Benign Cervical Lesions

ANATOMY

The cervix (Latin for neck) is the inferior part of the uterus protruding into the vagina.

Gross anatomy

The cervix measures 2.5-3 cm in diameter and 3-5 cm in length. The normal anatomic position of the cervix is angulated slightly downward and backward. Inferiorly, the cervix projects into the vagina as the portio vaginalis. The anterior and posterior fornices delimit the portio (exocervix). The cervical canal measures approximately 8 mm wide and contains longitudinal ridges. The area between the endocervical and endometrial cavity is called the isthmus or lower uterine segment.

The lymphatic drainage of the cervix is first to the parametrial nodes, then to the obturator, internal iliac, and external iliac nodes. Secondary drainage is to the presacral, common iliac, and para-aortic lymph nodes.

The innervation of the cervix is from the Frankenhäuser plexus, a terminal part of the presacral plexus. The nerves enter the lower uterine segment and upper cervix on either side and form 2 lateral semicircular plexuses. The major blood supply is from the descending branch of the uterine artery. Also contributing is the cervical branch of the vaginal artery. The venous return mirrors the arterial blood supply.

Microscopic anatomy

Microscopically, the cervical stroma is composed of an admixture of fibrous, muscular (15%), and elastic tissue. The epithelium is squamous on the ectocervix and columnar in the endocervix. The exposed (ie, vaginal) portion of the cervix is lined by nonkeratinizing stratified squamous epithelium that becomes continuous with the vaginal epithelium. This is referred to as the native portio epithelium. The native portio epithelium is replaced every 4-5 days, is sensitive to estrogen and progesterone, and contains glycogen. In postmenopausal women, the squamous epithelium is atrophic with little or no glycogen and the cellular alterations can be confused with cervical intraepithelial neoplasia.

The mucosa of the cervical canal (endocervix) is composed of a single layer of mucin-secreting columnar epithelium, which lines both the surface and the underlying glandular crypts. Isolated neuroendocrine epithelial cells of argentaffin type or argyrophil type are admixed with the normal endocervical cells. Under normal conditions, mitotic figures are rarely identified in endocervical epithelium. True lymphoid follicles, with or without germinal centers, are encountered in the stroma of both the ectocervix and endocervix. During pregnancy, a marked increase occurs in the vascularity and edema within the cervical stroma and an inflammatory infiltrate is present.

Squamocolumnar junction

The squamocolumnar junction is the border between the squamous epithelium of the ectocervix and the columnar epithelium of the endocervix. Just distal to the squamocolumnar junction, an area of immature squamous metaplastic epithelium is present. Trauma, chronic irritation, and cervical infections play a role in the development and maturation of the squamous epithelium of the cervix. Immature squamous metaplasia shares biochemical and immunohistochemical features of both mature squamous epithelium and columnar mucinous epithelium.

The transformation zone

The transformation zone is a dynamic area, usually located on the ectocervix. At times, the distal edge of the transformation zone extends into the upper vagina. The transformation zone, by definition, is the area between the original squamocolumnar junction and the current squamocolumnar junction. The transformation zone is that portion of the cervix that originally was columnar epithelium and now is squamous epithelium. Squamous metaplasia occurs continuously; however, this process is most active during fetal development, around the time of menarche, and during pregnancy. Local hormonal changes, as reflected by vaginal pH, influence this process.

In young females, the endocervical tissue tends to roll out from the cervical os; this is called cervical eversion and corresponds to the original squamocolumnar junction. In a normal transformation, one can find remnants of gland openings and nabothian cysts. On the other hand, in postmenopausal women, the squamocolumnar junction frequently is located within the cervical canal. In this position, it is not visualized through speculum examination. Understanding the transformation is of utmost importance because cervical cancer and its precursors typically begin within the transformation zone.

CONGENITAL ANOMALIES

Congenital anomalies of the cervix reflect only the lower part of the spectrum of congenital anomalies involving the müllerian system. The cervix has 3 types of anomalies: fusion abnormalities, congenital absence, and changes due to in utero exposure to diethylstilbestrol (DES) and other nonsteroidal estrogens.

Fusion anomalies

A failure to fuse or incomplete fusion of the müllerian ducts results in duplication of the vagina, cervix, or uterus. Failure of fusion of the distal müllerian duct can result in any of the anomalies discussed below.

Uterus didelphys results from a complete lack of fusion of the müllerian ducts. Duplication of the vagina, cervix, and/or uterus occurs. A longitudinal vaginal septum is present, with 2 separate cervices and 2 separate endometrial cavities.

With septate cervix, the appearance is that of 1 cervix with 2 separate cervical openings. The septum may be partial. The gross appearance is of 2 separate cervices but 1 endometrial cavity. On the other hand, the septum may extend through the entire length of the uterus, with 2 separate endometrial cavities. Depending on the shape of the uterine fundus, the anomaly is either a septate uterus or an arcuate uterus. Laparoscopy is necessary to distinguish between these 2 anatomic variations.

Congenital absence of the cervix

Congenital absence of the cervix usually occurs as part of the syndrome of müllerian agenesis, also known as Mayer-Rokitansky-Küster-Hauser syndrome. This syndrome occurs in approximately 1 per 4000 female births.

Women with müllerian agenesis typically have a blind vagina and normal ovaries. Approximately one third of patients have urinary tract anomalies, and 12% have skeletal anomalies, usually involving the spine. Imaging of these structures should be part of the evaluation.

In women with partial müllerian agenesis, a uterine bud or fundus may be present without a cervix and proximal vagina. If endometrium is present in this uterine bud, hematometra occurs at puberty, producing cyclic abdominal pain. These patients require excision of the uterine bud. Although vaginal patency has been surgically created in a few patients, pregnancy has not occurred in the absence of a cervix.

In utero exposure to diethylstilbestrol and other nonsteroidal estrogens

Changes associated with in utero exposure to DES and other nonsteroidal estrogens are encountered. The epidemiologic association of in utero exposure to DES with clear cell vaginal adenocarcinoma has been known since 1970. The use of DES, which initially was prescribed for thousands of women to prevent miscarriage, was discontinued at approximately that time. However, unique anomalies of the müllerian system are present in women exposed to DES.

The classic anomaly is a hypoplastic T-shaped uterus, referring to the T shape of the endometrial cavity. Defects limited to the cervix, in addition to hypoplastic cervix, include local interesting gross and colposcopic findings.

In addition to vaginal adenosis, other findings unique to in utero DES exposure include the so-called cockscomb cervix, cervical rings, cervical collars, and cervical hoods. The cockscomb cervix refers to the abnormal stromal development causing the epithelium to be thrown into firm transverse ridges in the anterior vaginal fornix, including the upper ectocervix.

Incompetent cervix with pregnancy wastage is a potential problem in females exposed to DES.

INFLAMMATORY DISEASES

Inflammation of the cervix is extremely common. Chronic inflammation is present in the cervix of almost every sexually active woman. On a microscopic level, regardless of the etiology, the tissue response of the cervix is limited to inflammation and repair.

Infectious cervicitis

Susceptibility of the cervix to bacterial infection depends on the virulence of the organism, the epithelial integrity, and the vaginal pH. Infections of the endocervical canal include infection with Neisseria gonorrhoeae and Chlamydia trachomatis. Organisms infecting the portio of the cervix can produce either exophytic or ulcerative lesions. These include human papilloma virus (HPV), herpes simplex virus (HSV), Treponema pallidum, Haemophilus ducreyi, and donovanosis.

Infections of the endocervical canal (mucopurulent cervicitis)

Infection with C trachomatis or N gonorrhoeae requires no predisposing factor and primarily depends on the size of the inoculum.

Mucopurulent secretions have been reported in more than 60% of women with cervical chlamydial infections. Mucopurulent discharge is present in 12% of women with no cervical pathology. Yellow mucopus collected from the endocervix and visualized on a white cotton-tipped applicator may correlate with chlamydia, gonorrhea, or HSV infections. It also correlates with the identification of trichomonads in the vagina.

Traditionally, mucopurulent cervicitis has been associated with chlamydial infection and, to a lesser extent, gonorrhea; however, in published studies, the sensitivity, specificity, and positive predictive values have been quite variable. Thus, the color and consistency of the discharge alone is not enough to make a specific diagnosis.

Gram stain findings of gram-negative intracellular diplococci within the cytoplasm of neutrophils are highly specific for gonorrhea but can be identified in only 50-60% of women with gonococcal infections. On occasion, cervical cytology identifies inclusion-containing vacuoles in endocervical or metaplastic cells. The presence of these inclusions correlates well with C trachomatis infection.

The best guide to therapy for endocervicitis is identification of the specific microbiologic agent. This is accomplished best by the isolation of N gonorrhoeae, C trachomatis, HSV, or Trichomonas vaginalis in appropriate culture. DNA amplification and detection methods are gaining in popularity for screening and diagnosing women who are at risk or who are symptomatic.

Treatment for mucopurulent cervicitis after identifying the causative organism is outlined in Table 1. The US Centers for Disease Control and Prevention do not recommend a test of cure in uncomplicated gonorrheal or chlamydial infection when treated with any of the outlined regimens, unless symptoms persist. Pregnant women should not be treated with quinolones or tetracyclines.

Infections involving the portio of the cervix

• Human papilloma virus
  • HPV can infect the ectocervix and can cause warty lesions similar to those seen in the vagina or on the vulva; however, the virus on the cervix typically causes flat warts. These are macular or papular lesions that become more visible to the naked eye when swabbed with 3-5% acetic acid. The acetic acid causes cellular dehydration. The resulting increase in nuclear density appears clinically as a white lesion. This phenomenon is transient. The term aceto-white describes this finding. In addition to HPV, squamous metaplasia and cervical intraepithelial neoplasia can appear aceto-white.
    

