG, de Lange SA, Singh R, Stefanko SZ, Birkenhager JC. The incidence of complications during pregnancy after treatment of hyperprolactinemia with bromocriptine in patients with radiologically evident pituitary tumors. Fertil Steril 1979;31:614619 (Level III) 13. Griffith RW, Turkalj I, Braun P. Pituitary tumors during pregnancy in mothers treated with bromocriptine. Br J Clin Pharmacol 1979;7:393396 (Level III) 14. Sisam DA, Sheehan JP, Sheeler LR. The natural history of untreated microprolactinomas. Fertil Steril 1987;48: 6771 (Level II-3) 15. Schlechte J, Dolan K, Sherman B, Chapler F, Luciano A. The natural history of untreated hyperprolactinemia: a prospective analysis. J Clin Endocrinol Metab 1989;68: 412418 (Level III) 16. Scott RT Jr, Hofmann GE. Prognostic assessment of ovarian reserve. Fertil Steril 1995;63:111 (Level III) 17. van Kasteren YM, Hoek A, Schoemaker J. Ovulation induction in premature ovarian failure: a placebo-controlled randomized trial combining pituitary suppression with gonadotropin stimulation. Fertil Steril 1995;64: 273278 (Level II-1) 18. Davis OK, Berkeley AS, Naus GJ, Cholst IN, Freedman KS. The incidence of luteal phase defect in normal, fertile women, determined by serial endometrial biopsy. Fertil Steril 1989;51:582586 (Level III) 19. Hull MG, Knuth UA, Murray MA, Jacobs HS. The practical value of the progestogen challenge test, serum oestradiol estimation or clinical examination in assessment of the oestrogen state and response to clomiphene in amenorrhea. Br J Obstet Gynaecol 1979;86:799805 (Level II-3) 20. Murakawa H, Hasegawa I, Kurabayashi T, Tanaka K. Polycystic ovary syndrome. Insulin resistance and ovulatory responses to clomiphene citrate. J Reprod Med 1999;44:2327 (Level II-2) 21. Derman SG, Adashi EY. Induction of ovulation. Compr Ther 1995;21:583589 (Level III) 22. Sills ES, Levy DP, Moomjy M, McGee M, Rosenwaks Z. A prospective, randomized comparison of ovulation induction using highly purified follicle-stimulating hormone alone and with recombinant human luteinizing hormone in in-vitro fertilization. Hum Reprod 1999;14: 22302235 (Level I) 23. Verhelst J, Abs R, Maiter D, van den Bruel A, vandeweghe M, Velkeniers B. Cabergoline in the treatment of hyperprolactinemia: a study in 455 patients. J Clin Endocrinol Metab 1999;84:25182522 (Level II-3) 24. Weil C. The safety of bromocriptine in hyperprolactinaemic female infertility: a literature review. Curr Med Res Opin 1986;10:172195 (Level III)

References
1. Collins JA. Unexplained infertility. In: Keye WR, Chang RJ, Rebar RW, Soules MR, eds. Infertility: evaluation and treatment. Philadelphia: WB Saunders, 1995:249262 (Level III) 2. Hull MG, Glazener CM, Kelly NJ, Conway DI, Foster PA, Hinton RA, et al. Population study of causes, treatment, and outcome of infertility. Br Med J (Clin Res Ed) 1985;291:16931697 (Level II-3) 3. Knochenhauer ES, Key TJ, Kashar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab 1998;83:30783082 (Level II-3) 4. Reindollar RH, Novak M, Tho SP, McDonough PG. Adult-onset amenorrhea: a study of 262 patients. Am J Obstet Gynecol 1986;155:531543 (Level III) 5. Bates GW, Bates SR, Whitworth NS. Reproductive failure in women who practice weight control. Fertil Steril 1982;37:373378 (Level II-3) 6. Santoro N. Efficacy and safety of intravenous pulsatile gonadotropin-releasing hormone: Lutrepulse for injection. Am J Obstet Gynecol 1990;163:17591764 (Level III) 7. Martin KA, Hall JE, Adams JM, Crowley WF Jr. Comparison of exogenous gonadotropins and pulsatile gonadotropin-releasing hormone for induction of ovulation in hypogonadotropic amenorrhea. J Clin Endocrinol Metab 1993;77:125129 (Level II-3) 8. Reichlin S. Neuroendocrinology. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds. Williams textbook of endocrinology. Philadelphia: WB Saunders, 1998: 165 248 (Level III) 9. Grubb MR, Chakeres D, Malarkey WB. Patients with primary hypothyroidism presenting as prolactinomas. Am J Med 1987;83:765769 (Level III) 10. Gsponer J, De Tribolet N, Deruaz JP, Janzer R, Uske A, Mirimanoff RO, et al. Diagnosis, treatment, and outcome

