The nurse knows which is the primary test performed to determine fetal lung maturity

Overview

Overview

Premature rupture of membranes (PROM) refers to a patient who is beyond 37 weeks' gestation and has presented with rupture of membranes (ROM) prior to the onset of labor. Preterm premature rupture of membranes (PPROM) is ROM prior to 37 weeks' gestation. Spontaneous preterm rupture of the membranes (SPROM) is ROM after or with the onset of labor occurring prior to 37 weeks. Prolonged ROM is any ROM that persists for more than 24 hours and prior to the onset of labor.

At term, programmed cell death and activation of catabolic enzymes, such as collagenase and mechanical forces, result in ruptured membranes. Preterm PROM occurs probably due to the same mechanisms and premature activation of these pathways. However, early PROM also appears to be linked to underlying pathologic processes, most likely due to inflammation and/or infection of the membranes. Clinical factors associated with preterm PROM include low socioeconomic status, low body mass index, tobacco use, preterm labor history, urinary tract infection, vaginal bleeding at any time in pregnancy, cerclage, and amniocentesis. [1]

Eighty-five percent of neonatal morbidity and mortality is a result of prematurity. PPROM is associated with 30-40% of preterm deliveries and is the leading identifiable cause of preterm delivery. PPROM complicates 3% of all pregnancies and occurs in approximately 150,000 pregnancies yearly in the United States. [2] When PPROM occurs remote from term, significant risks of morbidity and mortality are present for both the fetus and the mother. Thus, the physician caring for the pregnant woman whose pregnancy has been complicated with PPROM plays an important role in management and needs to be familiar with potential complications and possible interventions to minimize risks and maximize the probability of the desired outcome. This article focuses on information the physician needs to achieve these goals. [1, 3, 4]

For patient education resources, see the Pregnancy Center and Labor Signs.

Premature Rupture of Membranes (at Term)

Premature rupture of membranes (PROM) at term is rupture of membranes prior to the onset of labor at or beyond 37 weeks' gestation. PROM occurs in approximately 10% of pregnancies. Patients with PROM present with leakage of fluid, vaginal discharge, vaginal bleeding, and pelvic pressure, but they are not having contractions.

ROM is diagnosed by speculum vaginal examination of the cervix and vaginal cavity. Pooling of fluid in the vagina or leakage of fluid from the cervix, ferning of the dried fluid under microscopic examination, and alkalinity of the fluid as determined by Nitrazine paper confirm the diagnosis.

Blood contamination of the Nitrazine paper and ferning of cervical mucus may produce false-positive results. Pooling of fluid is by far the most accurate for diagnosis of ROM. If all fluid has leaked out as in early PROM, an ultrasonographic examination may then show absence of or very low amounts of amniotic fluid in the uterine cavity.

New evidence suggests that the use of biochemical markers to diagnose ROM in uncertain cases may be appropriate and cost effective. Echebiri et al reported cost effectiveness compared to standard methods of diagnoses between 34 and 37 weeks. [5]

Ng et al reported placental alpha-microglobulin-1 levels have a 95.7% sensitivity, 100% specificity, 100% positive predictive value, and 75% negative predictive value. [6]  In select cases when the diagnoses or ROM is not clear, placental alpha-microglobulin-1 should be used to provide additional information for appropriate management. 

Given the importance of making the correct diagnoses, the associated morbidity with hospitalization and delivery prior to term in PROM reaching 34 weeks and beyond, and the potential neonatal morbidity resulting from prematurity in cases of incorrect diagnoses of PROM, it is mandatory to confirm the diagnosis of PROM with pooling of amniotic fluid with some evidence of decreased or absence of amniotic fluid in all cases of suspected PROM.

Most patients (90%) enter spontaneous labor within 24 hours when they experience ROM at term. The major question regarding management of these patients is whether to allow them to enter labor spontaneously or to induce labor. In large part, the management of these patients depends on their desires; however, the major maternal risk at this gestational age is intrauterine infection. The risk of intrauterine infection increases with the duration of ROM. Evidence supports the idea that induction of labor, as opposed to expectant management, decreases the risk of chorioamnionitis without increasing the cesarean delivery rate. [7, 8, 9]

Hannah et al studied 5041 women with PROM who were randomly assigned to induction of labor with intravenous oxytocin or vaginal prostaglandin E2 gel versus expectant management for as many as 4 days with induction of labor for complications. [10] They concluded that, in women with PROM, induction of labor and expectant management resulted in similar rates of cesarean delivery and neonatal infection. However, induction with oxytocin resulted in a lower risk of maternal infection (endometritis) when compared with expectant management. Additionally, the women in the study viewed induction of labor more favorably than expectant management.