• • HPV lesions tend to have indistinct and feathered borders, and the lesions may appear broken or flocculated. Unlike cervical intraepithelial neoplasia (CIN), satellite lesions may be present, and HPV lesions may be within or outside the transformation zone on the portio of the cervix. Another appearance of HPV may be snow-white, shiny, and raised lesions. Frequently, fine-caliber blood vessels are present.
    

• • Lesions suggestive of HPV should be confirmed by performing a biopsy. The hallmark histologic feature is the koilocyte. On both cytologic preparations of cervical biopsy specimens, koilocytes are cells with wrinkled nuclear membranes (like raisins) that frequently are binucleate and occasionally are multinucleate. The nuclei are surrounded by a clear halo, which gives the cells their name. Cytologic and nuclear atypia typically is present. In cervical biopsy specimens, a few normal mitotic figures may be seen in the basal layer of the squamous epithelium, while koilocytes occupy the intermediate and superficial layers.
    

• • Currently, more than 60 types of HPV are described, but only a few types cause genital tract lesions. The typical exophytic warts that present on the vulva, vagina, and cervix are type 6 or type 11. Types 16, 18, 31, 33, and 35 are more commonly associated with flat warts and have an epidemiologic link to CIN. Kits are available that classify HPV lesions as either benign (ie, 6 or 11) or at risk (ie, 16, 18, 31, 33, and 35). Currently, for reflex HPV testing of thin layer cervical cytology, 14 different oncogenic HPV types are tested: HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68.
    

• • A vaccine for HPV (Gardasil) has been recently approved by the FDA. It is a quadrivalent HPV recombinant vaccine containing activity against HPV types 6, 11, 16, and 18. The vaccine is indicated for prevention of HPV-associated dysplasias and neoplasias, including cervical cancer, genital warts (condyloma acuminata), and precancerous genital lesions (eg, cervical adenocarcinoma in situ; cervical intraepithelial neoplasia grades 1, 2, and 3; vulvar intraepithelial neoplasia grades 2 and 3; vaginal intraepithelial neoplasia grades 2 and 3). The immunization series should be completed in girls and young women aged 9-26 years
    

• Herpes simplex virus
  • Of women with their first episode of HSV-2 infection, 70-90% have herpetic cervicitis as part of the manifestation. In recurrent infections, cervicitis is present in 15-20% of women.
    

• • Primary herpetic cervicitis frequently is asymptomatic; however, it may present as a purulent or bloody vaginal discharge. Grossly, the cervix may appear diffusely red and friable. At times, ulcerations, which may be extensive, are present on the ectocervix.
    

• • Making a clinical diagnosis may be difficult. Colposcopic findings of acute cervicitis are identifiable in two thirds of women with primary herpes cervicitis. Multinucleate cells with typical ground-glass inclusions may be identified on cervical cytology results in 60% of these women.
    

• • The differential diagnosis includes the chancre of syphilis. Gonorrhea and chlamydia infection can cause a similar type of discharge, although ulceration in these conditions is uncommon. Syphilis, gonorrhea, and chlamydia infection may coexist with HSV-2 infection. Women with primary genital herpes involving the cervix should be started on antiviral therapy.
    

• • The other presentation of herpes involving the cervix is asymptomatic shedding. In these instances, the classic multinucleate cells with ground-glass inclusions may be identified on cervical cytology results as an incidental finding. In a sexually transmitted disease clinic, HSV was isolated from 4% of randomly selected women. Treatment for asymptomatic shedding is not recommended
    

• T pallidum
  • The primary lesion of syphilis develops at the site of inoculation 2-6 weeks after infection. The primary lesion begins as a papule and then ulcerates. Typically, the diameter is 0.5-1.5 cm.
    

• • In women, besides the labia and posterior fourchette, the cervix is a common site for the primary chancre. Because the primary lesion is asymptomatic and the cervix is not visualized readily, primary lesions in this location frequently remain undiagnosed. If untreated, they heal in 3-6 weeks. The disease then enters the latent period.
    

• • The differential diagnosis of these ulcers includes HSV-2 and H ducreyi. Diagnosis is best made using a dark-field microscopic examination of exudate taken from the surface of the lesion. The rapid plasma reagin (RPR) test results may be positive at a relatively low titer (1:16 or less) at this time. If syphilis is strongly considered and both the dark-field examination and the RPR test findings are negative, a repeat RPR test in 2 weeks will have positive results.
    

• • Treatment for primary syphilis is benzathine penicillin G at 2.4 million units. If the patient is allergic to penicillin, doxycycline at 100 mg twice daily for 2 weeks by mouth or tetracycline at 500 mg 4 times/d by mouth for 2 weeks is acceptable. If the patient is pregnant, desensitization followed by treatment with penicillin is recommended.
    

• • All patients with a diagnosis should be tested for HIV
    

• H ducreyi (ie, chancroid)
  • The primary ulcer is typically on the fourchette, labia, or vestibule.
    

• • Vaginal wall ulcers can occur and, at times, involve the cervix. Involvement of the cervix alone is very rare.
    

• Donovanosis (ie, granuloma inguinale)
  • The typical site of infection in women is the labia minora and the fourchette. Lesions of the cervix are uncommon but are easily confused with cervical carcinoma.
    

• • Four distinct types of lesions are described; the most common lesion on the cervix is the necrotic, deep, foul-smelling ulcer associated with tissue destruction.
    

• • A tissue smear is the mainstay of diagnosis. A Giemsa stain typically is used. The Donovan bodies are identified in monocytes. The characteristic histologic picture is that of chronic inflammation, with plasma cells and polymorphonuclear leukocytes. Rarely, Donovan bodies are identified on cervical cytology.
    

• • Treatment is with trimethoprim-sulfamethoxazole double-strength tablets twice daily or doxycycline at 100 mg orally twice daily. Alternative regimens include ciprofloxacin at 750 mg twice daily or erythromycin base at 500 mg 4 times daily. Treatment is for a minimum of 3 weeks
    

• Actinomyces organisms
  • Actinomyces organisms are isolated most commonly in women with intrauterine devices (IUDs), but infection can be a result of surgical instrumentation and abortion.
    

• • Demonstrating the organism in the center of large abscesses confirms the diagnosis.
    

• • Lesions appear yellow and granular to the naked eye, hence the term sulfur granule
    

• Tuberculosis
  • When the cervix is involved, the lesion almost always is secondary to tuberculous salpingitis, which is secondary to pulmonary tuberculosis.
    

• • The gross appearance can be confused with invasive carcinoma.
    

• • Histologically, multiple granulomas or tubercles with central caseation necrosis, epithelioid histiocytes, and multinucleated Langhans giant cells characterize the lesions.
    

• • The differential diagnosis includes lymphogranuloma venereum and sarcoidosis. An unequivocal diagnosis requires the identification of acid-fast Mycobacterium tuberculosis
    

• Protozoal and parasitic cervicitis: These are usually part of a more generalized process.

• Schistosomiasis and amebiasis: These are common in certain geographic areas.

Atypia of repair

This is a response to any injury that is characterized by epithelial disorganization and nuclear atypia. In reactive atypia, the nuclei are uniform in shape and size and the chromatin is aggregated in prominent chromocenters. Mitotic figures are normal and confined to the parabasal and basal cells. Maturation occurs in a normal manner. In the endocervix, reparative changes include nuclear enlargement, hyperchromasia, cytoplasmic eosinophilia, and loss of the mucin droplets.

Hyperkeratosis and parakeratosis

This usually involves the portio and may appear as whitish plaques (ie, leukoplakia). When diffuse, the portio is covered by a thickened, white, wrinkled epithelial membrane. The thick keratin layer on the surface is referred to as hyperkeratosis. When pyknotic nuclei are found within the keratin layer, the term parakeratosis is used. Acanthosis (ie, elongation of the rete pegs) is usually present.

Noninfectious cervicitis

This includes chemical irritation (eg, deodorants, douching), local trauma from foreign bodies (eg, tampons, pessaries, IUDs), surgical instrumentation, and therapeutic intervention. Clinically, the cervix is swollen, erythematous, and friable, and an associated purulent discharge may be present. The epithelium may be denuded and ulcerated. In chronic cervicitis, the cervix may be extremely friable and postcoital bleeding is a presenting complaint. Microscopically, lymphocytes, histiocytes, and plasma cells are present, with varying amounts of granulation tissue and stromal fibrosis. Lymphoid follicles with germinal centers are occasionally found beneath the epithelium. Chlamydia infection is isolated in some of these women.

BENIGN TUMORS

Endocervical polyps

Endocervical polyps are the most common benign neoplasms of the cervix. They are focal hyperplastic protrusions of the endocervical folds, including the epithelium and substantia propria. They are most common in the fourth to sixth decades of life and usually are asymptomatic but may cause profuse leukorrhea or postcoital spotting.

Grossly, they appear as typical polypoid structures protruding from the cervical os. At times, endometrial polyps protrude through the cervical os. They cannot be distinguished from endocervical polyps by gross appearance. Microscopically, a variety of histologic patterns are observed, including (1) typical endocervical mucosal, (2) inflammatory (granulation tissue), (3) fibrous, (4) vascular, (5) pseudodecidual, (6) mixed endocervical and endometrial, and (7) pseudosarcomatous.

Treatment is removal, which can usually be accomplished by twisting the polyp with a dressing forceps if the pedicle is slender. Smaller polyps may be removed with punch biopsy forceps. Polyps with a thick stalk may require surgical removal.