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25. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 1999;84:165169 (Level II-2) 26. Gleicher N, Campbell DP, Chan CL, Karande V, Rao R, Balin M, et al. The desire for multiple births in couples with infertility problems contradicts present practice patterns. Hum Reprod 1995;10:10791085 (Level III) 27. Paulson RJ, Ory SJ, Giudice LC, Schlaff WD, Santoro NF, Coddington C 3rd. Multiple pregnancies: what action should we take? [comment] Fertil Steril 2001;75:1415; discussion 16 17 (Level III) 28. Yen SS. Chronic anovulation due to CNS-hypothalamicpituitary dysfunction. In: Yen SS, Jaffe RB, Barbieri RL, eds. Reproductive endocrinology: physiology, pathophysiology, and clinical management. 4th ed. Philadelphia: WB Saunders, 1999:516 561 (Level III) 29. Grodstein F, Goldman MB, Cramer DW. Body mass index and ovulatory infertility. Epidemiology 1994;5:247250 (Level II-2) 30. Bates GW, Whitworth NS. Effect of body weight reduction on plasma androgens in obese, infertile women. Fertil Steril 1982;38:406 409 (Level II-2) 31. Pasquali R, Antenucci D, Casimirri F, Venturoli S, Paradisi R, Fabbri R, et al. Clinical and hormonal characteristics of obese amenorrheic hyperandrogenic women before and after weight loss. J Clin Endocrinol Metab 1989;68:173179 (Level III) 32. Guzick DS, Wing R, Smith D, Berga SL, Winters SJ. Endocrine consequences of weight loss in obese, hyperandrogenic, anovulatory women. Fertil Steril 1994;61: 598604 (Level II-2) 33. Green BB, Daling JR, Weiss NS, Liff JM, Koepsell T. Exercise as a risk factor for infertility with ovulatory dysfunction. Am J Public Health 1986;76:14321436 (Level II-2) 34. Wu CH, Winkel CA. The effect of therapy initiation day on clomiphene citrate therapy. Fertil Steril 1989;52: 564568 (Level II-3) 35. Gysler M, March CM, Mishell DR Jr, Bailey EJ. A decades experience with an individualized clomiphene treatment regimen including its effect on the postcoital test. Fertil Steril 1982;37:161167 (Level II-3) 36. Macgregor AH, Johnson JE, Bunde CA. Further clinical experience with clomiphene citrate. Fertil Steril 1968; 19:616622 (Level II-3) 37. Hammond MG. Monitoring techniques for improved pregnancy rates during clomiphene ovulation induction. Fertil Steril 1984;42:499509 (Level III) 38. Keenan JA, Herbert CM, Bush JR, Wentz AC. Diagnosis and management of out-of-phase endometrial biopsies among patients receiving clomiphene citrate for ovulation induction. Fertil Steril 1989;51:964 967 (Level II-2) 39. Dickey RP, Holtkamp DE. Development, pharmacology and clinical experience with clomiphene citrate. Hum Reprod Update 1996;2:483506 (Level III)

