Selasa, 29 Januari 2008
Minggu, 25 November 2007
Benign Cervical Lesions
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. 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 Infectious cervicitis
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. 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. 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 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.Atypia of repair
Hyperkeratosis and parakeratosis
Noninfectious cervicitis
Autoimmune Thyroid Disease and Pregnancy
- 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.
- 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.
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 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 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 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
| 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 |
- 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.
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 endocrine abnormalities
Treatment of unexplained infertility
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 |
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.