Microglandular hyperplasia

Microglandular hyperplasia refers to a clinically polypoid growth measuring 1-2 cm. It occurs most often in women who are on oral contraceptive therapy or Depo-Provera and in pregnant or postpartum women. It reflects the influence of progesterone.

Microscopically, it consists of tightly packed glandular or tubular units, which vary in size, lined by a flattened-to-cuboidal epithelium with eosinophilic granular cytoplasm containing small quantities of mucin. Nuclei are uniform, and mitotic figures are rare. Squamous metaplasia and reserve cell hyperplasia are common. An atypical form of hyperplasia can be mistaken for clear cell carcinoma. Unlike clear cell carcinoma, it lacks stromal invasion, has scant mitotic activity, and lacks intracellular glycogen

Squamous papilloma

Squamous papilloma is a benign solid tumor typically located on the ectocervix. It arises most commonly as a result of inflammation or trauma.

Grossly, the tumors are usually small, measuring 2-5 mm in diameter. Microscopically, the surface epithelium may show acanthosis, parakeratosis, and hyperkeratosis. The stroma has increased vascularity and a chronic inflammatory infiltrate. Treatment is removal. The squamous papilloma resembles a typical condyloma acuminatum but lacks the koilocytes microscopically.

Smooth muscle tumors (leiomyomas)

These benign neoplasms may originate in the cervix and account for approximately 8% of all uterine smooth muscle tumors. They are similar to tumors in the fundus. When located in the cervix, they usually are small, ie, 5-10 mm in diameter.

Symptoms depend on size and location. Microscopically, leiomyomas resemble the typical smooth muscle tumor found in the uterine corpus. Treatment is required only for those patients who are symptomatic. The cervical leiomyoma is usually part of the spectrum of uterine smooth muscle tumors.

Mesonephric duct remnants

When present, mesonephric duct remnants are typically located at the 3-o'clock and the 9-o'clock positions, deep within the cervical stroma. They usually are incidental findings and are present in approximately 15-20% of serially sectioned cervices. As the name implies, mesonephric duct remnants are vestiges of the mesonephric or Wolffian duct. Usually, they are only a few millimeters in diameter and seldom are grossly visible.

Microscopically, they consist of a proliferation of small round tubules lined by epithelium that is cuboidal to low columnar. The tubules tend to cluster around a central duct. The cells lining the tubules contain no glycogen or mucin, but the center of the tubule may contain a pink material that contains glycogen or mucin.

Endometriosis

When present in the cervix, endometriosis is usually an incidental finding. Grossly, it may appear as a bluish-red or bluish-black lesion, typically 1-3 mm in diameter. Microscopically, the implants are typical endometriosis, consisting of endometrial glands, endometrial stroma, and hemosiderin-laden macrophages. The implants usually gain access to the cervix during childbirth or previous surgery.

Papillary adenofibroma

This neoplasm is uncommon. Grossly, it appears as a polypoid structure. Microscopically, the neoplasm contains branching clefts and papillary excrescences lined by mucinous epithelium with foci of squamous metaplasia. A compact, cellular, fibrous tissue composed of spindle-shaped and stellate fibroblasts supports the epithelium. The stroma is devoid of smooth muscle, and mitoses are rare. Similar growths occur in the endometrium and the fallopian tubes.

Heterologous tissue

Heterologous tissue includes cartilage, glia, and skin with appendages. This type of tumor rarely occurs in the cervix. While they may arise de novo, these tumors probably represent implants of fetal tissue from a previous aborted pregnancy.

Hemangiomas

Hemangiomas in the cervix are rare and are similar to those found elsewhere in the body.

Autoimmune Thyroid Disease and Pregnancy

Background: Thyroid disorders are the second most common endocrinopathies found in pregnancy. Thyroid disorders are estimated to affect 0.2% of all pregnancies.

Autoimmune thyroid dysfunctions remain a common cause of both hyperthyroidism and hypothyroidism in pregnant women. Graves disease accounts for more than 85% of hyperthyroid cases, while Hashimoto thyroiditis remains the most common cause of hypothyroidism. In the postpartum period, postpartum thyroiditis (PPT) is reported to affect 4-10% of women. Interestingly, symptoms of autoimmune thyroid diseases tend to improve during pregnancy. A postpartum exacerbation is not uncommon, perhaps because of an alteration in the maternal immune system during pregnancy.

Pathophysiology: The defect that predisposes an individual to autoimmune thyroid disease is still unknown. Proposed mechanisms include a tissue-specific defect in suppressor T-cell activity, a genetically programmed presentation of a thyroid-specific antigen, and an idiotype-antiidiotype reaction. Regardless of the cause, the common outcome is the production of one or more types of autoantibodies.

Adams and Purves described the concept of Graves disease as autoimmune dysfunction of the thyroid gland. These investigators noted that the sera of patients with Graves disease contained a factor that stimulated the mouse thyroid and had a longer duration of action than thyrotropin, namely the long-acting thyroid stimulator. Further studies revealed that these long-acting thyroid stimulators are actually autoantibodies directed against the thyrotropin receptor. The activating version of the thyrotropin receptor is the thyroid-stimulating autoantibodies, which activate adenylate cyclase and stimulate thyroid function. Histologically, the thyroid glands of patients with Graves disease show follicular hypertrophy and hyperplasia.

Hashimoto thyroiditis is also known as goitrous chronic thyroiditis. Almost all of these patients have positive test results for the antithyroid peroxidase (anti-TPO) antibodies, autoantibodies against the thyroid peroxidase enzyme. Of these patients, 50-70% also have positive test results for antithyroglobulin antibodies. Extensive lymphocytic infiltration, follicular rupture, eosinophilia, varying degrees of hyperplasia, and fibrosis are the classic findings upon histologic examination.

Atrophic chronic thyroiditis is a rare autoimmune cause of hypothyroidism and is characterized by the presence of blocking autoantibodies to the thyrotropin receptors.

PPT is a variant of chronic autoimmune thyroiditis (Hashimoto thyroiditis). PTT is characterized by the presence of antimicrosomal antibodies. Histologic examination of thyroid glands affected by PPT shows destructive lymphocytic thyroiditis.

Frequency:

• In the US: Hyperthyroidism affects 2 in 1000 pregnancies. Graves disease accounts for 90-95% of these cases. Hypothyroidism affects 1 in 1600-2000 pregnancies. Hashimoto thyroiditis is the most common cause. Atrophic thyroiditis is less common. PPT affects 1 in 20 women in the postpartum period.

• Internationally: The reported range in frequency for PPT is wide. In Thailand, as few as 2 in 100 postpartum women are affected. On the other hand, some Canadian studies report a frequency of 2 in 10 postpartum women. These differences in frequency may be due to variation in diagnostic criteria, genetic factors, and differences in iodine consumption.

Mortality/Morbidity: Fetal and maternal outcomes are improved with normalization of thyroid function.

• Hyperthyroidism: Uncontrolled hyperthyroidism, especially in the second half of pregnancy, can lead to numerous complications. Maternal complications include miscarriage, infection, preeclampsia, preterm delivery, congestive heart failure (CHF), thyroid storm, and placental abruption. Fetal and neonatal complications include prematurity, size that is small for gestational age, intrauterine fetal death, toxemia, and fetal or neonatal thyrotoxicosis.

• Hypothyroidism: Maternal complications of untreated hypothyroidism include microcytic anemia, preeclampsia, placental abruption, postpartum hemorrhage, cardiac dysfunction, and miscarriage. Fetal or neonatal complications include prematurity, low birth weight, congenital anomalies, stillbirths, and poor neuropsychological development.

• Postpartum thyroiditis: Complications associated with PPT are maternal in nature, and depression is common. Permanent hypothyroidism occurs in as many as 30% of patients. These patients are also at high risk for recurrent PPT with subsequent pregnancies.

Sex:

• Autoimmune thyroid diseases occur more often in females than in males. The female-to-male ratio is 7:1.

Age:

• Autoimmune thyroid dysfunction most often affects women of reproductive age.

Treatment
Medical Care:

• Hyperthyroidism: The goal of treatment is to maintain clinical euthyroidism, with the mother's FT4 level in the high-normal range.

• Thioamide drugs (antithyroid drugs [ATDs]) are the first-line treatment in pregnancy. PTU, methimazole (MMI), and carbimazole (CMI) are the ATDs available in the United States. These drugs inhibit iodination of thyroglobulin and thyroglobulin synthesis by competing with iodine for the enzyme peroxidase. PTU and MMI or CMI are equally effective. PTU has not been associated with fetal scalp defects, aplastic cutis, or choanal atresia. Therefore, PTU tends to be the first choice in this class of drugs. ATDs should be maintained at the lowest dose needed to keep the mother's FT4 level in the high-normal range. Weight gain, pulse rate, FT4, and thyrotropin should be monitored monthly.

• Beta-blockers (eg, atenolol, nadolol, propranolol) are a valuable adjunct to ATDs. These drugs effectively alleviate symptoms of hypermetabolic states. With prolonged use, beta-blockers are associated with fetal morbidity; therefore, these drugs should only be used for a short period (ie, 2 wk), while waiting for the ATDs to take effect.
• Iodide decreases serum T4 and T3 levels by 30-50% in 10 days. Iodide is used in combination with ATDs and beta-blockers during the preoperative treatment of patients with hyperthyroidism. Iodide can also be used in the medical treatment of patients with thyroid storm. Fetal hypothyroidism resulting from placental passage is reported with prolonged use of iodide products; therefore, iodide use should be limited to less than 2 weeks.
• Radioactive iodine is contraindicated in pregnancy.

