Hyperemesis Gravidarum

Hyperemesis Gravidarum

Synonyms and related keywords: HEG, nausea in pregnancy, vomiting in pregnancy, morning sickness, difficult pregnancy, pregnancy complications, ketosis, pregnancy, pregnancy weight loss, Helicobacter pylori, H pylori 

AUTHOR INFORMATION  Section 1 of 10     

Author: Giulia A Michelini, MD, Associate Clinical Professor of Medicine, IMedicine, University of California at Los Angeles School of Medicine

Giulia A Michelini, MD, is a member of the following medical societies: American College of Physicians, and Society of General Internal Medicine

INTRODUCTION  Section 2 of 10     

Nausea and vomiting in pregnancy is extremely common. Studies estimate nausea occurs in 66-89% of pregnancies and vomiting in 38-57%. The nausea and vomiting associated with pregnancy almost always begins by 9-10 weeks of gestation, peaks at 11-13 weeks, and resolves (in 50% of cases) by 12-14 weeks. In 1-10% of pregnancies, symptoms may continue beyond 20-22 weeks.

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, altered electrolytes, and even death. Hospitalization is not infrequent.

The physiologic basis of HEG is controversial.
The following theories have been proposed:
Psychological abnormalities
Early work on the cause of both nausea and vomiting in pregnancy and HEG suggested that women with these symptoms were unable to accept pregnancy, had problems with their relationships with their mothers, or had personality disorders and/or hysteria. However, nausea and vomiting in pregnancy is now recognized as affecting the majority of women. Retrospectively, many of the earlier studies appear flawed. Newer evidence is conflicting. Some cases of HEG may represent psychiatric illnesses, including Munchausen syndrome, conversion or somatization disorder, and major depression, or they may occur under situations of stress or ambivalence surrounding the pregnancy. However, HEG may occur in the absence of psychological illness or stress.

Hormonal changes
Homology exists between the human chorionic gonadotropin (HCG) molecule and its receptor and the thyroid-stimulating hormone (TSH) molecule and its receptor. HCG can physiologically stimulate the thyroid. HCG levels peak in the first trimester. Some women with HEG appear to have clinical hyperthyroidism. However, in a larger proportion (50-60%), 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 some cases of HEG, some investigators have found a positive correlation between the level of serum HCG elevation and free T4 levels. In these studies, the severity of nausea also appeared to be related to the degree of thyroid stimulation. For these patients, HCG levels were linked to increased levels of immunoglobulin M, complement, and lymphocytes. 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 nausea and vomiting is not a usual symptom of hyperthyroidism, signs of biochemical hyperthyroidism are not universal in cases of HEG, and 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.

Gastrointestinal dysfunction
Elevations in female sex hormones during pregnancy may change esophageal, gastric, and small bowel motility. Although progesterone appears to decrease lower-esophageal sphincter pressure, a number of studies have found no decrease in lower-esophageal sphincter pressure during pregnancy. Studies on gastric emptying demonstrate that it is unchanged in pregnancy. However, some studies have correlated alterations in gastric myoelectrical activity in the first trimester of pregnancy with nausea. Small bowel transit time increases in pregnancy, but only in the second and third trimester.

Hepatic dysfunction
Many investigators have targeted changes in liver function as a possible cause of HEG. Patients with HEG often demonstrate abnormalities of liver enzymes. Liver disease can cause symptoms of nausea and vomiting, and abnormalities have been found on liver biopsy samples from patients with pregnancies complicated by HEG. Theories postulate either an increased sensitivity of the liver to the hormonal alterations of pregnancy or abnormalities in steroid inactivation; however, not all patients with HEG show liver abnormalities. In one study by Jarnfelt-Samsioe et al, pregnant women with vomiting had lower bilirubin and gamma-glutamyl transferase levels compared to women without vomiting.

Lipid alterations
In another study, Jarnfelt-Samsioe et al found higher levels of triglycerides, total cholesterol, and phospholipids in women with HEG compared to matched, nonvomiting, pregnant and nonpregnant controls. This may be related to the abnormalities in hepatic function in pregnant women.

Newer studies have found a relationship between infection with Helicobacter pylori and HEG. In a study by Kocak et al of 95 patients with HEG and 116 matched controls, H pylori infection was found in 91% of patients with HEG compared to 45% in controls.

