Hyperemesis Gravidarum

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Practice Essentials

Hyperemesis gravidarum is the most severe form of nausea and vomiting in pregnancy, characterized by persistent nausea and vomiting associated with ketosis and weight loss (>5% of prepregnancy weight). This condition may cause volume depletion, electrolytes and acid-base imbalances, nutritional deficiencies, and even death. Severe hyperemesis requiring hospital admission occurs in 0.3-2% of pregnancies.[1]

Signs and symptoms

The defining symptoms of hyperemesis gravidarum are gastrointestinal in nature and include nausea and vomiting. Other common symptoms include ptyalism (excessive salivation), fatigue, weakness, and dizziness.

Patients may also experience the following:

See Clinical Presentation for more detail.

Diagnosis

Physical examination in women with suspected hyperemesis gravidarum is usually unremarkable. Findings may be more helpful if the patient has unusual complaints suggestive of other disorders (eg, bleeding, abdominal pain).

Examination includes the following:

Laboratory tests

Initial laboratory studies used in the evaluation of women with hyperemesis gravidarum should include the following:

Imaging studies

The following imaging studies may be used to assess women with hyperemesis gravidarum:

Additional imaging studies may be warranted if the patient’s clinical presentation is atypical (eg, nausea and/or vomiting beginning after 9-10 wk of gestation, nausea and/or vomiting persisting after 20-22 wk, acute severe exacerbation) or if another disorder is suggested based on the history or physical examination findings.

Procedures

In patients with abdominal pain or upper gastrointestinal bleeding, upper gastrointestinal endoscopy appears to be safe in pregnancy, although careful monitoring is suggested.

See Workup for more detail.

Management

Initial management in pregnant women with hyperemesis gravidarum should be conservative and may include reassurance, dietary recommendations, and support. Alternative therapies may include acupressure and hypnosis.[4]

Pharmacotherapy

The only FDA-approved drug for treating nausea and vomiting in pregnancy is doxylamine/pyridoxine. However, antihistamines, antiemetics of the phenothiazine class, and promotility agents (eg, metoclopramide) have also been used to manage nausea and vomiting during pregnancy. In cases refractory to standard therapy, ondansetron and steroids may be considered.

The following medications may be used in women with hyperemesis gravidarum:

Surgery

In some refractory severe cases of hyperemesis gravidarum, if maternal survival is threatened, or if hyperemesis gravidarum is causing severe physical and psychological burden, termination of the pregnancy should be considered.[5]

See Treatment and Medication for more detail.

Background

Nausea and vomiting in pregnancy is extremely common. Hyperemesis gravidarum (HEG) is the most severe form of nausea and vomiting in pregnancy. A continuous spectrum of the severity of nausea and vomiting ranges from the nausea and vomiting that occurs in most pregnancies to the severe disorder of hyperemesis gravidarum.

Studies estimate that nausea and vomiting occurs in 50-90% of pregnancies. The nausea and vomiting associated with pregnancy usually begins by 9-10 weeks of gestation, peaks at 11-13 weeks, and resolves in most cases by 12-14 weeks. In 1-10% of pregnancies, symptoms may continue beyond 20-22 weeks.[6, 7]

Normal nausea and vomiting may be an evolutionary protective mechanism—it may protect the pregnant woman and her embryo from harmful substances in food, such as pathogenic microorganisms in meat products and toxins in plants, with the effect being maximal during embryogenesis (the most vulnerable period of pregnancy). This is supported by studies showing that women who had nausea and vomiting were less likely to have miscarriages and stillbirth.[8, 9]

Hyperemesis gravidarum is characterized by persistent nausea and vomiting associated with ketosis and weight loss (>5% of prepregnancy weight). Hyperemesis gravidarum may cause volume depletion, electrolytes and acid-base imbalances, nutritional deficiencies, and even death. Severe hyperemesis requiring hospital admission occurs in 0.3-2% of pregnancies.[1]

Pathophysiology

The physiologic basis of hyperemesis gravidarum is controversial. Hyperemesis gravidarum appears to occur as a complex interaction of biological, psychological, and sociocultural factors. The following theories have been proposed:

Hormonal changes

Women with hyperemesis gravidarum often have high hCG levels that cause transient hyperthyroidism. hCG can physiologically stimulate the thyroid gland thyroid-stimulating hormone (TSH) receptor. hCG levels peak in the first trimester. Some women with hyperemesis gravidarum appear to have clinical hyperthyroidism. However, in a larger portion (50-70%), TSH is transiently suppressed and the free thyroxine (T4) index is elevated (40-73%) with no clinical signs of hyperthyroidism, circulating thyroid antibodies, or enlargement of the thyroid. In transient hyperthyroidism of hyperemesis gravidarum, thyroid function normalizes by the middle of the second trimester without antithyroid treatment. Clinically overt hyperthyroidism and thyroid antibodies are usually absent.[9, 10, 11, 1]

A report on a unique family with recurrent gestational hyperthyroidism associated with hyperemesis gravidarum showed a mutation in the extracellular domain of the TSH receptor that made it responsive to normal levels of hCG. Thus, cases of hyperemesis gravidarum with a normal hCG may be due to varying hCG isotypes.[12, 13]

A positive correlation between the serum hCG elevation level and free T4 levels has been found, and the severity of nausea appears to be related to the degree of thyroid stimulation. hCG may not be independently involved in the etiology of hyperemesis gravidarum but may be indirectly involved by its ability to stimulate the thyroid. For these patients, hCG levels were linked to increased levels of immunoglobulin M, complement, and lymphocytes. Thus, an immune process may be responsible for increased circulating hCG or isoforms of hCG with a higher activity for the thyroid. Critics of this theory note that (1) nausea and vomiting are not usual symptoms of hyperthyroidism, (2) signs of biochemical hyperthyroidism are not universal in cases of hyperemesis gravidarum, and (3) some studies have failed to correlate the severity of symptoms with biochemical abnormalities.[14, 15, 16]

Some studies link high estradiol levels to the severity of nausea and vomiting in patients who are pregnant, while others find no correlation between estrogen levels and the severity of nausea and vomiting in pregnant women. Previous intolerance to oral contraceptives is associated with nausea and vomiting in pregnancy. Progesterone also peaks in the first trimester and decreases smooth muscle activity; however, studies have failed to show any connection between progesterone levels and symptoms of nausea and vomiting in pregnant women. Lagiou et al studied prospectively 209 women with nausea and vomiting who showed that estradiol levels were positively correlated while prolactin levels were inversely associated with nausea and vomiting in pregnancy and no correlation existed with estriol, progesterone, or sex-hormone binding globulin.[17]

Gastrointestinal dysfunction

The stomach pacemaker causes rhythmic peristaltic contractions of the stomach. Abnormal myoelectric activity may cause a variety of gastric dysrhythmias, including tachygastrias and bradygastrias. Gastric dysrhythmias have been associated with morning sickness. The presence of dysrhythmias was associated with nausea while normal myoelectrical activity was present in the absence of nausea. Mechanisms that cause gastric dysrhythmias include elevated estrogen or progesterone levels, thyroid disorders, abnormalities in vagal and sympathetic tone, and vasopressin secretion in response to intravascular volume perturbation. Many of these factors are present in early pregnancy. These pathophysiologic factors are hypothesized to be more severe or the gastrointestinal tract more sensitive to the neural/humoral changes in those who develop hyperemesis gravidarum.[18]

Hepatic dysfunction

Liver disease, usually consisting of mild serum transaminase elevation, occurs in almost 50% of patients with hyperemesis gravidarum. Impairment of mitochondrial fatty acid oxidation (FAO) has been hypothesized to play a role in the pathogenesis of maternal liver disease associated with hyperemesis gravidarum. It has been suggested that women heterozygous for FAO defects develop hyperemesis gravidarum associated with liver disease while carrying fetuses with FAO defects due to accumulation of fatty acids in the placenta and subsequent generation of reactive oxygen species. Alternatively, it is possible that starvation leading to peripheral lipolysis and increased load of fatty acids in maternal-fetal circulation, combined with reduced capacity of the mitochondria to oxidize fatty acids in mothers heterozygous for FAO defects, can also cause hyperemesis gravidarum and liver injury while carrying nonaffected fetuses.