• Hypothyroidism: The goal of treatment is to normalize maternal thyrotropin levels.

• Thyroid hormone replacement is the treatment for patients with hypothyroidism. A full replacement dose should be instituted at the time of diagnosis.

• Patients with subclinical hypothyroidism should be treated to normalize maternal thyrotropin levels.
• In general, the thyroid hormone requirement increases approximately 50% during pregnancy; therefore, the thyrotropin level should be monitored closely. Serum thyrotropin levels should be measured 4-6 weeks after each change in T4 dosage.

Surgical Care:

• Hyperthyroidism

• Subtotal thyroidectomy, for reasons that remain unclear, induces remission in most patients with Graves disease. Surgery should be used as the second line of treatment in pregnant patients.

• Surgery is reserved for those patients who meet one of the following criteria:
  • High doses of ATDs (PTU >300 mg, MMI >20 mg) required
  • Inability to control clinical hyperthyroidism
  • Fetal hypothyroidism occurring at dose needed for maternal control
  • Inability to tolerate ATDs
  • Noncompliance
  • Suspected malignancy

• When surgery is needed, it should be performed during the second trimester.

• Hypothyroidism: No surgical care is recommended.

Consultations: Consultation with perinatologists and endocrinologists is recommended in difficult cases or in those with potential fetal compromise.

Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Antithyroid drugs -- Effective reversible treatment of hyperthyroidism. Consensus among experts is that ATDs should be first-line treatment for pregnant patients with hyperthyroidism. ATDs inhibit iodination of thyroid thyroglobulin and thyroglobulin synthesis by competing with iodine for peroxidase. PTU and MMI are available in the United States. PTU and MMI are equally effective. Both PTU and MMI cross the placenta and can cause fetal hypothyroidism and goiter.

Drug Name	Propylthiouracil -- Derivative of thiourea that inhibits organification of iodine by thyroid gland. Blocks oxidation of iodine in thyroid gland, thereby inhibiting thyroid hormone synthesis. Inhibits T4-to-T3 conversion (advantage over other agents). DOC in patients with hyperthyroidism during pregnancy. This is in response to reports of fetal aplasia cutis, a reversible scalp defect associated with MMI or CMI use. Taper gradually to minimum dose required to keep patient clinically euthyroid and to avoid fetal hypothyroidism.
Adult Dose	50-150 mg PO q8h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Has anti–vitamin K activity; may potentiate activity of oral anticoagulants
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Monitor PT during therapy; may cause hypoprothrombinemia and bleeding; once symptoms of hyperthyroidism resolve, lower maintenance dose if serum thyrotropin levels are elevated; associated with 1-5% risk of allergic reactions, including minor or major skin changes, arthralgias, metallic taste, lupuslike syndrome, fever, bronchospasm, ulcerations, and hepatitis

Drug Name	Methimazole (Tapazole) -- Inhibits thyroid hormone by blocking oxidation of iodine in thyroid gland; however, not known to inhibit peripheral conversion of thyroid hormone. Taper gradually to minimum dose required to keep patient clinically euthyroid and to avoid fetal hypothyroidism. Cases of fetal aplasia cutis reported.
Adult Dose	20-40 mg/d PO
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Has anti–vitamin K activity; may potentiate activity of oral anticoagulants
Pregnancy	D - Unsafe in pregnancy
Precautions	Monitor PT during therapy; may cause hypoprothrombinemia and bleeding; once symptoms of hyperthyroidism resolve, presence of elevated serum thyrotropin indicates lower maintenance dose should be used

Drug Category: Iodides -- Inhibit release of stored thyroid hormones. Decrease serum T4 and T3 by 30-50% by the 10th day of treatment. Reserved for treatment of severe thyrotoxicosis or for use preoperatively in combination with ATDs and beta-blockers. Readily cross placenta by 12th week of gestation and are taken up readily by fetal thyroid. Long-term use can lead to fetal hypothyroidism and goiter. Generally recommended for no more than 2 wk in pregnant patients.

Drug Name	Iodide (SSKI, Pima) -- DOC, rapidly inhibits release of thyroid hormones via a direct effect on thyroid gland and inhibits synthesis of thyroid hormones. Also appears to attenuate cAMP-mediated effects of thyrotropin.
Adult Dose	1-5 gtt solution containing 1 g/mL (50-250 mg of iodide) bid for 10-14 d; 3 gtt SSKI q8h or sodium iodide IV 0.5 mg q12h for thyroid storm
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; pulmonary edema, bronchitis, tuberculosis, hyperkalemia
Interactions	Increases lithium toxicity by producing additive hypothyroid effects; coadministration with potassium-sparing agents can lead to hyperkalemia
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Prolonged use may result in hypothyroidism; caution in renal failure and GI obstruction; large doses can lead to iodism (metallic taste, soreness of teeth, coryza, sneezing, eye irritation, headache, pulmonary edema, fatal eruptions); prolonged use in pregnancy can lead to fetal hypothyroidism

Drug Category: Thyroid hormones -- Several forms of thyroid hormones are commercially available, including levothyroxine, liothyronine, and liotrix. Levothyroxine is DOC for treatment of pregnant patients with hypothyroidism.

Drug Name	Levothyroxine (Synthroid) -- Levo isomer of T4. Once absorbed, T4 is deiodinated to T3 in extrathyroidal tissues. First choice in treatment of hypothyroidism during pregnancy because it mimics physiologic state. Measure thyrotropin q4wk and adjust dosage.
Adult Dose	0.1-0.15 mg/d PO or 2 mcg/kg actual weight/d PO
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; uncorrected adrenal insufficiency; acute MI
Interactions	Cholestyramine may decrease absorption; estrogens may decrease response to thyroid hormone therapy in patients with nonfunctioning thyroid glands; effect of anticoagulants increased when coadministered; activity of some beta-blockers may decrease when hypothyroid patient is converted to a euthyroid state
Pregnancy	A - Safe in pregnancy
Precautions	Caution in angina pectoris or cardiovascular disease; monitor thyroid status periodically; skin reactions reported but are very rare

Drug Category: Beta-adrenergic blocking agents -- Valuable adjunct to ATDs. Effective for alleviating symptoms of hypermetabolic state (eg, palpitation, sweating, nervousness, tremor). Safe during pregnancy for immediate control of symptomatic thyrotoxicosis. Goal is to reduce maternal heart rate to <100>

Drug Name	Propranolol (Inderal) -- DOC in treating cardiac arrhythmias resulting from hyperthyroidism. Controls cardiac and psychomotor manifestations within minutes.
Adult Dose	20-40 mg PO q6-8h; adjust to keep maternal resting heart rate <100>
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; uncompensated CHF; bradycardia, Raynaud phenomenon, cardiogenic shock; AV conduction abnormalities
Interactions	Coadministration with aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease effects; calcium channel blockers, cimetidine, loop diuretics, and MAOIs may increase toxicity; toxicity of hydralazine, haloperidol, benzodiazepines, and phenothiazines may increase; potentiates peripheral vasoconstrictive effect of ergot
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Beta-adrenergic blockade may decrease signs of acute hypoglycemia and hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; withdraw drug slowly and monitor closely; caution in renal and hepatic impairment

Assisted Reproduction Technology

Background Infertility is a very common condition affecting approximately 13-14% of reproductive-aged couples. Despite a stable prevalence of infertility in this population, the demand for infertility services has increased substantially over the past decade. This increase is primarily due to the "Baby Boom generation" (ie, the significantly large US generation conceived immediately after World War II) entering into the reproductive age group at a time of highly publicized technological advances. Although infertility represents a small facet of the broad intellectual scope of reproductive endocrinology, patients seeking infertility treatment represent the mainstay of a clinical reproductive endocrinologist's practice.

Infertility is defined as the inability to conceive after 1 year of properly timed unprotected intercourse. This definition is based on the cumulative probability of pregnancy (see Table 1).

Table 1. Cumulative Probability of Pregnancy in Couples With Normal Fertility (All Reproductive-aged Women)

Month	Monthly Probability	Cumulative Probability
1	0.2	0.20
2	0.2	0.36
3	0.2	0.49
4	0.2	0.59
5	0.2	0.67
6	0.2	0.74
7	0.2	0.79
8	0.2	0.83
9	0.2	0.86
10	0.2	0.89
11	0.2	0.91
12	0.2	0.93

Assuming a constant monthly probability of conceiving (fecundability) of 20%, the cumulative pregnancy rate after 12 months is 93%. Approximately 50% of couples should become pregnant after 3 months, but only an additional 25% conceive if attempting pregnancy an additional 2 months. During patient counseling, fostering an understanding of the cumulative probability of pregnancy and emphasizing that most fertility therapy (other than in vitro fertilization [IVF]) is designed to improve monthly fecundability to as close to the 20% baseline (normal fertile couples) as possible is important.

Conventional infertility treatment (excluding IVF) is usually continued until the cumulative pregnancy rate is at least 50%. Because fecundability rates are clearly higher in younger women and lower in older women, counseling a 40-year-old woman to wait 1 year before seeking fertility services is not appropriate. In women older than 35 years, a complete evaluation at 4-6 months is best because their potential response to any therapy may be suboptimal due to diminished ovarian reserve.

Treatment
Treatment of ovulatory dysfunction

If a patient has a normal ovarian reserve, determining the potential cause of the ovulatory defect is prudent. The practitioner should consider the following scenarios prior to initiating treatment. In the presence of obesity and chronic anovulation, polycystic ovarian (PCO) syndrome or Cushing disease may be evident and in the case of hirsutism, the patient may have elevated androgen levels or hyperinsulinemia, requiring further testing. If the physical examination findings are unremarkable, ovulation induction is the next treatment approach to consider.