Other smaller studies have shown results with higher cesarean and/or operative delivery rates when the cervix was unfavorable.

At term, infection remains the most serious complication associated with PROM for the mother and the neonate. The risk of chorioamnionitis with term PROM has been reported to be less than 10% and to increase to 40% after 24 hours of PROM. [11] This points out the importance of appropriate management strategies for PROM at term.

Since risk of infection at term with ROM is small during the first 24 hours, expectant management and waiting for spontaneous labor may be considered in selected patients for the first 12-24 hours if a patient desires expectant management. The use of expectant management after the first 24 hours is questionable.

Digital vaginal examinations should be avoided until labor is initiated; however, fetal presentation should be documented to avoid discovering malpresentation of the fetus long after admission for ROM. All patients with ROM should be asked to come to the hospital to ensure fetal well being.

The neonatal risks of expectant management of PROM include infection, placental abruption, fetal distress, fetal restriction deformities and pulmonary hypoplasia, and fetal/neonatal death. Fetal death does occur in approximately 1% of patients with PROM after viability who have been expectantly managed [1] and in about 1:1000 term PROM. [12]

The primary determinant of neonatal morbidity and mortality is gestational age at delivery, again stressing the importance of conservative management when possible. (See the Gestational Age from Estimated Date of Delivery calculator.)

In general, prognosis is good after 32 weeks' gestation as long as no other complicating factor, such as congenital malformation or pulmonary hypoplasia, exists.

Premature Preterm Rupture of Membranes

Premature preterm rupture of membranes (PPROM) occurring from 24-37 weeks' gestation is far more difficult to manage than premature rupture of membranes (PROM) at term. Several issues need to be considered in formulating a plan of management. Prematurity is the principal risk to the fetus, while infection morbidity and its complications are the primary maternal risks. All plans for management of PPROM remote from term should include the family and the medical team caring for the pregnancy, including the neonatal and maternal medical team. Remote from term, PPROM should only be cared for in facilities where a NICU is available and capable of caring for the neonate. Because most PPROM pregnancies deliver within a week of ROM, transfer of the pregnant mother to a qualified facility is urgent and should be facilitated immediately upon diagnoses.

The vast majority of women proceed to active labor and deliver soon after PPROM. With appropriate therapy and conservative management, approximately 50% of all remaining pregnancies deliver each subsequent week after PPROM. Thus, very few women remain pregnant more than 3-4 weeks after PPROM. This is important information to give the woman considering expectant management remote from viability. [1]

Spontaneous sealing of the membranes does occur occasionally (< 10% of all cases), mostly after PPROM that has occurred subsequent to amniocentesis; however, this is the exception rather than the rule.

Several areas of controversies exist regarding the best medical approach or management of PROM remote from term. Expectant management and immediate delivery are potential options in these patients, and each has its own advantages and disadvantages. With appropriate care, the maternal risks of expectant management are generally accepted to be minimal and a clear neonatal advantage exists by reducing risks of prematurity.

Controversies exist as to interventions such as steroids for acceleration of lung maturity, antibiotics, and tocolytics. See Medical Treatment.

A study by Ekin et al suggested that mean platelet volume (MPV) in the first trimester of pregnancy can be used to predict the likelihood of PPROM. In a retrospective record review of 318 women with PPROM and 384 controls, the investigators found that, comparing values between the 7th and 14th weeks of gestation, the MPVs were significantly lower and the platelet counts significantly higher in patients who had experienced PPROM than in pregnant women who had not. Using cutoff values of less than or equal to 8.6 fL for MPV and greater than or equal to 216 x 103/µL for platelet count, the study found that these measurements had a sensitivity and specificity for predicting PPROM of 58% and 65%, respectively, and 62% and 44%, respectively. Ekin and colleagues concluded that MPV is more efficient than platelet count for predicting PPROM. [13]

Maternal and Fetal Surveillance

After an initial period of continuous monitoring of fetal heart rate and uterine contractions (24-48 h), if findings are suggestive of reassuring surveillance, then the patient would be a candidate for expectant management. In general, common practice has been to place the patient on bed rest on the obstetric floor. However, the the existing data show no benefit to bed rest for any obstetric condition.  Because bed rest in pregnancy is associated with an increased chance of deep venous thrombosis, prophylaxis to reduce this risk should be instituted.