40. Kurachi K, Aono T, Minagawa J, Miyuake A. Congenital malformations of newborn infants after clomiphene induced ovulation. Fertil Steril 1983;40:187189 (Level II-2) 41. Clomid. In: Physicians desk reference. 55th ed. Montvale, New Jersey: Medical Economics Company, 2001: 700702 (Level III) 42. Daly DC, Walters CA, Soto-Albors CE, Tohan N, Riddick DH. A randomized study of dexamethasone in ovulation induction with clomiphene citrate. Fertil Steril 1984;41: 844848 (Level I) 43. Swyer GI, Radwanska E, Mcgarrigle HH. Plasma oestradiol and progesterone estimation for the monitoring of induction of ovulation with clomiphene and chorionic gonadotrophin. Br J Obstet Gynaecol 1975;82:794804 (Level II-2) 44. Branigan EF, Estes MA. Treatment of chronic anovulation resistant to clomiphene citrate (CC) by using oral contraceptive ovarian suppression followed by repeat CC treatment. Fertil Steril 1999;71:544546 (Level III) 45. Donesky BW, Adashi EY. Surgically induced ovulation in the polycystic ovary syndrome: wedge resection revisted in the age of laparoscopy. Fertil Steril 1995;63:439463 (Level III) 46. Lunenfeld B, Insler V. Human gonadotropins. In: Wallach EE, Zacur HA, eds. Reproductive medicine and surgery. St. Louis: Mosby-Year Book, 1995:611638 (Level III) 47. Vance ML, Evans WS, Thorner MO. Drugs five years later. Bromocriptine. Ann Intern Med 1984;100:7891 (Level III) 48. Homburg R, Levy T, Ben-Rafael Z. A comparative study of conventional regimen with chronic low-dose administration of follicle-stimulating hormone for anovulation associated with polycystic ovary syndrome. Fertil Steril 1995;63:729733 (Level II-2) 49. Barbieri RL. Induction of ovulation in infertile women with hyperandrogenism and insulin resistance. Am J Obstet Gynecol 2000;183:14121418 (Level III) 50. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomipheneinduced ovulation in the polycystic ovary syndrome. N Engl J Med 1998;38:18761880 (Level II-2) 51. Vandermolen DT, Ratts VS, Evans WS, Stovall DW, Kauma SW, Nestler JE. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril 2001;75: 310315 (Level I) 52. De Leo V, la Marca A, Ditto A, Morgante G, Cianci A. Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome. Fertil Steril 1999;72:282285 (Level I) 53. Glatstein IZ, Best CL, Palumbo A, Sleeper LA, Friedman AJ, Hornstein MD. The reproducibility of the postcoital test: a prospective study. Obstet Gynecol 1995;85: 396400 (Level III) 54. Griffith CS, Grimes DA. The validity of the postcoital test. Am J Obstet Gynecol 1990;162:615620 (Level III)

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55. Oei SG, Helmerhorst FM, Bloemenkamp KW, Hollants FA, Meerpoel DE, Keirse MJ. Effectiveness of the postcoital test: randomised controlled trial. BMJ 1998;317: 502505 (Level I) 56. Callahan TL, Hall JE, Ettner SL, Christiansen CL, Green MF, Crowley WF Jr. The economic impact of multiplegestation pregnancies and the contribution of assistedreproduction techniques to their incidence. N Engl J Med 1994;331:244249 (Level III) 57. Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. N Engl J Med 1994;331:771776 (Level II-2) 58. Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Collaborative Ovarian Cancer Group. Am J Epidemiol 1992;136:11841203 (Level II-2)

The MEDLINE database, the Cochrane Library, and ACOGs own internal resources and documents were used to conduct a literature search to locate relevant articles published between January 1985 and June 2001. The search was restricted to articles published in the English language. Priority was given to articles reporting results of original research, although review articles and commentaries also were consulted. Abstracts of research presented at symposia and scientific conferences were not considered adequate for inclusion in this document. Guidelines published by organizations or institutions such as the National Institutes of Health and the American College of Obstetricians and Gynecologists were reviewed, and additional studies were located by reviewing bibliographies of identified articles. When reliable research was not available, expert opinions from obstetriciangynecologists were used. Studies were reviewed and evaluated for quality according to the method outlined by the U.S. Preventive Services Task Force: I Evidence obtained from at least one properly designed randomized controlled trial. II-1 Evidence obtained from well-designed controlled trials without randomization. II-2 Evidence obtained from well-designed cohort or casecontrol analytic studies, preferably from more than one center or research group. II-3 Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments could also be regarded as this type of evidence. III Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. Based on the highest level of evidence found in the data, recommendations are provided and graded according to the following categories: Level ARecommendations are based on good and consistent scientific evidence. Level BRecommendations are based on limited or inconsistent scientific evidence. Level CRecommendations are based primarily on consensus and expert opinion. Copyright February 2002 by the American College of Obstetricians and Gynecologists. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without prior written permission from the publisher. Requests for authorization to make photocopies should be directed to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400. The American College of Obstetricians and Gynecologists 409 12th Street, SW, PO Box 96920 Washington, DC 20090-6920 12345/65432
Management of infertility caused by ovulatory dysfunction. ACOG Practice Bulletin No. 34. American College of Obstetricians and Gynecologists. Obstet Gynecol 2002;99:347358

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ACOG
EDUCATIONAL and PRACTICE BULLETINS
LIST
OF

TITLES FEBRUARY 2002

Educational and Practice Bulletins provide obstetricians and gynecologists with current information on established techniques and clinical management guidelines. ACOG continuously surveys the field for advances to be incorporated in these series and monitors existing bulletins to ensure they are current. Individual bulletins are withdrawn from and added to these series on a continuing basis. Also listed are current Practice Patterns, which provide evidence-based guidelines. A list of withdrawn and replaced titles appears at the end.