The following clomiphene citrate (CC) treatment regimens are often used for ovulation induction in patients with idiopathic ovulatory dysfunction or PCO syndrome:

• Clomiphene citrate (50 mg on days 5-9)
• Clomiphene citrate (100 mg on days 2-6) plus FSH (1-2 amps starting on day 8)
• Clomiphene citrate plus human chorionic gonadotropin (hCG) for ovulation induction
• Elevated androgen levels – Dexamethasone (0.25 mg/d) plus clomiphene citrate
• Hyperinsulinemia with elevated androgens - Metformin (500 mg tid) plus clomiphene citrate (Many women spontaneously ovulate on metformin alone; thus, many clinicians allow a trial of 1-3 mo prior to adding clomiphene citrate.)
• Aromatase inhibitors (Letrozole) (2.5 mg PO on cycle days 3-7) has been shown in early studies to work as well as clomiphene citrate to induce mono-ovulation and to have little or no adverse affect on endometrial thickness.

The goal of therapy is to achieve 3 ovulatory cycles; 40-50% of women should become pregnant in this timeframe in the absence of any other abnormalities. If conception has not occurred after 3 clomiphene citrate cycles, the practitioner should investigate other causes of infertility. No more than 6 consecutive cycles are recommended because of the theoretical risk of borderline ovarian tumors and extremely low pregnancy success rates after this point.

Evidence suggests that starting clomiphene citrate earlier (day 2 or 3) is more beneficial because this conforms to a more typical cycle length of 28 days. Beginning a clomiphene citrate cycle on day 2 or 3 promotes ovulation around days 12-16, which is more physiologic and may avoid delayed ovulation and excessive maturity of the oocyte. Studies from the 1970s in women with documented delayed ovulation (after cycle day 16) revealed a higher relative miscarriage rate. This was believed to be caused by meiotic dysfunction within the oocyte.

Ovulation (LH) predictor kits are much easier for patients to use when clomiphene citrate is started on day 2 or 3. LH levels are normally elevated after the patient takes clomiphene citrate, and the half-life of the medication is 5 days. Thus, in a cycle day 5-9 regimen, a patient may receive a false-positive reading if she follows the directions on the kit and starts monitoring on cycle days 12-13.

Evidence demonstrates that a day 2 or 3 clomiphene citrate start allows the endometrium to thicken to a more normal, physiologic range. Endometrial thinning is a well-known adverse effect of clomiphene citrate. An endometrium that is thinner than 7-8 mm has been associated with a lower pregnancy rate in IVF cycles.

Treatment of male factor

Confirm any abnormal study result with a repeat semen analysis. If the results remain abnormal, refer the patient to a urologist to eliminate any genetic, anatomic, hormonal, or infectious causes. If the volume is less than 1 mL, consider retrograde ejaculation and obtain an analysis of the urine.

If the sperm concentration is less than 20 million/mL, yet the swim-up extraction yields at least 1 million total motile sperm, IUI is the treatment of choice. Simple sperm washing can be performed in the office if a centrifuge is available. Allow the semen to liquify on a warming plate at 37°C; then, suspend the semen in approximately 15-20 mL of washing medium (eg, Earl) and centrifuge it for 60 seconds. Resuspend the pellet in another 15-20 mL of medium and centrifuge again. The supernatant is removed, and 0.5 mL of the medium is used to resuspend the sperm pellet. Using an intrauterine catheter, deposit the sperm into the uterus on the day of ovulation

Treatment of tubal disease

IVF offers the best chance for conception in patients with significant tubal disease. Often, if only 1 tube is affected, ovarian stimulation with gonadotropins produces mature oocytes in the ovary near the patent tube. In patients with minimal or moderate tubal disease, laparoscopic lysis of adhesions and procedures should be performed to normalize tubal function, with an emphasis on prevention of adhesion recurrence. In patients with an irreparable hydrosalpinx, removing the tube or disconnecting it from the uterus may reduce the risk of a tubal pregnancy and enhance embryo implantation if the patient requires IVF.

Pregnancy rate following treatment can be dependent upon location of tubal disease.

Laparoscopic lysis of adhesions offers the patient a window of opportunity to conceive either naturally or with minimal types of therapy. If only proximal tubal occlusion is present, these obstructions can be fixed with a balloon tuboplasty under fluoroscopic guidance similar to the common angioplastic procedure in cardiology.

Table 4. Treatment of Tubal Pathology

Procedure	Pregnancy Rate (3-6 mo)
Lysis of adhesions	50%
Mild distal obstructive disease	80%
Moderate distal obstructive disease	30%
Severe distal obstructive disease	15%
Proximal tubal obstruction:	30%

Treatment of cervical factor

In most patients, IUIs offer the most reasonable option for treatment. Some patients remain adamant that they want to continue with timed coitus despite a cervical issue. In women with thick mucus (poor spinnbarkeit), the addition of conjugated estrogen (Premarin at 0.625 mg or Estrace at 2 mg) 8-9 days prior to ovulation has its supporters but lacks clear clinical value. In some studies, if the pH is less than 7.0, a precoital douche of 1 tablespoon of sodium bicarbonate in 1 quart of water has shown good results. The presence of antisperm antibodies in the female or male warrants IUIs. If the antibodies are on the sperm itself, washing the sperm with a chymotrypsin/galactose preparation may improve sperm motility.

Treatment of uterine factor

An operative hysteroscopy is usually required to lyse adhesions or remove endometrial polyps or submucosal fibroids. Intramural fibroids often must be removed by laparotomy and myomectomy, paying close attention to microsurgical technique and adhesion prevention. Many times, subserosal fibroids may impinge on a fallopian tube. In severe cases of intrauterine adhesions that encompass most of the uterine cavity, the best option for conception may be through the use of a gestational carrier.

Treatment of endocrine abnormalities

Ensure that any endocrine abnormality is normalized prior to attempts at conception. Keep in mind that women with luteal phase defects also have ovulatory dysfunction. Clomiphene citrate, as previously mentioned, and luteal phase progesterone supplementation may be potentially effective treatments. The recommended progesterone is either micronized progesterone in vaginal suppositories (50-100 mg bid) or progesterone vaginal cream (Crinone 8%; 90 mg/d). Oral micronized progesterone may be used but causes significant somnolence and adverse central nervous system effects (eg, depression).

Treatment of unexplained infertility

The choice of treatment protocol depends on how aggressive the couple wants to be with their efforts to conceive. Most physicians start with either clomiphene citrate or gonadotropins in conjunction with IUIs. Involve the couple in the decision-making process, and ensure that they completely understand the success rates (see Table 5) and the risks of multiple pregnancy with each treatment protocol.

Table 5. Unexplained Infertility and Pregnancy Rates per Cycle According to Treatment

Protocol	Pregnancy Rate, %
No treatment	1.3-4.1
IUI alone	3.8
Clomiphene with timed coitus	5.6
Clomiphene with IUI	10
Gonadotropins with timed coitus	7.7
Gonadotropins with IUI	17.1
IVF	35-50

In vitro fertilization (IVF)

The first IVF pregnancy was achieved in 1978. Since then, the number of IVF centers and IVF procedures performed has increased dramatically. An intense effort to obtain insurance coverage for these services has also occurred. With the support of organizations such as (ie, the National Fertility Association), 13 US states have the opportunity to provide coverage for these services. Currently, 2 states (Massachusetts and Rhode Island) offer full coverage. Other states exempt health maintenance organization programs, private insurers, or companies with few employees. Other states offer lifetime limits to their coverage (eg, Ohio, $2000; Arkansas, $15,000). Still other states require insurers to offer coverage but do not require employers to purchase plans that actually provide that coverage. The actual cost per paid subscriber is not substantial. A recent study in Massachusetts, which has approximately 5000 IVF cycles per year, calculated that the increase is only$25 per year per subscriber.

As a result of the Fertility Clinic Success Rate and Certification Act, the US Centers for Disease Control and Prevention (CDC) gathers information from 391 of the 428 fertility clinics throughout the United States. Information from 2002 shows that 115,392 ART cycles were performed.

Assisted reproductive techniques

Gamete intrafallopian transfer (GIFT) was developed in 1984 for women with unexplained infertility. At that time, GIFT provided much better pregnancy rates, had a much greater degree of naturalness, and was more acceptable in certain religious and ethnic communities (in which fertilization inside the woman's body is the only type allowed). During this procedure, the patient undergoes a controlled ovarian hyperstimulation. The oocytes are retrieved transvaginally under ultrasonographic guidance, and 3-4 oocytes are placed via laparoscopy into one of the fallopian tubes along with sperm.

Zygote intrafallopian transfer (ZIFT) is used for couples with a significant male factor. The oocytes are retrieved similar to GIFT, but they are allowed to fertilize in vitro in the laboratory. At the 2-pronuclear stage (usually 24 h later), 3-4 embryos are transferred via laparoscopy into one of the fallopian tubes. If the embryos are allowed to develop to greater than a 2-cell stage, the procedure is termed tubal embryo transfer (TET). The only benefit to a ZIFT or TET versus the more traditional IVF is for women who are thought to have compromised embryo quality due to embryo in vitro culture. Placing these zygotes or embryos back into their own natural incubators is thought to enhance subsequent development, with improved pregnancy rates.

With the development of enhanced culture media, the success rates for IVF are now comparable, if not better, to those of GIFT and ZIFT.