Lipid alterations

Jarnfelt-Samsioe et al found higher levels of triglycerides, total cholesterol, and phospholipids in women with hyperemesis gravidarum compared with matched, nonvomiting, pregnant and nonpregnant controls. This may be related to the abnormalities in hepatic function in pregnant women. However, Ustun et al found decreased levels of total cholesterol, LDL cholesterol, apoA and apoB in women with hyperemesis gravidarum compared with controls.[19, 20]

Infection

Helicobacter pylori is a bacterium found in the stomach that may aggravate nausea and vomiting in pregnancy. Studies have found conflicting evidence of the role of H pylori in hyperemesis gravidarum. Recent studies in the United States have not shown association with hyperemesis gravidarum. However, persistent nausea and vomiting beyond the second trimester may be due to an active peptic ulcer caused by H pylori infection.[21, 22]

Vestibular and olfaction

Hyperacuity of the olfactory system may be a contributing factor to nausea and vomiting during pregnancy. Many pregnant women report the smell of cooking food, particularly meats, as triggers to nausea. Striking similarities between hyperemesis gravidarum and motion sickness suggest that unmasking of subclinical vestibular disorders may account for some cases of hyperemesis gravidarum.[23, 24]

Genetic

In studies examining the familial link of hyperemesis gravidarum, research suggests a possible genetic aspect to hyperemesis. A study was performed looking at 544,087 pregnancies from Norway’s mandatory birth registry from 1967-2005. This study demonstrated that daughters born from a pregnancy complicated by hyperemesis had a 3% risk of having hyperemesis in their own pregnancy. Women who were born after an unaffected pregnancy had a risk of 1.1%.[25] In surveys administered to mothers who had pregnancies complicated by hyperemesis, higher rates of hyperemesis were reported among their relatives. This was particularly so in their sisters.[26]

Overall, the data suggest that a genetic predisposition may play a role in the development of hyperemesis gravidarium.

Biochemical research

Hyperemesis gravidarum is associated with overactivation of sympathetic nerves and enhanced production of tumor necrosis factor (TNF)-alpha.[27] Increased adenosine levels have also been noted; since adenosine is an established suppressor of excessive sympathetic nerves activation and cytokine production, the increase in plasma adenosine in hyperemesis gravidarum may be modulatory.[28] Trophoblast-derived cytokines have been reported to induce secretion of hCG.

Immunoglobulins C3 and C4 and lymphocyte counts are significantly higher in women with hyperemesis gravidarum. T-helper 1/T-helper 2 balance is decreased in women with hyperemesis gravidarum, which results in increased humoral immunity. Increased fetal DNA has been found in the maternal plasma of women with hyperemesis gravidarum, and the increased DNA is speculated to be derived from trophoblasts that have been destroyed by the hyperactive maternal immune system. Thus, hyperemesis gravidarum may be mediated by immunologic aberrations in pregnancy.[29, 30, 31, 32]

Psychological issues

Physiological changes associated with pregnancy interact with each woman's psychologic state and cultural values. Psychologic responses may interact with and exacerbate the physiology of nausea and vomiting during pregnancy. Nonetheless, hyperemesis gravidarum is typically the cause of, as opposed to the result of, psychologic stress. In very unusual instances, cases of hyperemesis gravidarum could represent psychiatric illness, including conversion or somatization disorder or major depression.[33, 34, 35]

Frequency

United States

Of all pregnancies, 0.3-2% are affected by hyperemesis gravidarum (approximately 5 per 1000 pregnancies).

International

Hyperemesis gravidarum appears to be more common in westernized industrialized societies and urban areas than rural areas.

Mortality/Morbidity

Hyperemesis gravidarum was a significant cause of maternal death before 1940. In Great Britain, mortality decreased from 159 deaths per million births from 1931-1940 to 3 deaths per million births from 1951-1960. Charlotte Brontë is thought to have died of hyperemesis gravidarum in 1855. In the United States, 7 deaths from hyperemesis gravidarum were reported in the 1930s. Today, although hyperemesis gravidarum is still associated with significant morbidity, it is still a rare cause of maternal mortality.

Race

No clear racial predominance is noted for hyperemesis gravidarum.

Sex

Hyperemesis gravidarum affects females.

Age

The risk of hyperemesis gravidarum appears to decrease with advanced maternal age.