General
Current Bulletins
1 3 9 10 16 17 23 24 30 31 218 222 247 248
v v v v v

255
8 15 22 29 210 246 260
v

w w w w w w w w w w w w w w w w w w

4 11 18 25 32 227 251

5 12 19 26 33 230 253

6 13 20 27 34 236 255

7 14 21 28 207 244 258

Psychosocial Risk Factors: Perinatal Screening and Intervention (November 1999, Obstet Gynecol Vol. 94, No. 5) Breastfeeding: Maternal and Infant Aspects (July 2000, Obstet Gynecol Vol. 96, No. 1)

VOL. 99, NO. 2, FEBRUARY 2002

v v v v

v v

258

v v

v v v

v v v

v v

Obstetrics
1 Premature Rupture of Membranes (June 1998, Obstet Gynecol Vol. 91, No. 6) 4 Prevention of Rh D Alloimmunization (May 1999, Obstet Gynecol Vol. 93, No. 5) 5 Vaginal Birth After Previous Cesarean Delivery (July 1999, Obstet Gynecol Vol. 94, No. 1) 6 Thrombocytopenia in Pregnancy (September 1999, Obstet Gynecol Vol. 94, No. 3) 8 Management of Herpes in Pregnancy (October 1999, Obstet Gynecol Vol. 94, No. 4) 9 10 12 13 Antepartum Fetal Surveillance (October 1999, Obstet Gynecol Vol. 94, No. 4) Induction of Labor (November 1999, Obstet Gynecol Vol. 94, No. 5) Intrauterine Growth Restriction (January 2000, Obstet Gynecol Vol. 95, No. 1) External Cephalic Version (February 2000, Obstet Gynecol Vol. 95, No. 2)

17 Operative Vaginal Delivery (June 2000, Obstet Gynecol Vol. 95, No. 6) 19 Thromboembolism in Pregnancy (August 2000, Obstet Gynecol Vol. 96, No. 2) 20 Perinatal Viral and Parasitic Infections (September 2000, Obstet Gynecol Vol. 96, No. 3) 22 Fetal Macrosomia (November 2000, Obstet Gynecol Vol. 96, No. 5) 24 Management of Recurrent Early Pregnancy Loss (February 2001, Obstet Gynecol Vol. 97, No. 2) 27 Prenatal Diagnosis of Fetal Chromosomal Abnormalities (May 2001, Obstet Gynecol Vol. 97, No. 5) 29 Chronic Hypertension in Pregnancy (Obstet Gynecol 2001;98:177185) *30 Gestational Diabetes (Obstet Gynecol 2001;98:525538) *31 Assessment of Risk Factors for Preterm Birth (Obstet Gynecol 2001;98:709716)

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Obstetrics
w

(continued)

*32 Thyroid Disease in Pregnancy (Obstet Gynecol 2001;98:879888) *33 Diagnosis and Management of Preeclampsia and Eclampsia (Obstet Gynecol 2002;99:159167) 207 Fetal Heart Rate Patterns: Monitoring, Interpretation and Management (July 1995) 218 Dystocia and the Augmentation of Labor (December 1995) 227 Management of Isoimmunization in Pregnancy (August 1996) 230 Assessment of Fetal Lung Maturity (November 1996) 244 Antiphospholipid Syndrome (February 1998) 236 Teratology (April 1997) 248 Viral Hepatitis in Pregnancy (July 1998, Obstet Gynecol Vol. 92, No. 1) 251 Obstetric Aspects of Trauma Management (September 1998, Obstet Gynecol Vol. 92, No. 3) 253 Special Problems of Multiple Gestation (November 1998, Obstet Gynecol Vol. 92, No. 5) 260 Smoking Cessation During Pregnancy (September 2000, Obstet Gynecol Vol. 96, No. 3)