Interpreting IVF success rates

Comparing one program's success rate to another is difficult because of all the variables involved. For instance, perhaps a program is very selective with its patients, allowing only those with a chance for success based on diagnosis, age, or ovarian reserve. Programs in states that are mandated to cover fertility therapy may be more likely to treat patients with a low chance for success simply because the patient has insurance or, perhaps, because the programs may perform more IVF cycles than programs in states without such a mandate. Some have suggested that programs in mandated states, due to the treatment algorithms enforced by the insurance companies, often have to treat patients without a male or tubal factor for many months with insemination cycles before getting approval for IVF coverage. Thus, these patients may actually be the most difficult patients to treat when they eventually get to IVF.

On the other hand, programs in states without a mandate may be dealing with more difficult patients who have had multiple surgeries and other covered or less costly therapy before ultimately deciding on IVF. However, some argue that many of these programs often take patients directly to IVF, or after a few insemination cycles, and, thus, these patients are more likely to be successful.

In general, like any statistical analysis, the more IVF cycles a program has performed, the more valid the numbers. The cancellation rate is a critical number. If the rate is high, the program is possibly very selective for those patients it allows to proceed to egg retrieval. This type of program would rather cancel the patient's procedure than have a low chance for success that may ultimately hurt its overall success rates. The pregnancy rate per retrieval is higher compared with the pregnancy rate per transfer. If this difference is large, it may reflect the quality of the laboratory. The implantation rate refers to thepregnancy rate divided by the number of embryos transferred. If the implantation rate is low and the pregnancy rate is high, this suggests that the program is transferring a large number of embryos per patient to achieve that success. Chances are good that the program's multiple pregnancy rate is high. Optimally, the better programs have a low cancellation rate and good pregnancy and implantation rates.

The ultimate critical number is the birth rate because this represents the final goal of the patient and the physician. This goal is also less vulnerable to misinterpretation than the pregnancy rate (single positive hCG vs serial increases) or the clinical pregnancy rate (gestational sac vs fetal pole vs fetal pole with heartbeat).

IVF outcomes

In 2002, 115,392 IVF cycles were reported started with a 14.6% cancellation rate, and, 45,751 pregnancies were confirmed delivered. One of every 2.5 IVF cycles started ended in a live birth. When observing cycles that ended in a uterine pregnancy (30.5%), most ended in a singleton birth. The miscarriage rate is no higher than that with a spontaneous pregnancy (ie, 16.1%).

Guidelines for embryo transfer

In response to the significant numbers of higher order multiple pregnancies generated from ART, the American Society of Reproductive Medicine (ASRM) released guidelines for the number of embryos transferred in 1999. Shows the risk of having a multiple-fetus pregnancy using fresh, nondonor embryos.

In 2002, the total multiple-fetus pregnancy rate was 36%. A lower number of deliveries of triplets or more compared to pregnancies suggests that these pregnancies were either iatrogenically reduced, spontaneously reduced, or resulted in a miscarriage.

Increasing the number of embryos transferred from 1 to 2 not only increases the chance for a live birth but also increases the likelihood of a multiple-infant pregnancy. However, transferring more than 2 embryos may not increase the overall live birth rate.

Many variables affect the decision of how many embryos to transfer. Factors such as the patient's age, embryo quality, number of prior failed IVF cycles, and use of frozen-thawed embryos are important to consider. New data from Europe suggests that a single embryo transfer in the appropriate patient results in approximately a 35% pregnancy rate with a less than 1% multiple pregnancy rate. These patients typically have embryos that are frozen, ensuring that their cumulative pregnancy rate using either fresh or frozen embryos is similar to transferring 2 or more embryos. Show the relationship between the number of embryos transferred and the risk of having a multiple-infant birth in women of all ages and in women younger than 35 years. Single embryo transfer is appropriate in certain situations where the likelihood of a multiple pregnancy is high. This may include women younger than 35 years, women who conceived with first IVF cycle, women with only tubal factorinfertility, women with concerns about multiple gestation, and donor egg recipients.

Factors contributing to IVF success

The most important factor that determines a successful cycle is the female patient's age. As mentioned previously, decreases in fecundity rates are observed beginning as early as age 30 years. The dramatic effect that age has on fecundability is also observed in ART (see Image 7). Most egg donors are aged 20-35 years, allowing for an optimal control group to observe these differences.

Ultimately, the success of ARTs mimics the overall fecundity trend observed in the general fertile population. That is, pregnancy and live birth rates start to decrease beginning around age 30 years and continue to decrease until the chance of having a live birth is so low that the benefit of ARTs must be evaluated. In women older than 40 years, the chance of having a liveborn infant with a chromosomal abnormality also increases. The live birth rate with ARTs based on the patient's age and whether she uses her own oocytes or donor eggs, which are typically harvested from women aged 20-35 years.

Oocyte retrieval

Oocyte retrieval is performed approximately 36 hours after 10,000 U of hCG is administered to allow for the resumption of meiosis, cytoplasmic maturation, and loosening of the oocytes within the follicle. This allows for a lower optimal vacuum pressure during aspiration and ultimately less oocyte damage.

The 3 basic methods to retrieve oocytes are laparoscopic, transabdominal, or transvaginal. The laparoscopic approach was used frequently in the 1980s, especially when a GIFT procedure was planned. Often, only the follicles that could be seen on the surface of the ovary were removed, and, if the ovary was very mobile, traction was required to support the ovary as the follicles were aspirated. Associated morbidity occurred with the procedure, which included infection and injury to the pelvic organs. General endotracheal anesthesia was usually used, and the patient's recovery often lasted 2-3 days. As the quality of ultrasonographic images and culture media improved, the need for laparoscopy decreased.

In 1981, ultrasonographic-guided aspiration was first described. Initially, the transabdominal approach was used, usually with the aspirating needle going through the bladder, which, when full, provided a window of visualization for the person operating the abdominal ultrasonographic probe.

Although still used for retrieval of oocytes from ovaries that are adhered high up in the pelvis or to the fundus of the uterus, the transabdominal approach was superseded by the transvaginal approach. The first transvaginal retrieval was performed in 1984 and has now become the procedure of choice because of its ease and low morbidity.

Micromanipulation

Intracytoplasmic sperm injection (ICSI) is the treatment of choice for couples in whom the male partner has azoospermia or severe oligospermia. ICSI is also indicated for men with significant antisperm antibodies, low sperm motility, or significantly abnormal sperm morphology (Kruger strict morphology <4%).>

ICSI is used when poor fertilization occurs with regular insemination techniques in the laboratory. ICSI may be used when a limited amount of sperm is available, such as in couples where the man has stored sperm prior to chemotherapy. ICSI is indicated in certain preimplantation genetic (PGD) procedures—specifically those cases being evaluated for single-gene recessive disorders. This prevents the potential contamination of the specimen with sperm that may be attached to the egg.

Sperm can be obtained from the ejaculate or directly from the epididymis. Recently, success was obtained with spermatids from testicular biopsies.

The potential transmission of a genetic abnormality is a possibility when ICSI is performed. The normal barrier for morphologically abnormal sperm that tend to have genetic abnormalities (ie, zonal pellucida) is bypassed with ICSI. Morphologically normal sperm may also have genetic abnormalities. Approximately 10% of sperm from healthy men have chromosomal abnormalities. Men who are infertile have a 5-7% chance of having a chromosomal abnormality. Chromosomal abnormalities include microdeletions of the long arm of the Y chromosome in areas AZFa, AZFb, and AZFc (DAZ or deleted in azoospermia region). These deletions can be passed on to male offspring, with resulting oligospermia.

Some data suggest a 30% increase in birth defects in children conceived with ICSI. Overall, this implies that the risk of having a child with a birth defect from ART with ICSI goes from a normal baseline of 3% to, at most, 4%.

Approximately 1-2% of men with azoospermia have genetic translocation, Klinefelter syndrome (47XXY), or a congenital bilateral absence of the vas deferens, which is associated with mutations in the cystic fibrosis transmembrane regulator (CFTR) gene or the 5T allele.

In the situation where the male partner has the CFTR mutation, the female partner should also be screened for cystic fibrosis. In any couple undergoing ICSI for male factor infertility, a karyotype and Y-DNA mapping should be considered if the sperm concentration is less than 5 million/mL, and genetic counseling should be offered. Prenatal testing of ICSI pregnancies has revealed an incidence of 0.83% of sex chromosome abnormalities (higher than those reported for spontaneous pregnancies).

Assisted Reproduction Technology

Background Infertility is a very common condition affecting approximately 13-14% of reproductive-aged couples. Despite a stable prevalence of infertility in this population, the demand for infertility services has increased substantially over the past decade. This increase is primarily due to the "Baby Boom generation" (ie, the significantly large US generation conceived immediately after World War II) entering into the reproductive age group at a time of highly publicized technological advances. Although infertility represents a small facet of the broad intellectual scope of reproductive endocrinology, patients seeking infertility treatment represent the mainstay of a clinical reproductive endocrinologist's practice.

Infertility is defined as the inability to conceive after 1 year of properly timed unprotected intercourse. This definition is based on the cumulative probability of pregnancy (see Table 1).