In the US: Of all pregnancies, 0.3-2% are affected with HEG (approximately 5 per 1000 pregnancies).
Internationally: HEG appears to be more common in westernized industrialized societies and urban areas than rural areas.

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.

Many hours of productive work are lost because of nausea and vomiting during pregnancy. In one study of 200 pregnant women, 35% reported time lost from work.
HEG is a debilitating illness that can cause severe suffering and profoundly affects both patients and their families. In one study of 140 women with HEG, 27% required multiple hospitalizations.

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).

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

CLINICAL  Section 3 of 10     

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
Decreased gustatory discernment
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.

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.
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 pregnancies, 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.

Risk factors for HEG may include the following:
Previous pregnancies with HEG
Greater body weight
Multiple gestations
Trophoblastic disease
Cigarette smoking is associated with a decreased risk for HEG.
DIFFERENTIALS  Section 4 of 10     

Acute Renal Failure
Addison Disease
Biliary Disease
Fatty Liver
Gastroenteritis, Viral
Gastroesophageal Reflux Disease
Hepatitis, Viral
Pancreatitis, Acute
Peptic Ulcer Disease
Porphyria, Acute Intermittent
Preeclampsia (Toxemia of Pregnancy)

Other Problems to be Considered:
Intracranial lesions
Eating disorders

WORKUP  Section 5 of 10     

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: 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: HEG is associated with hyperthyroidism and suppressed TSH levels in 50-60% of cases.
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.

Imaging Studies:
An ultrasound 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 an ultrasound to evaluate the pancreas and/or biliary tree appears to be a low-risk study.

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     

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

In some studies, acupressure has been shown to have a beneficial effect on nausea and vomiting during pregnancy; however, it has not been studied in patients with HEG.

More controversy surrounds the benefit of hypnosis, but it has been studied in some cases of HEG and may 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.

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.

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 and protein.
Avoid emetogenic foods or smells.
Increase intake of foods containing dry carbohydrates.
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; however, in patients with HEG, vitamins (especially those containing iron) can sometimes exacerbate the symptoms.

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     

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. In one study, nausea decreased but vomiting did not. In another study, pyridoxine significantly reduced nausea scores, but only in patients with the most severe symptoms.

A number of randomized studies have been performed on drug treatment for HEG.

Ondansetron (Zofran), a serotonin-receptor antagonist, showed no benefit over the antiemetic promethazine (Phenergan), at much greater cost. Intramuscular adrenocorticotropic hormone showed no benefit over placebo. A randomized, double-blind, crossover trial showed ginger extract to be more beneficial for reducing symptoms than placebo.

Promethazine (Phenergan) has also been compared to 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.

Diazepam (Valium) was used in one randomized study and appeared to shorten hospitalization, significantly reduce nausea, and decrease incidents of readmission for HEG. No significant adverse effects or fetal abnormalities were observed.

Drug Category:
Vitamins -- Essential for normal DNA synthesis and play a role in various metabolic processes.
Drug Name
Pyridoxine (Nestrex) -- 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. 
Adult Dose 10-50 mg PO bid/qid (often 30-100 mg/d) 
Pediatric Dose Not established 
Contraindications Documented hypersensitivity 
Interactions May decrease levodopa, phenytoin, and phenobarbital serum levels 
Pregnancy A - Safe in pregnancy 
Precautions >200 mg/d may precipitate withdrawal effects when medication is discontinued

Drug Category:
Herbal medications -- Not approved by the US Food and Drug Administration but are remedies believed to improve symptoms.
Drug Name
Ginger -- A randomized, double-blind, crossover trial of a ginger extract was shown to be more beneficial for reducing symptoms than placebo. 
Adult Dose 250 mg PO qid (powdered ginger root) 
Pediatric Dose Not established 
Contraindications Documented hypersensitivity 
Interactions None reported 
Pregnancy C - Safety for use during pregnancy has not been established. 
Precautions Not recommended in pregnancy because no conclusive data are available; potential effect on testosterone binding and thromboxane synthetase activity are current concerns