History

Physical

Causes

In a review of 1,301 cases of hyperemesis gravidarum from Canada, Fell et al showed that medical complications of hyperthyroid disorders, psychiatric illness, previous molar disease, gastrointestinal disorders, pregestational diabetes, and asthma were significantly independent risk factors for hyperemesis gravidarum, whereas maternal smoking and maternal age older than 30 years decreased the risk. Pregnancies with female fetuses and multiple fetuses were also at increased risk.[36, 37]

In some studies, women from low to middle socioeconomic class, women with lower levels of education, women with previous pregnancies with nausea and vomiting, women in their first pregnancy, and women with previous intolerance to oral contraceptives more commonly experience nausea and vomiting during pregnancy. Nausea and vomiting during pregnancy is also more common with multiple-gestation pregnancies.

Other factors that have been proposed include ethnicity, occupational status, fetal anomalies, increased body weight, nausea and vomiting in a prior pregnancy, history of infertility, interpregnancy interval, corpus luteum in right ovary, and prior intolerance to oral contraceptives.

Laboratory Studies

Initial lab studies for hyperemesis gravidarum should include the following:

Imaging Studies

Procedures

In patients with abdominal pain or upper gastrointestinal bleeding, upper gastrointestinal endoscopy appears to be safe in pregnancy, although careful monitoring is suggested.

Medical Care

Initial management should be conservative and may include reassurance, dietary recommendations, and support. Alternative therapies may include acupressure and hypnosis.[4]

Pharmacologic therapy

If pharmacologic therapy is necessary, treatment may be initiated by giving vitamin B-6 10-25 mg 3-4 times daily; doxylamine 12.5 mg 3-4 times daily can be used in addition. Ginger capsules 250 mg 4 times daily can be added at this point if the patient is still vomiting; this has been shown to be effective in randomized trials.[39]

Metoclopramide 5-10 mg orally every 8 hours may be used next. Promethazine 12.5 mg orally or rectally q4h or dimenhydrinate 50-100 mg orally q4-6h may be added as well. Ondansetron 4-8 mg orally or IV q8h can be used for further refractory cases. Methylprednisolone 16 mg orally or IV q8h for 3 days, tapered to the lowest effective dose, can be used if persistent vomiting occurs despite the above therapy. Steroids seem to increase risk for oral clefts in first 10 weeks of gestation.[40, 1]

The only FDA-approved drug for treating nausea and vomiting in pregnancy is doxylamine-pyridoxine (Diclegis).[41, 42] Originally sold between 1956 and 1983 under a different brand name, it was pulled from the market because of safety concerns, which have since been disproved. The new dosage form approved in April 2013 is a delayed-release tablet that, when taken at bedtime, is at its peak serum concentrations in the morning, when nausea and vomiting may be worse.

Approval of the new formulation of doxylamine-pyridoxine was based on a study of pregnant women between 7 and 14 weeks' gestation who were suffering from nausea and vomiting. Compared with placebo, doxylamine-pyridoxine significantly improved both the Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) scores and quality of life of the trial participants.[43]

Doxylamine-pyridoxine’s approval did not include hyperemesis gravidarum, but a study by Koren and Maltepe showed that the drug may work best when administered before the onset of symptoms. A greater reduction in the recurrence of hyperemesis gravidarum was observed in those who used the doxylamine-pyridoxine combination preemptively compared to those who took the drug at symptom onset (43% vs 17%).[44]

Metoclopramide is widely used for nausea and vomiting during pregnancy, but information regarding human teratogenicity has been lacking. Matok et al found no increased risk for major congenital malformations, low birth weight, preterm delivery, Apgar scores, or perinatal death between infants of mothers who took metoclopramide within the first trimester compared with infants’ mothers who did not take metoclopramide. The retrospective cohort study included a total of 81,703 infants who were born to women registered in a single health system with computerized maternal and infant hospital records. Of these, 3458 (4.2%) had first trimester exposure to metoclopramide.[45]

Since confirmation of adherence was unavailable, a secondary analysis was performed on infants of mothers who refilled their prescription for metoclopramide at least once (n=758), and no increased risk was found in this subpopulation exposed to metoclopramide compared with infants not exposed. Additionally, the results of the study were unchanged when therapeutic abortions of exposed and unexposed fetuses were included in the analysis.

The study provides clinicians reassurance that metoclopramide does not cause congenital malformations; although, dopamine antagonists can cause maternal extrapyramidal symptoms (ie, acute dystonic reactions, tardive dyskinesia).