Table 1. Cumulative Probability of Pregnancy in Couples With Normal Fertility (All Reproductive-aged Women)

Month	Monthly Probability	Cumulative Probability
1	0.2	0.20
2	0.2	0.36
3	0.2	0.49
4	0.2	0.59
5	0.2	0.67
6	0.2	0.74
7	0.2	0.79
8	0.2	0.83
9	0.2	0.86
10	0.2	0.89
11	0.2	0.91
12	0.2	0.93

Assuming a constant monthly probability of conceiving (fecundability) of 20%, the cumulative pregnancy rate after 12 months is 93%. Approximately 50% of couples should become pregnant after 3 months, but only an additional 25% conceive if attempting pregnancy an additional 2 months. During patient counseling, fostering an understanding of the cumulative probability of pregnancy and emphasizing that most fertility therapy (other than in vitro fertilization [IVF]) is designed to improve monthly fecundability to as close to the 20% baseline (normal fertile couples) as possible is important.

Conventional infertility treatment (excluding IVF) is usually continued until the cumulative pregnancy rate is at least 50%. Because fecundability rates are clearly higher in younger women and lower in older women, counseling a 40-year-old woman to wait 1 year before seeking fertility services is not appropriate. In women older than 35 years, a complete evaluation at 4-6 months is best because their potential response to any therapy may be suboptimal due to diminished ovarian reserve.

Treatment
Treatment of ovulatory dysfunction

If a patient has a normal ovarian reserve, determining the potential cause of the ovulatory defect is prudent. The practitioner should consider the following scenarios prior to initiating treatment. In the presence of obesity and chronic anovulation, polycystic ovarian (PCO) syndrome or Cushing disease may be evident and in the case of hirsutism, the patient may have elevated androgen levels or hyperinsulinemia, requiring further testing. If the physical examination findings are unremarkable, ovulation induction is the next treatment approach to consider.

The following clomiphene citrate (CC) treatment regimens are often used for ovulation induction in patients with idiopathic ovulatory dysfunction or PCO syndrome:

• Clomiphene citrate (50 mg on days 5-9)
• Clomiphene citrate (100 mg on days 2-6) plus FSH (1-2 amps starting on day 8)
• Clomiphene citrate plus human chorionic gonadotropin (hCG) for ovulation induction
• Elevated androgen levels – Dexamethasone (0.25 mg/d) plus clomiphene citrate
• Hyperinsulinemia with elevated androgens - Metformin (500 mg tid) plus clomiphene citrate (Many women spontaneously ovulate on metformin alone; thus, many clinicians allow a trial of 1-3 mo prior to adding clomiphene citrate.)
• Aromatase inhibitors (Letrozole) (2.5 mg PO on cycle days 3-7) has been shown in early studies to work as well as clomiphene citrate to induce mono-ovulation and to have little or no adverse affect on endometrial thickness.

The goal of therapy is to achieve 3 ovulatory cycles; 40-50% of women should become pregnant in this timeframe in the absence of any other abnormalities. If conception has not occurred after 3 clomiphene citrate cycles, the practitioner should investigate other causes of infertility. No more than 6 consecutive cycles are recommended because of the theoretical risk of borderline ovarian tumors and extremely low pregnancy success rates after this point.

Evidence suggests that starting clomiphene citrate earlier (day 2 or 3) is more beneficial because this conforms to a more typical cycle length of 28 days. Beginning a clomiphene citrate cycle on day 2 or 3 promotes ovulation around days 12-16, which is more physiologic and may avoid delayed ovulation and excessive maturity of the oocyte. Studies from the 1970s in women with documented delayed ovulation (after cycle day 16) revealed a higher relative miscarriage rate. This was believed to be caused by meiotic dysfunction within the oocyte.

Ovulation (LH) predictor kits are much easier for patients to use when clomiphene citrate is started on day 2 or 3. LH levels are normally elevated after the patient takes clomiphene citrate, and the half-life of the medication is 5 days. Thus, in a cycle day 5-9 regimen, a patient may receive a false-positive reading if she follows the directions on the kit and starts monitoring on cycle days 12-13.

Evidence demonstrates that a day 2 or 3 clomiphene citrate start allows the endometrium to thicken to a more normal, physiologic range. Endometrial thinning is a well-known adverse effect of clomiphene citrate. An endometrium that is thinner than 7-8 mm has been associated with a lower pregnancy rate in IVF cycles.

Treatment of male factor

Confirm any abnormal study result with a repeat semen analysis. If the results remain abnormal, refer the patient to a urologist to eliminate any genetic, anatomic, hormonal, or infectious causes. If the volume is less than 1 mL, consider retrograde ejaculation and obtain an analysis of the urine.

If the sperm concentration is less than 20 million/mL, yet the swim-up extraction yields at least 1 million total motile sperm, IUI is the treatment of choice. Simple sperm washing can be performed in the office if a centrifuge is available. Allow the semen to liquify on a warming plate at 37°C; then, suspend the semen in approximately 15-20 mL of washing medium (eg, Earl) and centrifuge it for 60 seconds. Resuspend the pellet in another 15-20 mL of medium and centrifuge again. The supernatant is removed, and 0.5 mL of the medium is used to resuspend the sperm pellet. Using an intrauterine catheter, deposit the sperm into the uterus on the day of ovulation

Treatment of tubal disease

IVF offers the best chance for conception in patients with significant tubal disease. Often, if only 1 tube is affected, ovarian stimulation with gonadotropins produces mature oocytes in the ovary near the patent tube. In patients with minimal or moderate tubal disease, laparoscopic lysis of adhesions and procedures should be performed to normalize tubal function, with an emphasis on prevention of adhesion recurrence. In patients with an irreparable hydrosalpinx, removing the tube or disconnecting it from the uterus may reduce the risk of a tubal pregnancy and enhance embryo implantation if the patient requires IVF.

Pregnancy rate following treatment can be dependent upon location of tubal disease.

Laparoscopic lysis of adhesions offers the patient a window of opportunity to conceive either naturally or with minimal types of therapy. If only proximal tubal occlusion is present, these obstructions can be fixed with a balloon tuboplasty under fluoroscopic guidance similar to the common angioplastic procedure in cardiology.

Table 4. Treatment of Tubal Pathology

Procedure	Pregnancy Rate (3-6 mo)
Lysis of adhesions	50%
Mild distal obstructive disease	80%
Moderate distal obstructive disease	30%
Severe distal obstructive disease	15%
Proximal tubal obstruction:	30%

Treatment of cervical factor

In most patients, IUIs offer the most reasonable option for treatment. Some patients remain adamant that they want to continue with timed coitus despite a cervical issue. In women with thick mucus (poor spinnbarkeit), the addition of conjugated estrogen (Premarin at 0.625 mg or Estrace at 2 mg) 8-9 days prior to ovulation has its supporters but lacks clear clinical value. In some studies, if the pH is less than 7.0, a precoital douche of 1 tablespoon of sodium bicarbonate in 1 quart of water has shown good results. The presence of antisperm antibodies in the female or male warrants IUIs. If the antibodies are on the sperm itself, washing the sperm with a chymotrypsin/galactose preparation may improve sperm motility.

Treatment of uterine factor

An operative hysteroscopy is usually required to lyse adhesions or remove endometrial polyps or submucosal fibroids. Intramural fibroids often must be removed by laparotomy and myomectomy, paying close attention to microsurgical technique and adhesion prevention. Many times, subserosal fibroids may impinge on a fallopian tube. In severe cases of intrauterine adhesions that encompass most of the uterine cavity, the best option for conception may be through the use of a gestational carrier.

Treatment of endocrine abnormalities

Ensure that any endocrine abnormality is normalized prior to attempts at conception. Keep in mind that women with luteal phase defects also have ovulatory dysfunction. Clomiphene citrate, as previously mentioned, and luteal phase progesterone supplementation may be potentially effective treatments. The recommended progesterone is either micronized progesterone in vaginal suppositories (50-100 mg bid) or progesterone vaginal cream (Crinone 8%; 90 mg/d). Oral micronized progesterone may be used but causes significant somnolence and adverse central nervous system effects (eg, depression).

Treatment of unexplained infertility

The choice of treatment protocol depends on how aggressive the couple wants to be with their efforts to conceive. Most physicians start with either clomiphene citrate or gonadotropins in conjunction with IUIs. Involve the couple in the decision-making process, and ensure that they completely understand the success rates (see Table 5) and the risks of multiple pregnancy with each treatment protocol.

Table 5. Unexplained Infertility and Pregnancy Rates per Cycle According to Treatment

Protocol	Pregnancy Rate, %
No treatment	1.3-4.1
IUI alone	3.8
Clomiphene with timed coitus	5.6
Clomiphene with IUI	10
Gonadotropins with timed coitus	7.7
Gonadotropins with IUI	17.1
IVF	35-50

In vitro fertilization (IVF)

The first IVF pregnancy was achieved in 1978. Since then, the number of IVF centers and IVF procedures performed has increased dramatically. An intense effort to obtain insurance coverage for these services has also occurred. With the support of organizations such as (ie, the National Fertility Association), 13 US states have the opportunity to provide coverage for these services. Currently, 2 states (Massachusetts and Rhode Island) offer full coverage. Other states exempt health maintenance organization programs, private insurers, or companies with few employees. Other states offer lifetime limits to their coverage (eg, Ohio, $2000; Arkansas, $15,000). Still other states require insurers to offer coverage but do not require employers to purchase plans that actually provide that coverage. The actual cost per paid subscriber is not substantial. A recent study in Massachusetts, which has approximately 5000 IVF cycles per year, calculated that the increase is only$25 per year per subscriber.

As a result of the Fertility Clinic Success Rate and Certification Act, the US Centers for Disease Control and Prevention (CDC) gathers information from 391 of the 428 fertility clinics throughout the United States. Information from 2002 shows that 115,392 ART cycles were performed.