In addition, fetal monitoring should be performed at least once a day. If evidence of frequent cord compression is present as determined by moderate-to-severe variables, continuous monitoring should be reinstituted. Maternal vitals need to be monitored closely. Tachycardia and fever are both suggestive of chorioamnionitis and require careful evaluation to determine the presence of intra-amniotic infections, in which case delivery and initiation of broad-spectrum antibiotics should be promptly facilitated.

Ultrasonographic examination for amniotic fluid index and fetal growth and well being should be used liberally to ensure appropriateness of continued expectant management. While oligohydramnios, defined as an amniotic fluid index of less than 2 cm, has been associated with short latency and chorioamnionitis, it alone is not an indication for delivery when other means of surveillance are reassuring. White blood cell count is not predictive of outcome and does not need to be monitored other than to support clinical suspicion of chorioamnionitis.

Digital cervical examinations should be avoided. [14] In a noncephalic presentation, especially with a dilated cervix, continuous monitoring should be considered to avoid missing the diagnosis of cord prolapse.

Intra-amniotic infection should invoke prompt delivery. Practitioners should have a low threshold for diagnosing infection in a patient with PPROM as evidence clearly shows poor outcome in an infected neonate compared with a similar uninfected neonate.

PPROM in the Second Trimester

Premature preterm rupture of membranes (PPROM) prior to fetal viability is a unique and relatively rare problem that is often difficult to manage. It occurs in less than 0.4% of all pregnancies. [15] The major maternal risk is infection, namely chorioamnionitis, which occurs in about 35%; abruption, which occurs in 19%; and sepsis, which is rare and occurs in less than 1%. [15] The major morbidity in the fetus with midtrimester ROM is lethal pulmonary hypoplasia from prolonged, severe, early oligohydramnios, which occurs in about 20% of cases. Other morbidities such as RDS (66%), sepsis (19%), grade III-IV IVH (5%), and contractures (3%) also occur with high frequency, resulting in intact survival rates of more than 67%. Fetal death is common and occurs in more than 30%. [15]

Older studies have reported that approximately 50% of all remaining pregnancies deliver each subsequent week after PPROM. [1] More recent studies have shown better prognosis and may be more relevant to today’s clinical practice. With appropriate therapy and conservative management, more recent studies have reported less than 40% delivering in a week and more than 30% remaining pregnant after 5 weeks. This information is probably better suited to be used in counseling patients regarding early PROM. [16]

The risk of infection increases with the duration of PPROM. Outpatient management of PPROM prior to viability is appropriate in the well-informed and educated patient. The patient needs to be informed of warning signs that indicate the need for immediate evaluation. These signs include fever, abdominal pain, vaginal spotting, foul-smelling discharge, and rapid heart rate. The woman should monitor her temperature at home at least 3 times daily and report any elevation beyond 100.4°F (38°C). Frequent examinations are necessary to ensure maternal safety. Patients must be educated about the warning signs of intra-amniotic infection, and they must take their temperature 3 times a day at home. After viability is reached, inpatient management needs to be considered.

Midtrimester (13-26 wk) PPROM has a poor prognosis, although more recent studies have reported better outcome. Expectant management may be appropriate in select patients who are well informed and educated about the risks and the dismal prognosis for the neonate. Delivery is also appropriate when the mother is concerned about her own risks, especially when PPROM has occurred prior to 20 weeks' gestation. Incomplete abortion may be the appropriate term for the condition, as products of conception (the amniotic fluid) have passed the cervical opening and into the vagina in these cases. Other heroic measures such as amnioinfusion, tocolysis, and cervical plug to seal the membranes are unproven and should be considered in research protocols.