If hypokalemia is severe or symptomatic, potassium should be replaced parenterally. Before administering IV potassium, renal function should be evaluated. Potassium is usually added to intravenous fluid to achieve a concentration of 40 mEq/L (and not >80 mEq/L). An infusion rate of 10 mEq of potassium per hour should be safe as long as urine output is adequate.

When administrating intravenous hydration to a patient who has severe volume depletion in an effort to prevent the development of Wernicke encephalopathy, avoid intravenous glucose until intravenous thiamine has been administered.

If persistent dehydration, electrolyte loss, and/or weight loss occur despite above therapy, nutrition supplementation by either the parenteral or enteral route is indicated. The standard method has been via total parenteral nutrition (TPN). However, documented risks of bacteremia, sepsis, and thrombosis have been associated with the PICC lines required for TPN supplementation. Nasogastric tube placement and subsequent enteral feeding has been shown in small series and reports to be a valid alternative, with less complication risks, similar efficacy, and similar outcomes in regard to neonatal outcome when compared with TPN.[46]

Surgical Care

In some refractory severe cases of hyperemesis gravidarum, if maternal survival is threatened, or if hyperemesis gravidarum is causing severe physical and psychological burden, termination of the pregnancy should be considered.[5]

Consultations

Diet

Initial suggestions for dietary modification in patients with nausea and vomiting associated with pregnancy include the following:

Activity

Some patients note improvement of nausea and vomiting with decreased activity and increased rest. Other patients suggest that fresh outdoor air may improve symptoms.

Medication Summary

Antihistamines, antiemetics of the phenothiazine class, and promotility agents (eg, metoclopramide) have been used in the treatment of nausea and vomiting during pregnancy.

Vitamin B-6 (pyridoxine) has also been studied in the treatment of nausea and vomiting during pregnancy and reduced nausea and vomiting when compared with placebo.

Ondansetron (Zofran), a serotonin-receptor antagonist, showed no benefit over the antiemetic promethazine (Phenergan), at much greater cost. It may be reserved for refractory cases. A meta-analysis of 6 randomized, double-blind trials showed that ginger was an effective treatment for HEG.

Steroids may be used in patient's refractory to standard therapy. Promethazine (Phenergan) was compared with methylprednisolone in a randomized, double-blind, controlled trial. Methylprednisolone appeared to decrease the rate of readmission for hyperemesis gravidarum; however, the patients randomized to promethazine had a significantly longer duration of symptoms prior to treatment.

However, concerns exist about association between oral clefts and methylprednisolone use in the first trimester; thus, it should be used with caution before 10 weeks of gestation.

Pyridoxine (Nestrex)

Clinical Context:  Marketed in combination formulations with doxylamine (Benedectin, Dilectin).

Benedectin was taken off the market in the United States in the 1980s because of liability issues, but it is available in Canada. Doxylamine is probably not teratogenic and can be used in combination with pyridoxine at a dose of 10-12.5 mg PO qd/bid.

Class Summary

Essential for normal DNA synthesis and play a role in various metabolic processes.

Ginger

Clinical Context:  A randomized, double-blind, crossover trial of a ginger extract was shown to be more beneficial for reducing symptoms than placebo.

Class Summary

Not approved by the US Food and Drug Administration but are remedies believed to improve symptoms.

Doxylamine/pyridoxine (Diclegis)

Clinical Context:  Mechanism of action for efficacy to treat morning sickness is unknown. It contains doxylamine, an ethanolamine antihistamine derivative, and pyridoxine, a vitamin B6 analog. It is the only FDA-approved medication for treatment of nausea and vomiting of pregnancy who have not adequately responded to dietary and lifestyle changes.

Prochlorperazine (Compazine)

Clinical Context:  May relieve nausea and vomiting by blocking postsynaptic mesolimbic dopamine receptors through anticholinergic effects and depressing reticular activating system. In a placebo-controlled study, 69% of patients given prochlorperazine reported significant symptom relief, compared to 40% of patients in the placebo group.

Promethazine (Phenergan)

Clinical Context:  For symptomatic treatment of nausea in vestibular dysfunction. Antidopaminergic agent effective in treating emesis. Blocks postsynaptic mesolimbic dopaminergic receptors in brain and reduces stimuli to brainstem reticular system.

Chlorpromazine (Thorazine, Ormazine)

Clinical Context:  Mechanisms responsible for relieving nausea and vomiting include blocking postsynaptic mesolimbic dopamine receptors, anticholinergic effects, and depression of RAS. Blocks alpha-adrenergic receptors and depresses release of hypophyseal and hypothalamic hormones.

