AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Nausea and vomiting in pregnancy is extremely common. 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.

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.

The most severe form of nausea and vomiting in pregnancy is called hyperemesis gravidarum (HEG). 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 HEG. HEG is characterized by persistent nausea and vomiting associated with ketosis and weight loss (>5% of prepregnancy weight). HEG 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.

Pathophysiology

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

Psychological abnormalities

Some cases of HEG may represent psychiatric illnesses, including Munchausen syndrome, conversion or somatization disorder, or major depression. They may occur under situations of stress or ambivalence surrounding the pregnancy. It appears that psychologic responses can interact and exacerbate the physiology of nausea and vomiting during pregnancy. Most likely, physiological changes associated with pregnancy interact with each woman's psychologic state and cultural values. However, HEG may occur in the absence of psychologic illness or stress.

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 HEG 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 HEG, thyroid function normalizes by the middle of the second trimester without antithyroid treatment. Clinically overt hyperthyroidism and thyroid antibodies are usually absent.

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 HEG with a normal hCG may be due to varying hCG isotypes.

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 HEG 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 HEG, and (3) some studies have failed to correlate the severity of symptoms with biochemical abnormalities.

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.

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 bradycardias. 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 HEG.

Hepatic dysfunction

Liver disease, usually consisting of mild serum transaminase elevation, occurs in almost 50% of patients with HEG. Impairment of mitochondrial fatty acid oxidation (FAO) has been hypothesized to play a role in the pathogenesis of maternal liver disease associated with HEG. It has been suggested that women heterozygous for FAO defects develop HEG 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 HEG 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 HEG 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 HEG compared with controls.

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 HEG. Recent studies in the United States have not shown association with HEG. However, persistent nausea and vomiting beyond the second trimester may be due to an active peptic ulcer caused by H pylori infection.

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 HEG and motion sickness suggest that unmasking of subclinical vestibular disorders may account for some cases of HEG.

Biochemical research

HEG is associated with overactivation of sympathetic nerves and enhanced production of tumor necrosis factor (TNF)-alpha. 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 HEG may be modulatory. Trophoblast-derived cytokines have been reported to induce secretion of hCG. Immunoglobulins C3 and C4 and lymphocyte counts are significantly higher in HEG. T-helper 1/T-helper 2 balance is decreased in women with HEG, which results in increased humoral immunity. Increased fetal DNA has been found in the maternal plasma of women with HEG, and the increased DNA is speculated to be derived from trophoblasts that have been destroyed by the hyperactive maternal immune system. Thus, HEG may be mediated by immunologic aberrations in pregnancy.

Frequency

United States

Of all pregnancies, 0.3-2% are affected with HEG (approximately 5 per 1000 pregnancies).

International

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

Mortality/Morbidity

HEG was a significant cause of maternal death before 1940. Mortality from HEG in Great Britain 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 HEG in 1855. In the United States, 7 deaths from HEG were reported in the 1930s, but today, although HEG is still associated with significant morbidity, it is a rare cause of maternal mortality.

• 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.



• HEG 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 HEG, 27% required multiple hospitalizations. The financial burden of HEG on the American health system has been estimated as approximately $130 million dollars per year, excluding physician fees.



• Women with HEG 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.

Race

No clear racial predominance is noted for HEG.

• HEG is less common in American Indian and Eskimo populations.
• HEG is less common in African and some Asian populations (but not industrialized Japan).

Sex

HEG affects females.

Age

The risk of HEG appears to decrease with advanced maternal age.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• The defining symptoms of HEG are gastrointestinal in nature and include nausea and vomiting.
• Other common symptoms include ptyalism (excessive salivation), fatigue, weakness, and dizziness.
• Patients may experience the following:
• • Sleep disturbance
  • Hyperolfaction
  • Dysgeusia
  • Decreased gustatory discernment
  • Depression
  • Anxiety
  • Irritability
  • Mood changes
  • Decreased concentration

• When obtaining history from the patient, discuss present symptoms. Obtain information pertaining to the timing, onset, severity, pattern, and alleviating and exacerbating factors (eg, relationship to meals, medications, prenatal vitamins, stress, other triggers).
• A thorough review of systems for any symptoms that might suggest other gastrointestinal, renal, endocrine, and central nervous system disorders is vital.
• Review past medical history, placing emphasis on past medical conditions, surgeries, medications, allergies, adverse drug reactions, family history, social history (including support system), employment, habits, and diet.
• Obtaining a thorough gynecologic history of symptoms, such as vaginal bleeding or spotting, past pregnancies, past use of oral contraceptives, and response to oral contraceptives used, is important.

Physical

• The physical examination is usually unremarkable in patients with HEG.
• The physical examination findings may be more helpful if the patient has unusual complaints suggestive of other disorders (eg, bleeding, abdominal pain).
• Pay attention to the 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 examination findings, abdominal examination findings, cardiac examination findings, and neurologic examination findings.

Causes

In a review of 1,301 cases of HEG 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 HEG, 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.