Survival varies with gestational age at diagnosis (from 12% when diagnosed at 16-19 wk, to as much as 60% when diagnosed at 25-26 wk). [17] Until viability, maternal safety should be the primary concern.

A study by Lorthe et al that included 1435 women with a diagnosis of PROM reported that of the 427 fetuses at 22-25 weeks' gestation, 51.7% were survivors at discharge, 38.8% were survivors at discharge without severe morbidity, and 46.4% were survivors at 2 years without cerebral palsy. [44]

Management of PPROM

The initial evaluation of premature preterm rupture of membranes (PPROM) should include a sterile speculum examination to document ROM. Cervical cultures including Chlamydia trachomatis and Neisseria gonorrhoeae and anovaginal cultures for Streptococcus agalactiae should be obtained. Maternal vital signs should be documented as well as continuous fetal monitoring initially to establish fetal status. Ultrasonographic documentation of gestational age, fetal weight, fetal presentation, and amniotic fluid index should be established. Digital examination should be avoided, but visual inspection of the cervix can accurately estimate cervical dilatation. Digital examination of the cervix with PPROM has been shown to shorten latency and increase risk of infections without providing any additional useful clinical information. [14]

In certain circumstances, immediate delivery of the fetus with PPROM is indicated. These circumstances include chorioamnionitis, advanced labor, fetal distress, and placental abruption with nonreassuring fetal surveillance. If fetal lung maturity has been documented by either amniocentesis or collection of vaginal fluid, delivery should be facilitated. In a noncephalic fetus with advanced cervical dilatation (more than or equal to 3 cm), the risk of cord prolapse may also outweigh the benefits of expectant management and delivery should be considered.

If after initial evaluation of the mother and fetus, they are both determined to be clinically stable, expectant management of PPROM may be considered to improve fetal outcome. The primary maternal risk with expectant management of PPROM is infection. This includes chorioamnionitis (13-60%), endometritis (2-13%), sepsis (< 1%), and maternal death (1-2 cases per 1000). Complications related to the placenta include abruption (4-12%) and retained placenta or postpartum hemorrhage requiring uterine curettage (12%). [3]

The risks and potential benefits of expectant management should be discussed with the patient and her family, and informed consent should be obtained. The maternal and fetal status need to be reevaluated daily, and the safety and potential benefits of expectant management should be reassessed. If the condition remains stable, the immature fetus may benefit from expectant management, even if for a short period, to allow administration of steroids and antibiotics. Once maturity has been reached, the benefit from expectant management of PPROM is unclear and the risks of infection outweigh any potential benefits.

Amniocentesis can provide information about lung maturity accuracy and correctness of the diagnoses of PROM and infection. However, in most cases of PPROM, the amount of fluid is scant; thus, amniocentesis should be performed only by individuals with experience in performing difficult amniocentesis, and the appropriate risks with potential for fetal complications and the need for immediate delivery should be discussed with patients before attempting amniocentesis.

Medical Treatment of PPROM

Antibiotics

The initial step in management of PPROM is informed consent. The patient needs to be given risks and benefits information and must participate in decision making. Once the decision to manage a patient expectantly has been made, the institution of broad-spectrum antibiotics should be considered. Multiple trials have examined the advantages and disadvantages of using antibiotics and the choice of antibiotics. In most studies, use of antibiotics has been associated with prolongation of pregnancy and reduction in infant and maternal morbidity. However, a few studies have reported increased neonatal morbidity with certain types of antibiotics, as discussed below.

Two of the largest studies that have looked at the efficacy of antibiotic use in PPROM are the National Institute of Child Health and Human Development - Maternal Fetal Medicine Units (NICHD-MFMU) study of PROM and the ORACLE trial. In the NICHD study, intravenous antibiotics were used for 48 hours—ampicillin 2 g q6h and erythromycin 250 mg q6h. The patients were then placed on oral amoxicillin 250 mg q8h and enteric-coated, erythromycin-base 333 mg q8h to complete a 7-day course of antibiotic therapy. In this study, the control group, compared with the antibiotic group, had a significantly shorter duration of latency. The antibiotic group was twice as likely to remain undelivered after 7 days. The increased latency continued for up to 3 weeks after discontinuation of antibiotics. Composite and individual morbidities for the neonate were lower in the antibiotic group. The incidence of chorioamnionitis and neonatal sepsis, including group B streptococci sepsis, was decreased. [18]