16 Surgical Alternatives to Hysterectomy in the Management of Leiomyomas (May 2000, Obstet Gynecol Vol. 95, No. 5) 18 The Use of Hormonal Contraception in Women with Coexisting Medical Conditions (July 2000, Obstet Gynecol Vol. 96, No. 1) 21 Prevention of Deep Vein Thrombosis and Pulmonary Embolism (October 2000, Obstet Gynecol Vol. 96, No. 4) 23 Antibiotic Prophylaxis for Gynecologic Procedures (January 2001, Obstet Gynecol Vol. 97, No. 1) 25 Emergency Oral Contraception (March 2001, Obstet Gynecol Vol. 97, No. 3) 26 Medical Management of Abortion (April 2001, Obstet Gynecol Vol. 97, No. 4) 28 Use of Botanicals for Management of Menopausal Symptoms (June 2001, Obstet Gynecol Vol. 97, No. 6) *34 Management of Infertility Caused by Ovulatory Dysfunction (Obstet Gynecol 2002;99:347358) 210 Health Maintenance for Perimenopausal Women (August 1995) 222 Sterilization (April 1996)

Gynecology
3 Medical Management of Tubal Pregnancy (December 1998, Obstet Gynecol Vol. 92, No. 6) 7 Prophylactic Oophorectomy (September 1999, Obstet Gynecol Vol. 94, No. 3) 11 Medical Management of Endometriosis (December 1999, Obstet Gynecol Vol. 94, No. 6) 14 Management of Anovulatory Bleeding (March 2000, Obstet Gynecol Vol. 95, No. 3) 15 Premenstrual Syndrome (April 2000, Obstet Gynecol Vol. 95, No. 4)

Reproductive Endocrinology and Fertility

246 Osteoporosis (April 1998, Obstet Gynecol Vol. 91, No. 4) 247 Hormone Replacement Therapy (May 1998, Obstet Gynecol Vol. 91, No. 5)

Practice Patterns
5 Routine Ultrasound in Low-Risk Pregnancy (August 1997) 6 Management of Postterm Pregnancy (October 1997) 7 Shoulder Dystocia (October 1997)

For ordering information, contact the ACOG Distribution Center at 800-762-2264, or order online at sales.acog.com.

*Title issued since publication of last listing Practice Bulletin

AT005

360

ACOG Educational and Practice Bulletins List of Titles

OBSTETRICS & GYNECOLOGY

The following Educational and Technical Bulletins will be replaced by Ethics in Obstetrics and Gynecology: 136 Ethical Decision-Making in Obstetrics and Gynecology The following Educational and Technical Bulletins will be replaced by Adolescent Health: 249 Confidentiality in Adolescent Health Care 254 Primary and Preventive Health Care for Female Adolescents 256 Oral Contraceptives for Adolescents: Benefits and Safety The following Educational and Technical Bulletins will be replaced by Special Issues in Womens Health: 194 Substance Abuse 201 Pediatric Gynecologic Disorders 240 Smoking and Womens Health 242 Sexual Assault 252 Adolescent Victims of Sexual Assault 257 Domestic Violence 259 Adult Manifestations of Childhood Sexual Abuse The following Educational and Technical Bulletins have been withdrawn from circulation: 109 Methods of Midtrimester Abortion 125 Infertility 128 Amenorrhea 156 Nonmalignant Conditions of the Breast 160 Immunization During Pregnancy 162 Carcinoma of the Endometrium 163 Fetal and Neonatal Neurologic Injury 164 The Intrauterine Device 171 Rubella and Pregnancy 173 Women and Exercise 175 Invasive Hemodynamic Monitoring in Obstetrics and Gynecology 176 Diagnosis and Management of Fetal Death 178 Management of Gestational Trophoblastic Disease 181 Thyroid Disease in Pregnancy (replaced by Practice Bulletin No. 32) 182 Depression in Women 183 Cervical Cytology: Evaluation and Management of Abnormalities 186 Vulvar Cancer 187 Ultrasonography in Pregnancy 189 Exercise During Pregnancy and the Postpartum Period 191 Hysteroscopy 193 Genital Human Papillomavirus Infections 195 Substance Abuse in Pregnancy 197 Managing the Anovulatory State: Medical Induction of Ovulation 198 Hormonal Contraception 199 Blood Component Therapy 200 Diabetes and Pregnancy (replaced by Practice Bulletin No. 30) 202 Hyperandrogenic Chronic Anovulation 203 Evaluation and Treatment of Hirsute Women 204 Septic Shock 205 Preconceptional Care 206 Preterm Labor (replaced by Practice Bulletin No. 31) 208 Genetic Technologies 211 Sexual Dysfunction 213 Urinary Incontinence 214 Pelvic Organ Prolapse 215 Gynecologic Ultrasonography 216 Umbilical Artery Blood AcidBase Analysis 223 Chronic Pelvic Pain 224 Pulmonary Disease in Pregnancy 225 Obstetric Analgesia and Anesthesia 226 Vaginitis 229 Nutrition and Women 231 Seizure Disorders in Pregnancy 235 Hemorrhagic Shock 238 Lower Urinary Tract Operative Injuries 239 Operative Laparoscopy 241 Vulvar Nonneoplastic Epithelial Disorders 243 Postpartum Hemorrhage 245 Antimicrobial Therapy for Obstetric Patients 250 Ovarian Cancer