Trimethobenzamide: (Tebamide, Tigan)

Clinical Context:  Acts centrally to inhibit the medullary chemoreceptor trigger zone.

Metoclopramide (Reglan)

Clinical Context:  Blocks dopamine receptors and (when given in higher doses) also blocks serotonin receptors in chemoreceptor trigger zone of the CNS; enhances the response to acetylcholine of tissue in upper GI tract causing enhanced motility and accelerated gastric emptying without stimulating gastric, biliary, or pancreatic secretions; increases lower esophageal sphincter tone.

Ondansetron: (Zofran)

Clinical Context:  Selective 5-HT3-receptor antagonist, blocking serotonin, both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone.

Class Summary

Useful in the treatment of symptomatic nausea.

Methylprednisolone (Medrol, Solu-Medrol)

Clinical Context:  May improve symptoms of nausea and vomiting.

Class Summary

These agents have profound and varied metabolic effects.

Meclizine (Antivert)

Clinical Context:  Decreases excitability of middle ear labyrinth and blocks conduction in middle ear vestibular-cerebellar pathways. These effects are associated with relief of nausea and vomiting.

Diphenhydramine (Benadryl)

Clinical Context:  Competes with histamine for H1-receptor sites on effector cells in the gastrointestinal tract, blood vessels, and respiratory tract; anticholinergic and sedative effects are also seen

Class Summary

Studied in nausea and vomiting during pregnancy and in small numbers of patients with HEG, providing relief in 82% of patients. Appears to be as efficacious as pyridoxine in another study.

Further Inpatient Care

Inpatient care of hyperemesis gravidarum may be necessary if outpatient treatment fails or if severe fluid and/or electrolyte imbalance and nutritional compromise exist (see Treatment).

Further Outpatient Care

Monitor patients regularly, paying attention to symptoms and to the state of mind of the patient and family. Monitor weight and urinary ketones at each visit.

Inpatient & Outpatient Medications

See Treatment.

Complications

Prognosis

Hyperemesis gravidarum is self-limited and, in most cases, improves by the end of the first trimester. However, symptoms may persist through 20-22 weeks of gestation and, in some cases, until delivery.

Author

Dotun A Ogunyemi, MD, Associate Professor of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA; Residency Program Director, Clerkship Director, Department of Obstetrics and Gynecology, Cedars Sinai Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Alex Fong, MD, Staff Physician, Obstetrics and Gynecology Department, Cedars-Sinai Medical Center

Disclosure: Nothing to disclose.

Tiffany Chen Herrero, MD, Resident Physician, Department of Obstetrics and Gynecology, Cedars Sinai Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

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

Disclosure: Nothing to disclose.

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

Disclosure: Medscape Salary Employment

Richard S Legro, MD, Professor, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, Pennsylvania State University College of Medicine; Consulting Staff, Milton S Hershey Medical Center

Disclosure: Korea National Institute of Health and National Institute of Health (Bethesda, MD) Honoraria Speaking and teaching; Greater Toronto Area Reproductive Medicine Society (Toronto, ON, CA) Honoraria Speaking and teaching; American College of Obstetrics and Gynecologists (Washington, DC) Honoraria Speaking and teaching; National Institute of Child Health and Human Development Pediatric and Adolescent Gynecology Research Think Tank Panel (Bethesda, MD) Honoraria Speaking and teaching; University of Illinois (Chicago, IL) Honoraria Speaking and teaching; Georgetown University Hospital (Washington, DC) Honoraria Speaking and teaching; Heilongjiang University (Harbin, China) Speaking and teaching; New England Fertility Society (Nashua, NJ) Honoraria Speaking and teaching; William Beaumont Hospital Division of Reproductive Endocrinology and Infertility (Detroit, MI) Honoraria Speaking and teaching; Wayne State University School of Medicine (Detroit MI) Honoraria Speaking and teaching

Frederick B Gaupp, MD, Consulting Staff, Department of Family Practice, Hancock Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Christine Isaacs, MD, Associate Professor, Department of Obstetrics and Gynecology, Division Head, General Obstetrics and Gynecology, Medical Director of Midwifery Services, Virginia Commonwealth University School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Giulia A Michelini, MD to the development and writing of this article.

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