The ORACLE trial used erythromycin alone, amoxicillin clavulanic acid alone, or amoxicillin clavulanic acid in combination with erythromycin. Their results were different in that no significant difference was noted in latency to delivery and neonatal morbidity was not decreased as defined in their primary outcome (death, chronic lung disease, and major cerebral abnormality on ultrasonography). Decreased need for supplemental oxygen and positive blood culture results were apparent. When amoxicillin clavulanic acid was used either alone or in combination with erythromycin, an increased risk of necrotizing enterocolitis (1.9% vs 0.5%, p =0.001) was present. [19]

Based on current evidence, 7 days of antibiotics, as proposed by the NICHD-MFMU study of PROM, should be the antibiotic regimen used in patients with PPROM who are being managed expectantly. When another antibiotic is being used for other indications, such as a urinary tract infection, attempts should be made to avoid duplicated therapy. For example, a patient being treated with a cephalosporin for a urinary tract infection does not need penicillin therapy. Therapy longer than 7 days should be avoided; it has not been shown to be more effective and may promote the emergence of resistance organisms.

Revised guidelines from the Centers for Disease Control and Prevention (CDC) recommend that women with preterm PROM who are not in labor should receive intravenous group B streptococcus (GBS) coverage for at least the first 48 hours of preterm PROM latency prophylaxis, until the GBS test results obtained on admission are available. [20] However, GBS test results should not affect the duration of antibiotic therapy. If the patient completes the full 7-day course of antibiotic prophylaxis has no evidence of infection or labor, intrapartum GBS prophylaxis can be managed based on the results of the baseline GBS test at the time of preterm PROM, unless 5 weeks have passed. This is because a negative GBS test result is considered valid for 5 weeks. [21, 22]

Antenatal corticosteroid treatment

The use of corticosteroids to accelerate lung maturity should be considered in all patients with PPROM with a risk of infant prematurity from 24-34 weeks' gestation. The latency period has been suggested to be too short for the effects of corticosteroids to make a difference in neonatal morbidity; however, this clearly does not appear to be the case. Most patients with PPROM remain pregnant at 48 hours and thus will benefit from corticosteroid therapy. The use of steroids has also been suggested to increase the risk of infection. However, the current evidence does not support this concern based on individual studies and meta-analyses; no difference (either higher or lower rates of infections) has been observed with corticosteroid use.

In contrast to these concerns, data indicate that the use of corticosteroids reduces neonatal morbidity and mortality. The rates of respiratory distress syndrome (RDS), necrotizing enterocolitis, and intraventricular hemorrhage were all lower when either 12 mg of betamethasone IM was given twice in a 24-hour interval or dexamethasone 6 mg q12h was given for 4 doses. [23]

Current ACOG recommendations [24, 2]

• A single course of corticosteroids is recommended for pregnant women 24-34 weeks' gestation who are at risk of preterm delivery within 7 days and as early as 23 weeks if delivery is imminent.

• A single rescue course of antenatal corticosteroids may be considered if the antecedent treatment was given more than 2 weeks prior, the gestational age is less than 32 6/7 weeks, and the woman is judged by the clinician to be likely to give birth within the next week. However, regularly scheduled repeat courses or more than 2 courses are not recommended.

• Further research regarding the risks and benefits, optimal dose, and timing of a single rescue course of steroid treatment is needed.

Tocolytics

The most common cause of labor in the setting of PPROM is underlying chorioamnionitis. The use of tocolysis in that setting is not justified. No data indicate that administering tocolysis benefits the neonate. [25] In one study, prophylactic tocolysis was found to briefly prolong latency. In another study by Jazayeri et al, latency was shorter when magnesium sulfate was given. [26] The use of tocolysis, unlike corticosteroids and antibiotics, should be considered only when a clear clinical benefit exists, such as in transport of the mother to a tertiary institution with a NICU.