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 HEG may include the following:
• • Previous pregnancies with HEG
  • Greater body weight
  • Multiple gestations
  • Trophoblastic disease
  • Nulliparity

• Cigarette smoking is associated with a decreased risk for HEG.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Intracranial lesions
Degenerating uterine leiomyoma
Drug toxicity
Eating disorders
Gastroparesis
Migraines
Ovarian torsion
Pseudotumor cerebri
Psychological disorders
Tumors of the central nervous system
Vestibular lesions

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Initial lab studies for HEG should include the following:
• • Urinalysis for ketones and specific gravity: A sign of starvation, ketones may be harmful to fetal development. High specific gravity occurs with volume depletion.
  • Serum electrolytes and ketones: Assess electrolyte status to evaluate for low potassium or sodium, identify hyperchloremic metabolic alkalosis or acidosis, and evaluate renal function and volume status.
  • Liver enzymes and bilirubin: Elevated transaminase levels may occur in as many as 50% of patients with HEG.
  • Amylase: This is elevated in approximately 10% of patients with HEG.
  • TSH, free thyroxine: HEG is associated with hyperthyroidism and suppressed TSH levels in 50-60% of cases.

  • Urine culture: This may be indicated because urinary tract infection is common in pregnancy and can be associated with nausea and vomiting.
  • Calcium level: Consider measuring Ca⁺⁺ levels. Some rare cases have been reported of hypercalcemia being associated with HEG, resulting from hyperparathyroidism.
  • Hematocrit: This may be elevated because of volume contraction.
  • Hepatitis panel: If clinically indicated, hepatitis A, B, or C may be confused with HEG.

Imaging Studies

• Obstetric ultrasonography is usually warranted in patients with HEG to evaluate for multiple gestations or trophoblastic disease.
• Additional imaging studies generally are not needed unless the 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 another disorder is suggested based on history or physical examination findings.
• If indicated clinically, performing upper abdominal ultrasonography to evaluate the pancreas and/or biliary tree appears to be a low-risk study.
• In rare cases, abdominal CT scan may be indicated if appendicitis is under consideration as a cause of nausea and vomiting in pregnancy.

Procedures

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

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

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

• Recent studies have not shown a clear benefit of acupressure in patients with HEG. However, a randomized study by Rosen et al using pressure or electrical stimulation at the P6 (or Neguian) point on the inside of the wrist showed some efficacy in reducing nausea and vomiting and promoting weight gain in women with HEG.

• More controversy surrounds the benefit of hypnosis, but it has been studied in some cases of HEG and has been shown to be beneficial.
• Psychological counseling may be considered.

• Reserve pharmacologic therapy for severe and refractory cases. First-line outpatient drug therapy can include oral pyridoxine. If vomiting persists, doxylamine may be added to the pyridoxine or conventional antiemetics may be administered.
• Initiate a full laboratory workup in cases of severe refractory HEG (weight loss or the presence of more than trace urine ketones). Outpatient or home intravenous hydration should be considered. If medications and outpatient hydration fail or if severe electrolyte disturbances persist, inpatient admission for intravenous hydration may be necessary.
• • If hypokalemia is severe or symptomatic, calcium should be replaced parenterally. Before administering intravenous 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 vomiting is recurrent with intravenous hydration and conventional medications fail, a trial of oral corticosteroids is appropriate. Failure of this regimen necessitates consideration of enteral nutrition (either central or peripheral total parenteral nutrition).

Surgical Care

In some refractory severe cases of HEG or if maternal survival is threatened, termination of the pregnancy should be considered as a last resort.

Consultations

• Patients with HEG should be under the care of an obstetrician who is familiar with this disorder.
• Consultation with a psychiatrist or psychologist may be warranted because psychological assessment may be needed. In some cases, even supportive or focal psychotherapy or psychiatric medications may be indicated. Behavioral therapy may be beneficial early in the course of HEG.
• When certain disorders are considered the cause of nausea and vomiting (see Differentials), referral to a gastroenterologist or surgeon may be necessary.

Diet

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

• Eat when hungry, regardless of normal meal times.

• Eat frequent small meals.

• Avoid foods high in fat.

• Avoid spicy foods.
• Avoid emetogenic foods or smells.
• Increase intake of bland or dry foods.

• Eliminate pills with iron.

• High protein snacks are helpful.

• Crackers in the morning may be helpful.
• Increase intake of carbonated beverages.
• Other suggested foods include herbal teas containing peppermint or ginger, other ginger-containing beverages, broth, crackers, unbuttered toast, gelatin, or frozen desserts.
• Preconception use of prenatal vitamins may decrease nausea and vomiting associated with pregnancy.

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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 HEG; however, the patients randomized to promethazine had a significantly longer duration of symptoms prior to treatment.

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

Drug Category: Vitamins

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

Drug Category: Herbal medications

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

Drug Category: Antiemetics

Useful in the treatment of symptomatic nausea.

Drug Category: Corticosteroids

These agents have profound and varied metabolic effects.

Drug Category: Antihistamines

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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Inpatient care 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.

In/Out Patient Meds

• See Treatment.

Complications

• Case reports describe the following maternal complications of HEG:
• • 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.

Prognosis

• HEG 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.

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 excellent patient education resources, visit eMedicine's Pregnancy and Reproduction Center. Also, see eMedicine's patient education articles Pregnancy and Pregnancy, Vomiting.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Considering other diagnoses in cases of severe refractory nausea and vomiting is important during pregnancy, especially if the presentation is atypical or other symptoms are present.
• Fully informing patients of the available evidence regarding potential risks and benefits of all treatments administered for HEG is vital, especially regarding the effects of medications on the fetus. If not emergently required, avoid the administration of drugs during the first 10 weeks of gestation if possible.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Apr 10, 2007