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Overview

Practice Essentials

Hyperemesis gravidarum is the most severe form of nausea and vomiting in pregnancy. It is characterized by persistent nausea and vomiting not related to other causes that is associated with a measure of acute starvation, such as 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 0.3-3% 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:

Sleep disturbance
Hyperolfaction
Dysgeusia
Decreased gustatory discernment
Depression
Anxiety
Irritability
Mood changes
Decreased concentration

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).

Scores from the Pregnancy-Unique Quantification of Emesis and Nausea (PUQE), a validated survey tool, have been found to be clinically useful, since the scores are associated with quality of life measurements.^[1]

Examination includes the following:

Vital signs, including standing and lying blood pressure and pulse
Volume status (eg, mucous membrane condition, skin turgor, neck veins, mental status)
General appearance (eg, nutrition, weight)
Thyroid evaluation
Abdominal evaluation
Cardiac evaluation
Neurologic evaluation

Laboratory tests

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

Urinalysis for ketones and specific gravity
Serum levels of electrolytes and ketones
Liver enzymes and bilirubin levels^[2]
Amylase/lipase levels
Thyroid stimulating hormone, free thyroxine levels^[3]
Urine culture
Calcium level
Hematocrit level
Hepatitis panel^[1]

Imaging studies

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

Obstetric ultrasonography: Usually warranted to evaluate for multiple gestations or trophoblastic disease
Upper abdominal ultrasonography: If clinically indicated, to evaluate the pancreas and/or biliary tree
Abdominal computed tomography scanning or magnetic resonance imaging: If appendicitis is suspected as a cause of nausea and vomiting in pregnancy

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 includes 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:

Vitamins (eg, pyridoxine)
Herbal medications (eg, ginger)
Antiemetics (eg, doxylamine-pyridoxine, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, metoclopramide, ondansetron)
corticosteroids (eg, methylprednisolone)
Antihistamines (eg, meclizine, diphenhydramine)

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 may 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. Several proposed theories are discussed below.

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.^{[1, 9, 10, 11]}

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]

A study by Fejzo et al found that increased levels of the hormone GDF15 are linked to vomiting during pregnancy and hyperemesis gravidarum. Fetal production of GDF15 and the pregnant person’s sensitivity to the hormone are both associated with a greater risk of hyperemesis gravidarum.^[18]

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.^[19]

Levels of the plasma gut satiety hormones peptide YY (PYY) and pancreatic polypeptide (PP) may play a role in hyperemesis gravidarum and pregnancy-related weight changes.^[20]In a prospective case-control study of 60 women (30 women with hyperemesis gravidarum, 30 control women), Köşüş et al found that affected women had significantly elevated plasma PYY and PP levels relative to the control group, and that PP levels were the the most important diagnostic and prognostic factors of hyperemesis gravidarum.^[20]

Hepatic dysfunction

Abnormal liver function studies are noted in approximately 3% of pregnancies, and pregnancy-related diseases are the most frequent causes of liver dysfunction during pregnancy.^[21]There appears to be a trimester-specific occurrence of liver disease during pregnancy.^[21]

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.

Metabolic derangement

Metabolic disturbance may have a role in the pathogenesis of hyperemesis gravidarum.^[22]Ergin et al noted that affected women had deficiencies in native and total thiol, and this deficiency was correlated with the severity of the disease. They noted that the dynamic serum thiol-disulfide homeostasis balance shifted to the oxidative side.^[22]

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.^{[23, 24]}

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.^{[25, 26]}

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.^{[27, 28]}

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%.^[29]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.^[30]

In a genome-wide association study, Fejzo et al found an association between the growth differentiation factor 15 (GDF15) gene and hyperemesis gravidarum. GDF15 is a member of the TGF-β family and is found at its highest levels in maternal serum in the first and second trimesters. GDF15 is known to have roles in both pregnancy and physiological regulation of body weight and appetite. Prior studies have shown overproduction of GDF15 in cancer models contributes to anorexia and cachexia. Additionally, GFRAL, the receptor for GDF15, located on the area postrema (vomiting center) in the brainstem was shown to be strongly associated with hyperemesis.^[31]

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

Biochemical research

Hyperemesis gravidarum is associated with overactivation of sympathetic nerves and enhanced production of tumor necrosis factor (TNF)-alpha.^[32]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.^[33]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.^{[34, 35, 36, 37]}

In a more recent study, Biberoglu et al suggest that changes in lipid peroxidation and T-cell activation may be a cause of or compensatory reaction to hyperemesis gravidarum.^[38]The investigations noted significantly elevated levels of serum malondialdehyde (MDA) and glutathione peroxidase (GPx) in 40 pregnant women with hyperemesis gravidarum compared to 40 unaffected, healthy pregnant women.