Many large clinical studies have evaluated neuroprotective benefits from exposure to magnesium sulfate in preterm neonates. The studies show a reduction in cerebral palsy in surviving infants who were exposed to magnesium. None of the individual studies found a benefit with regard to their primary outcome. However, available evidence suggests that magnesium sulfate given before anticipated early preterm birth reduces the risk of cerebral palsy in surviving infants, [27, 28] Physicians electing to use magnesium sulfate for fetal neuroprotection should develop specific guidelines regarding inclusion criteria, treatment regimens, concurrent tocolysis, and monitoring in accordance with one of the larger trials. [29]

In these studies, 12-24 hours of exposure was used with either a 4- or 6-g bolus and a maintenance dose of 1-2 g. These findings should be discussed with patients undergoing expectant management of PROM. [30]

Note that antenatal administration of magnesium sulfate in preterm children (at risk of being delivered at ≥24.0 weeks' gestation) in the setting of chorioamnionitis does not appear to provide neuroprotection. [31]

The use of tocolysis for 48 hours to administer steroids and allow acceleration of fetal lung maturity has been proposed and is being used by some obstetricians. No data support the efficacy of this practice and, as such, when used in this manner, the lack of evidence to support this practice should be discussed with patients to allow informed consent prior to the use of tocolytics and the potential complications and side effects.

Summary

PPROM is a common complication of pregnancy occurring in about 3% of all pregnancies. The obstetrician needs to be familiar with appropriate management of PPROM. High-risk consultation with a maternal-fetal medicine subspecialist should be considered in all cases to ensure appropriate current therapy is instituted.

In general, the following guidelines should be followed:

• ROM diagnosis needs to be confirmed.

• Digital vaginal examinations should be avoided.

• Ultrasonography should be performed to confirm gestational age, estimated fetal weight, presentation, amniotic fluid index, and fetal anatomy if not already fully evaluated.

• Antibiotics need to be given based on present evidence. See Medical Treatment.

• Corticosteroids should be given to accelerate lung maturity between 24 and 34 weeks.

• Informed consent should be obtained for expectant management versus delivery with careful documentation in the chart.

• In PPROM, the rule should be hospitalization after viability in an institution where care for a premature neonate can be provided.

• Maternal health is the primary indicator for the need to deliver. Any evidence of infection or maternal instability due to complications of PPROM, such as bleeding, requires careful evaluation and determination of the appropriateness of expectant management.

• Fetal monitoring should be performed at least daily until delivery, and fetal well being and growth should be evaluated periodically with ultrasonography.

• After 32 weeks' and certainly after 34 weeks' gestation, the appropriateness of expectant management of PPROM should be reevaluated individually for each case.

• PROM at term should be managed by delivery unless reasons exist to consider waiting for spontaneous labor. Large enough studies to document neonatal safety of expectant management of PROM at term do not exist.

Questions & Answers

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Author

Allahyar Jazayeri, MD, PhD, FACOG, DACOG, FSMFM Medical Director of Perinatal Services, Aspirus Hospital; Consulting Staff and Owner, Women's Specialty Care and NEWMOMS of Green Bay

Allahyar Jazayeri, MD, PhD, FACOG, DACOG, FSMFM is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, Association of Professors of Gynecology and Obstetrics, Society for Reproductive Investigation, Society for Maternal-Fetal Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Carl V Smith, MD The Distinguished Chris J and Marie A Olson Chair of Obstetrics and Gynecology, Professor, Department of Obstetrics and Gynecology, Senior Associate Dean for Clinical Affairs, University of Nebraska Medical Center

Carl V Smith, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, Association of Professors of Gynecology and Obstetrics, Central Association of Obstetricians and Gynecologists, Society for Maternal-Fetal Medicine, Council of University Chairs of Obstetrics and Gynecology, Nebraska Medical Association

Disclosure: Nothing to disclose.

Additional Contributors

Suzanne R Trupin, MD, FACOG Clinical Professor, Department of Obstetrics and Gynecology, University of Illinois College of Medicine at Urbana-Champaign; CEO and Owner, Women's Health Practice; CEO and Owner, Hada Cosmetic Medicine and Midwest Surgical Center

Suzanne R Trupin, MD, FACOG is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, International Society for Clinical Densitometry, AAGL, North American Menopause Society, American Medical Association, Association of Reproductive Health Professionals

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Paul T Wilkes, MD, and Henry Galan, MD, to the development and writing of this article.

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