Assisted reproductive techniques

Gamete intrafallopian transfer (GIFT) was developed in 1984 for women with unexplained infertility. At that time, GIFT provided much better pregnancy rates, had a much greater degree of naturalness, and was more acceptable in certain religious and ethnic communities (in which fertilization inside the woman's body is the only type allowed). During this procedure, the patient undergoes a controlled ovarian hyperstimulation. The oocytes are retrieved transvaginally under ultrasonographic guidance, and 3-4 oocytes are placed via laparoscopy into one of the fallopian tubes along with sperm.

Zygote intrafallopian transfer (ZIFT) is used for couples with a significant male factor. The oocytes are retrieved similar to GIFT, but they are allowed to fertilize in vitro in the laboratory. At the 2-pronuclear stage (usually 24 h later), 3-4 embryos are transferred via laparoscopy into one of the fallopian tubes. If the embryos are allowed to develop to greater than a 2-cell stage, the procedure is termed tubal embryo transfer (TET). The only benefit to a ZIFT or TET versus the more traditional IVF is for women who are thought to have compromised embryo quality due to embryo in vitro culture. Placing these zygotes or embryos back into their own natural incubators is thought to enhance subsequent development, with improved pregnancy rates.

With the development of enhanced culture media, the success rates for IVF are now comparable, if not better, to those of GIFT and ZIFT.

Interpreting IVF success rates

Comparing one program's success rate to another is difficult because of all the variables involved. For instance, perhaps a program is very selective with its patients, allowing only those with a chance for success based on diagnosis, age, or ovarian reserve. Programs in states that are mandated to cover fertility therapy may be more likely to treat patients with a low chance for success simply because the patient has insurance or, perhaps, because the programs may perform more IVF cycles than programs in states without such a mandate. Some have suggested that programs in mandated states, due to the treatment algorithms enforced by the insurance companies, often have to treat patients without a male or tubal factor for many months with insemination cycles before getting approval for IVF coverage. Thus, these patients may actually be the most difficult patients to treat when they eventually get to IVF.

On the other hand, programs in states without a mandate may be dealing with more difficult patients who have had multiple surgeries and other covered or less costly therapy before ultimately deciding on IVF. However, some argue that many of these programs often take patients directly to IVF, or after a few insemination cycles, and, thus, these patients are more likely to be successful.

In general, like any statistical analysis, the more IVF cycles a program has performed, the more valid the numbers. The cancellation rate is a critical number. If the rate is high, the program is possibly very selective for those patients it allows to proceed to egg retrieval. This type of program would rather cancel the patient's procedure than have a low chance for success that may ultimately hurt its overall success rates. The pregnancy rate per retrieval is higher compared with the pregnancy rate per transfer. If this difference is large, it may reflect the quality of the laboratory. The implantation rate refers to thepregnancy rate divided by the number of embryos transferred. If the implantation rate is low and the pregnancy rate is high, this suggests that the program is transferring a large number of embryos per patient to achieve that success. Chances are good that the program's multiple pregnancy rate is high. Optimally, the better programs have a low cancellation rate and good pregnancy and implantation rates.

The ultimate critical number is the birth rate because this represents the final goal of the patient and the physician. This goal is also less vulnerable to misinterpretation than the pregnancy rate (single positive hCG vs serial increases) or the clinical pregnancy rate (gestational sac vs fetal pole vs fetal pole with heartbeat).

IVF outcomes

In 2002, 115,392 IVF cycles were reported started with a 14.6% cancellation rate, and, 45,751 pregnancies were confirmed delivered. One of every 2.5 IVF cycles started ended in a live birth. When observing cycles that ended in a uterine pregnancy (30.5%), most ended in a singleton birth. The miscarriage rate is no higher than that with a spontaneous pregnancy (ie, 16.1%).

Guidelines for embryo transfer

In response to the significant numbers of higher order multiple pregnancies generated from ART, the American Society of Reproductive Medicine (ASRM) released guidelines for the number of embryos transferred in 1999. Shows the risk of having a multiple-fetus pregnancy using fresh, nondonor embryos.

In 2002, the total multiple-fetus pregnancy rate was 36%. A lower number of deliveries of triplets or more compared to pregnancies suggests that these pregnancies were either iatrogenically reduced, spontaneously reduced, or resulted in a miscarriage.

Increasing the number of embryos transferred from 1 to 2 not only increases the chance for a live birth but also increases the likelihood of a multiple-infant pregnancy. However, transferring more than 2 embryos may not increase the overall live birth rate.

Many variables affect the decision of how many embryos to transfer. Factors such as the patient's age, embryo quality, number of prior failed IVF cycles, and use of frozen-thawed embryos are important to consider. New data from Europe suggests that a single embryo transfer in the appropriate patient results in approximately a 35% pregnancy rate with a less than 1% multiple pregnancy rate. These patients typically have embryos that are frozen, ensuring that their cumulative pregnancy rate using either fresh or frozen embryos is similar to transferring 2 or more embryos. Show the relationship between the number of embryos transferred and the risk of having a multiple-infant birth in women of all ages and in women younger than 35 years. Single embryo transfer is appropriate in certain situations where the likelihood of a multiple pregnancy is high. This may include women younger than 35 years, women who conceived with first IVF cycle, women with only tubal factorinfertility, women with concerns about multiple gestation, and donor egg recipients.

Factors contributing to IVF success

The most important factor that determines a successful cycle is the female patient's age. As mentioned previously, decreases in fecundity rates are observed beginning as early as age 30 years. The dramatic effect that age has on fecundability is also observed in ART (see Image 7). Most egg donors are aged 20-35 years, allowing for an optimal control group to observe these differences.

Ultimately, the success of ARTs mimics the overall fecundity trend observed in the general fertile population. That is, pregnancy and live birth rates start to decrease beginning around age 30 years and continue to decrease until the chance of having a live birth is so low that the benefit of ARTs must be evaluated. In women older than 40 years, the chance of having a liveborn infant with a chromosomal abnormality also increases. The live birth rate with ARTs based on the patient's age and whether she uses her own oocytes or donor eggs, which are typically harvested from women aged 20-35 years.

Oocyte retrieval

Oocyte retrieval is performed approximately 36 hours after 10,000 U of hCG is administered to allow for the resumption of meiosis, cytoplasmic maturation, and loosening of the oocytes within the follicle. This allows for a lower optimal vacuum pressure during aspiration and ultimately less oocyte damage.

The 3 basic methods to retrieve oocytes are laparoscopic, transabdominal, or transvaginal. The laparoscopic approach was used frequently in the 1980s, especially when a GIFT procedure was planned. Often, only the follicles that could be seen on the surface of the ovary were removed, and, if the ovary was very mobile, traction was required to support the ovary as the follicles were aspirated. Associated morbidity occurred with the procedure, which included infection and injury to the pelvic organs. General endotracheal anesthesia was usually used, and the patient's recovery often lasted 2-3 days. As the quality of ultrasonographic images and culture media improved, the need for laparoscopy decreased.

In 1981, ultrasonographic-guided aspiration was first described. Initially, the transabdominal approach was used, usually with the aspirating needle going through the bladder, which, when full, provided a window of visualization for the person operating the abdominal ultrasonographic probe.

Although still used for retrieval of oocytes from ovaries that are adhered high up in the pelvis or to the fundus of the uterus, the transabdominal approach was superseded by the transvaginal approach. The first transvaginal retrieval was performed in 1984 and has now become the procedure of choice because of its ease and low morbidity.

Micromanipulation

Intracytoplasmic sperm injection (ICSI) is the treatment of choice for couples in whom the male partner has azoospermia or severe oligospermia. ICSI is also indicated for men with significant antisperm antibodies, low sperm motility, or significantly abnormal sperm morphology (Kruger strict morphology <4%).>

ICSI is used when poor fertilization occurs with regular insemination techniques in the laboratory. ICSI may be used when a limited amount of sperm is available, such as in couples where the man has stored sperm prior to chemotherapy. ICSI is indicated in certain preimplantation genetic (PGD) procedures—specifically those cases being evaluated for single-gene recessive disorders. This prevents the potential contamination of the specimen with sperm that may be attached to the egg.

Sperm can be obtained from the ejaculate or directly from the epididymis. Recently, success was obtained with spermatids from testicular biopsies.

The potential transmission of a genetic abnormality is a possibility when ICSI is performed. The normal barrier for morphologically abnormal sperm that tend to have genetic abnormalities (ie, zonal pellucida) is bypassed with ICSI. Morphologically normal sperm may also have genetic abnormalities. Approximately 10% of sperm from healthy men have chromosomal abnormalities. Men who are infertile have a 5-7% chance of having a chromosomal abnormality. Chromosomal abnormalities include microdeletions of the long arm of the Y chromosome in areas AZFa, AZFb, and AZFc (DAZ or deleted in azoospermia region). These deletions can be passed on to male offspring, with resulting oligospermia.

Some data suggest a 30% increase in birth defects in children conceived with ICSI. Overall, this implies that the risk of having a child with a birth defect from ART with ICSI goes from a normal baseline of 3% to, at most, 4%.

Approximately 1-2% of men with azoospermia have genetic translocation, Klinefelter syndrome (47XXY), or a congenital bilateral absence of the vas deferens, which is associated with mutations in the cystic fibrosis transmembrane regulator (CFTR) gene or the 5T allele.

In the situation where the male partner has the CFTR mutation, the female partner should also be screened for cystic fibrosis. In any couple undergoing ICSI for male factor infertility, a karyotype and Y-DNA mapping should be considered if the sperm concentration is less than 5 million/mL, and genetic counseling should be offered. Prenatal testing of ICSI pregnancies has revealed an incidence of 0.83% of sex chromosome abnormalities (higher than those reported for spontaneous pregnancies).