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Dennens

FORCEPS DELIVERIES
The Time-Honored Classic

Fourth Edition

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forceps. Now, thanks to the generous support of ACOGs Development Fund, this classic book has been revised and updated to find a place in current obstetric practice. The fourth edition retains much of the original, classic text, including explanations of forceps devices and techniques. It also provides the latest related ACOG guidelines, a chapter on vaccum assisted deliveries, and information on the current and changing status of forceps deliveries. Forceps and vacuum deliveries continue to play a role in modern obstetric practice as we strive to seek alternatives to cesarean delivery. Dennens Forceps Deliveries, the time-honored definitive treatise on the subject, can now serve as a resource to those physicians who want to take full advantage of every opportunity to promote maternal and fetal health. If you are involved with an obstetric practice in any way, you will find this book vital and relevant.

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The American College of Obstetricians and Gynecologists

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ACOG Committee Opinions

List of Titles
February 2002
Committee Opinions are intended to provide timely information on controversial issues, ethical concerns, and emerging approaches to clinical management. They represent the considered views of the sponsoring committee based on interpretation of published data in peer-reviewed journals. Committee Opinions are reviewed periodically for continued relevance or needed update. Note: Because individual Committee Opinions are withdrawn from and added to the series on a continuing basis, the titles listed in this index may not be identical to those contained in complete sets. A list of withdrawn and replaced titles appears at the end.
Number Title Publication Date Reaffirmed Date

Committee on Coding and Nomenclature 205 Tubal Ligation with Cesarean Delivery (Obstet Gynecol Vol. 92, No. 2) 249 Coding Responsibility (Obstet Gynecol Vol. 97, No. 1) 250 Inappropriate Reimbursement Practices by Third-Party Payers (Obstet Gynecol Vol. 97, No. 1) Committee on Genetics (to be published as a separate volume) 161 Fragile X Syndrome 162 Screening for TaySachs Disease 183 Routine Storage of Umbilical Cord Blood for Potential Future Transplantation (Joint with Committee on Obstetric Practice) 189 Advanced Paternal Age: Risks to the Fetus 192 Genetic Screening of Gamete Donors 212 Screening for Canavan Disease (Obstet Gynecol Vol. 92, No. 5) 223 First-Trimester Screening for Fetal Anomalies with Nuchal Translucency (Obstet Gynecol Vol. 94, No. 4) 230 Maternal Phenylketonuria (Obstet Gynecol Vol. 95, No. 1) 238 Genetic Screening for Hemoglobinopathies (Obstet Gynecol Vol. 96, No. 1) 239 BreastOvarian Cancer Screening (Obstet Gynecol Vol. 96, No. 2) 257 Genetic Evaluation of Stillbirths and Neonatal Deaths (Obstet Gynecol Vol. 97, No. 5) Committee on Gynecologic Practice 152 Recommendations on Frequency of Pap Test Screening 164 Incidental Appendectomy 186 Role of the ObstetricianGynecologist in the Diagnosis and Treatment of Breast Disease 191 Length of Hospital Stay for Gynecologic Procedures 195 Role of Loop Electrosurgical Excision Procedure in the Evaluation of Abnormal Pap Test Results 203 Hepatitis Virus Infections in ObstetricianGynecologists (Obstet Gynecol Vol. 92, No. 1) 224 Tamoxifen and the Prevention of Breast Cancer in High-Risk Women (Obstet Gynecol Vol. 94, No. 4) 226 Hormone Replacement Therapy in Women with Previously Treated Breast Cancer (Obstet Gynecol Vol. 94, No. 5) 232 Tamoxifen and Endometrial Cancer (Obstet Gynecol Vol. 95, No. 4) 235 Hormone Replacement Therapy in Women Treated for Endometrial Cancer (Obstet Gynecol Vol. 95, No. 5) 240 Statement on Surgical Assistants (Obstet Gynecol Vol. 96, No. 2) (Joint with Committee on Obstetric Practice) 242 Concurrent Chemoradiation in the Treatment of Cervical Cancer (Obstet Gynecol Vol. 96, No. 4) 243 Performance and Interpretation of Imaging Studies by ObstetricianGynecologists (Obstet Gynecol Vol. 96, No. 5)