Drug Category:
Antiemetics -- Useful in the treatment of symptomatic nausea.
Drug Name
 Prochlorperazine (Compazine) -- 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. 
Adult Dose PO: 5-10 mg tid/qid; not to exceed 40 mg/d
IV: 2.5-10 mg q3-4h prn; not to exceed 10 mg/dose or 40 mg/d
IM: 5-10 mg q3-4h
PR: 25 mg bid 
Pediatric Dose Not established 
Contraindications Documented hypersensitivity; bone marrow suppression; coma; narrow-angle glaucoma; severe liver or cardiac disease 
Interactions Coadministration with other CNS depressants or anticonvulsants may cause additive effects; with epinephrine, may cause hypotension 
Pregnancy C - Safety for use during pregnancy has not been established. 
Precautions Drug-induced Parkinson syndrome or pseudoparkinsonism occurs quite frequently; akathisia is most common extrapyramidal reaction in elderly patients; lowers seizure threshold; may lower convulsive threshold; adverse effects can include hypotension, sedation, and extrapyramidal and anticholinergic symptoms; data are conflicting regarding teratogenicity; crosses placenta and appears in breast milk
Drug Name
 Promethazine (Phenergan) -- 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. 
Adult Dose PO: 12.5-25 mg q4-6h prn (syr or tab)
PR: 12.5-25 mg q4-6h prn
IV/IM: 12.5-25 mg q4-6h; use caution with IV administration, concentration not to exceed 25 mg/mL, rate not to exceed 25 mg/min; do not administer SC or intra-arterially 
Pediatric Dose Not established 
Contraindications Documented hypersensitivity 
Interactions May have additive effects when used concurrently with other CNS depressants or anticonvulsants; coadministration with epinephrine may cause hypotension 
Pregnancy C - Safety for use during pregnancy has not been established. 
Precautions Caution in cardiovascular disease, impaired liver function, seizures, sleep apnea, and asthma
Drug Name
 Chlorpromazine (Thorazine, Ormazine) -- 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. 
Adult Dose PO: 10-25 mg q4-6h prn
PR: 50-100 mg q6-8h prn
IM: 12.5-25 mg once; if no hypotension, may administer 25-50 mg q3-4 h prn; caution with parenteral administration because of the potential for hypotension 
Pediatric Dose Not established 
Contraindications Documented hypersensitivity; bone marrow suppression, narrow-angle glaucoma, severe liver or cardiac disease 
Interactions Other CNS depressants, anticholinergics, or anticonvulsants; antihypertensives may cause additive effect; coadministration with epinephrine may cause hypotension 
Pregnancy C - Safety for use during pregnancy has not been established. 
Precautions May cause pseudoparkinsonism; akathisia is a common extrapyramidal reaction in elderly patients; lowers seizure threshold and increases risk of seizures in patient with history of seizures
Drug Name
 Methylprednisolone (Medrol) -- May improve symptoms of nausea and vomiting. 
Adult Dose 16 mg PO tid (48 mg/d) for 3 d initially, taper over 12 d; may be restarted or prior dose resumed if vomiting recurs during taper 
Pediatric Dose Not established 
Contraindications Documented hypersensitivity; viral, fungal, or tubercular skin infections 
Interactions Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels; phenobarbital, phenytoin, and rifampin may decrease levels (adjust dose); monitor patients for hypokalemia when taking concurrently with diuretics 
Pregnancy C - Safety for use during pregnancy has not been established. 
Precautions Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, osteoporosis, hypokalemia, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use

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.
Drug Name
 Meclizine (Antivert) -- 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. 
Adult Dose 25-50 mg PO qid 
Pediatric Dose Not established 
Contraindications Documented hypersensitivity 
Interactions May increase toxicity of CNS depressants, neuroleptics, and anticholinergics 
Pregnancy B - Usually safe but benefits must outweigh the risks. 
Precautions Caution in angle-closure glaucoma, prostatic hypertrophy, pyloric or duodenal obstruction, and bladder neck obstruction; should not be used when operating heavy machinery or driving; does not appear to be teratogenic

FOLLOW-UP  Section 8 of 10     

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.

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.
Interestingly, nausea and vomiting during pregnancy is associated with a lower risk of miscarriage, premature birth, low birth weight, and perinatal mortality. However, HEG may be associated with fetal complications of growth restriction and even fetal death, although this is controversial. One study found that in women with HEG and weight loss, 32% of children were below the 10th percentile for gestational weight at birth, versus only 6% of children in women with HEG and no weight loss. In most studies, an increase in congenital birth defects does not appear to be correlated with HEG.

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     

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.


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