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.^{[39, 40, 41, 42]}

Etiology

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.^{[43, 44]}

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.

Risk factors for hyperemesis gravidarum may include the following:

Previous pregnancies with hyperemesis gravidarum
Greater body weight
Multiple gestations
Trophoblastic disease
Nulliparity

Cigarette smoking is associated with a decreased risk for hyperemesis gravidarum.

United States statistics

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

International statistics

In a study conducted in Finland, the incidence of hyperemesis gravidarum was 1.3%.^[45]Hyperemesis gravidarum appears to be more common in westernized industrialized societies and urban areas than in rural areas.

Race-, sex-, and age-related demographics

No clear racial predominance is noted for hyperemesis gravidarum, although it is less common in American Indian and Eskimo populations, as well as less common in African and some Asian populations (but not industrialized Japan).

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

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.

Morbidity/mortality

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. A large population-based study of 999,161 women with singleton births by Fossum et al found no association between hyperemesis gravidarum and increased risk of long-term mortality.^[46]

Note the following:

Many hours of productive work are lost because of nausea and vomiting during pregnancy. Nearly 50% of employed women believe that their work is affected, and up to 25% require time off from work.
Hyperemesis gravidarum is a debilitating illness that can cause severe suffering, which profoundly affects both patients and their families. In about half of the women there is an adverse effect on spousal relationships, and 55% have feelings of depression. In one study of 140 women with hyperemesis gravidarum, 27% required multiple hospitalizations. The financial burden of hyperemesis gravidarum on the American health system has been estimated as approximately $130 million dollars per year, excluding physician fees.
Women with hyperemesis gravidarum who have a low pregnancy weight gain (< 15.4 lb or 7 kg) have increased risk for delivering neonates of low birth weight, delivering neonates who are small for gestational age, preterm delivery, and a 5-minute Apgar score of less than 7.

Complications

Case reports describe the following maternal complications of hyperemesis gravidarum:

Esophageal rupture or perforation
Pneumothorax and pneumomediastinum
Wernicke encephalopathy or blindness
Hepatic disease
Seizures, coma, or death

Others complications include renal failure, pancreatitis, deep venous thrombosis, pulmonary embolism, central pontine myelinolysis, rhabdomyolysis, vitamin K deficiency and coagulopathy, and splenic avulsion.

Complications associated with central hyperalimentation include sepsis, fungemia, tamponade, local infection, venous thrombosis, fatty infiltration of the placenta, and transaminitis.

Patient Education

Early patient education about the signs and symptoms of pregnancy may be beneficial. One study found an association between nausea and vomiting and insufficient knowledge about pregnancy, stress, doubts regarding the pregnancy, and poor communication with the doctor and spouse.

Early interventions may include reassurance and dietary counseling, including directing the patient to eat small meals, to avoid high-fat or spicy foods, to follow hunger cues, and to increase the intake of dry carbohydrates and carbonated beverages.

For patient education resources, see Pregnancy Center, as well as Pregnancy and Morning Sickness (Vomiting During Pregnancy).

Clinical Presentation

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Author

Dotun A Ogunyemi, MD Vice Chair of Patient Safety and Quality, William Beaumont Hospital; Professor, Oakland University, William Beaumont School of Medicine; Clinical Services Professor of Obstetrics and Gynecology, University of California, Los Angeles, David Geffen School of Medicine

Dotun A Ogunyemi, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, American Medical Association, National Medical Association, Society for Maternal-Fetal Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

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.

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

Richard S Legro, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, Society of Reproductive Surgeons, American Society for Reproductive Medicine, Endocrine Society, Phi Beta Kappa

Disclosure: Received honoraria from Korea National Institute of Health and National Institute of Health (Bethesda, MD) for speaking and teaching; Received honoraria from Greater Toronto Area Reproductive Medicine Society (Toronto, ON, CA) for speaking and teaching; Received honoraria from American College of Obstetrics and Gynecologists (Washington, DC) for speaking and teaching; Received honoraria from National Institute of Child Health and Human Development Pediatric and Adolescent Gynecology Research Thi.

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

Christine Isaacs, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists

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.

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

Alex Fong, MD is a member of the following medical societies: American Medical Association

Disclosure: Nothing to disclose.

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

Disclosure: Nothing to disclose.

Acknowledgements

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

Hyperemesis Gravidarum