August 1998 January 2001 January 2001 October 1995 November 1995 April 1997 October 1997 October 1997 November 1998 October 1999 January 2000 July 2000 August 2000 May 2001 March 1995 December 1995 September 1997 October 1997 November 1997 July 1998 October 1999 November 1999 April 2000 May 2000 August 2000 October 2000 November 2000 1998 2000 2000 2000 2000 2001 2001 2001 2001 2001 2000 2000 2000 2000 2001 2000 2001

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Number

Title

Publication Date

Reaffirmed Date

Committee on Gynecologic Practice (continued) 244 Androgen Treatment of Decreased Libido (Obstet Gynecol Vol. 96, No. 5) 245 Mifepristone for Medical Pregnancy Termination (Obstet Gynecol Vol. 96, No. 6) 246 Primary and Preventive Care: Periodic Assessments (Obstet Gynecol Vol. 96, No. 6) 247 Routine Cancer Screening (Obstet Gynecol Vol. 96, No. 6) 253 Nongynecologic Procedures (Obstet Gynecol Vol. 97, No. 3) *262 Risk of Breast Cancer with EstrogenProgestin Replacement Therapy (Obstet Gynecol 2001;98:11811183) *263 Von Willebrands Disease in Gynecologic Practice (Obstet Gynecol 2001;98:11851186) Committee on Obstetric Practice 125 Placental Pathology 138 Utility of Umbilical Cord Blood AcidBase Assessment 158 Guidelines for Diagnostic Imaging During Pregnancy 163 Perinatal Care at the Threshold of Viability (Joint with AAP Committee on Fetus and Newborn) 173 Prevention of Early-Onset Group B Streptococcal Disease in Newborns 174 Use and Abuse of the Apgar Score (Joint with AAP Committee on Fetus and Newborn) 180 New Ultrasound Output Display Standard 183 Routine Storage of Umbilical Cord Blood for Potential Future Transplantation (Joint with Committee on Genetics) 197 Inappropriate Use of the Terms Fetal Distress and Birth Asphyxia 210 Antenatal Corticosteroid Therapy for Fetal Maturation (Obstet Gynecol Vol. 92, No. 4) 228 Induction of Labor with Misoprostol (Obstet Gynecol Vol. 94, No. 5) 231 Pain Relief During Labor (Joint with American Society of Anesthesiologists) (Obstet Gynecol Vol. 95, No. 2) 234 Scheduled Cesarean Delivery and the Prevention of Vertical Transmission of HIV Infection (Obstet Gynecol Vol. 95, No. 5) 240 Statement on Surgical Assistants (Joint with Committee on Gynecologic Practice) (Obstet Gynecol Vol. 96, No. 2) 248 Response to Searles Drug Warning on Misoprostol (Obstet Gynecol Vol. 96, No. 6) 252 Fetal Surgery for Open Neural Tube Defects (Obstet Gynecol Vol. 97, No. 3) 256 Optimal Goals for Anesthesia Care in Obstetrics (Joint with American Society of Anesthesiologists) (Obstet Gynecol Vol. 97, No. 5) *258 Fetal Pulse Oximetry (Obstet Gynecol 2001;98:523524) *260 Circumcision (Obstet Gynecol 2001;98:707708) *264 Air Travel During Pregnancy (Obstet Gynecol 2001;98:11871188) *265 Mode of Term Singleton Breech Delivery (Obstet Gynecol 2001;98:11891190) *266 Placenta Accreta (Obstet Gynecol 2002;99:169170) *267 Exercise During Pregnancy and the Postpartum Period (Obstet Gynecol 2002;99:171173) *268 Management of Asymptomatic Pregnant or Lactating Women Exposed to Anthrax (Obstet Gynecol 2002;99:366368) *269 Analgesia and Cesarean Delivery Rates (Obstet Gynecol 2002;99:369370) Committee on Primary Care 227 Complementary and Alternative Medicine (Obstet Gynecol Vol. 94, No. 5) Committee on Professional Liability 236 Coping with the Stress of Malpractice Litigation (Obstet Gynecol Vol. 95, No. 6) 237 Informed Refusal (Obstet Gynecol Vol. 95, No. 6)

November 2000 December 2000 December 2000 December 2000 March 2001 December 2001 December 2001 July 1993 April 1994 September 1995 November 1995 June 1996 July 1996 November 1996 April 1997 February 1998 October 1998 November 1999 February 2000 May 2000 August 2000 December 2000 March 2001 May 2001 September 2001 October 2001 December 2001 December 2001 January 2002 January 2002 February 2002 February 2002 2000 2000 2000 1997 1999 1999 2000 2000 2001 2001 2001 2001

November 1999

2001

June 2000 June 2000

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*Title issued since publication of last index.

364

ACOG Committee Opinions List of Titles

OBSTETRICS & GYNECOLOGY

The following Committee Opinions will be replaced by Ethics in Obstetrics and Gynecology: 46 Endorsement of Institutional Ethics Committees 108 Ethical Dimensions of Informed Consent 136 Preembryo Research: History, Scientific Background, and Ethical Considerations 144 Sexual Misconduct in the Practice of Obstetrics and Gynecology: Ethical Considerations 156 End-of-Life Decision Making: Understanding the Goals of Care 159 Ethical Guidance for Patient Testing 170 Physician Responsibility Under Managed Care: Patient Advocacy in a Changing Health Care Environment 177 Sex Selection 181 Ethical Issues in ObstetricGynecologic Education 194 ObstetricianGynecologists Ethical Responsibilities, Concerns, and Risks Pertaining to Adoption 204 Institutional Responsibility to Provide Legal Representation 214 Patient Choice and the MaternalFetal Relationship 215 Nonselective Embryo Reduction: Ethical Guidance for the ObstetricianGynecologist 216 Sterilization of Women, Including Those with Mental Disabilities 217 Ethical Issues Related to Expert Testimony by Obstetricians and Gynecologists 225 Responsibilities of Physicians Regarding Surrogate Motherhood 233 Ethical Dimensions of Seeking and Giving Consultation 254 Commercial Enterprises in Medical Practice: Selling and Promoting Products 255 Human Immunodeficiency Virus: Ethical Guidelines for Obstetricians and Gynecologists 259 Guidelines for Relationships with Industry 261 Medical Futility The following Committee Opinions will be replaced by Adolescent Health: 139 Adolescents Right to Refuse Long-Term Contraceptives 154 Condom Availability for Adolescents 190 Prevention of Adolescent Suicide The following Committee Opinions will be replaced by Special Issues in Womens Health: 200 Mandatory Reporting of Domestic Violence 201 Cultural Competency in Health Care 202 Access to Health Care for Women with Physical Disabilities The following Committee Opinions have been withdrawn from circulation: 87 Deception 101 Current Status of Cystic Fibrosis Carrier Screening 104 Anesthesia for Emergency Deliveries 105 Postpartum Tubal Sterilization 121 Obstetric Management of Patients with Spinal Cord Injury 129 Commercial Ventures in Medicine: Concerns About the Patenting of Procedures 133 Colposcopy Training and Practice 149 Financial Influences on Mode of Delivery 151 Female Genital Mutilation 153 Absence of Endocervical Cells on a Pap Test 167 Perinatal and Infant Mortality Statistics 171 Cost Containment in Medical Care 172 Home Uterine Activity Monitoring (replaced by Practice Bulletin No. 31) 175 Scope of Services for Uncomplicated Obstetric Care 179 Rate of Vaginal Births After Cesarean Delivery 184 Hepatitis B Immunization for Adolescents 187 Fetal Fibronectin Preterm Labor Risk Test (replaced by Practice Bulletin No. 31) 196 Vitamin A Supplementation During Pregnancy 207 Liability Implications of Recording Procedures or Treatments 213 Ethical Considerations in Research Involving Pregnant Women 221 Telecommunication in Medicine 222 Quality of Laboratory and Imaging Services: Physician Responsibility in the Age of Managed Care 241 Screening for Hypothyroidism (replaced by Practice Bulletin No. 32) 251 SalEst as a Predictor of Risk for Preterm Labor (replaced by Practice Bulletin No. 31) Current Committee Opinions 125 189 228 244 262 138 191 230 245 263 152 192 231 246 264 158 195 232 247 265 161 197 234 248 266 162 203 235 249 267 163 205 236 250 268 164 210 237 252 269 173 212 238 253 174 223 239 256 180 224 240 257 183 226 242 258 186 227 243 260

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