Hyperemesis Gravidarum

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
Coauthor(s): Alex Fong, MD, Staff Physician, Obstetrics and Gynecology Department, Cedars-Sinai Medical Center

Introduction

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.1 ,2

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.3 ,4

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.5

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.4 ,6 ,7 ,5

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.8 ,9

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.10 ,11 ,12

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.13

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.14

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.15 ,16

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.17 ,18

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.19 ,20

Biochemical research

Hyperemesis gravidarum is associated with overactivation of sympathetic nerves and enhanced production of tumor necrosis factor (TNF)-alpha.21 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.22 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.23 ,24 ,25 ,26

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 .27 ,28 ,29

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.

  • 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.

Race

No clear racial predominance is noted for hyperemesis gravidarum.

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

Sex

Hyperemesis gravidarum affects females.

Age

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

Clinical

History

  • 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 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 hyperemesis gravidarum.
  • 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 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.30 ,31

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.

Differential Diagnoses

Appendicitis
Hyperthyroidism
Biliary Disease
Irritable Bowel Syndrome
Diabetic Ketoacidosis
Nephrolithiasis
Esophagitis
Pancreatitis, Acute
Fatty Liver
Paralytic Ileus/Bowel Obstruction
Gastroenteritis
Peptic Ulcer Disease
Gastroesophageal Reflux Disease
Porphyria, Acute Intermittent
Hepatitis
Preeclampsia
Hyperparathyroidism
 

Other Problems to Be Considered

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

Workup

Laboratory Studies

Initial lab studies for hyperemesis gravidarum 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 hyperemesis gravidarum. Mild transaminitis often resolves once the nausea has resolved. Significantly elevated liver enzymes, however, may be a sign of another underlying liver condition, such as hepatitis (viral, ischemic, autoimmune), or some other etiology of liver injury.32
  • Amylase/lipase: Amylase level is elevated in approximately 10% of patients with hyperemesis gravidarum. Lipase, when combined with amylase, can increase the specificity in diagnosing pancreatitis as an etiology.
  • TSH, free thyroxine: Hyperemesis gravidarum is often associated with a transient hyperthyroidism and suppressed TSH levels in 50-60% of cases. However, an elevated free thyroxine may suggest that overt hyperthyroidism is present, thus necessitating further workup and treatment.33
  • 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 hyperemesis gravidarum, 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 hyperemesis gravidarum.5

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 or even MRI 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

Medical Care

Initial management should be conservative and may include reassurance, dietary recommendations, and support. Alternative therapies may include acupressure and hypnosis.34

  • Studies have not shown a clear benefit of acupressure in patients with hyperemesis gravidarum. 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 hyperemesis gravidarum.35
  • More controversy surrounds the benefit of hypnosis, but it has been studied in some cases of hyperemesis gravidarum and has been shown to be beneficial.
  • Psychological counseling may be considered.34
  • 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.

Pharmacologic therapy

If pharmacologic therapy is necessary, treatment may be initiated using vitamin B-6, 10-25 mg daily, 3-4 times daily; doxylamine, 12.5 mg, 3-4 times daily can be used in addition. The herb, ginger capsules 250 mg 4 times daily, can be added at this point if patient is still vomiting since it has been shown to be effective in randomized trials.36 Metoclopramide, 5-10 mg taken orally q8h 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, with a taper to 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.37 ,5

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.38

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 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 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.39

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.40

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 fatty and spicy foods and 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

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 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.

Vitamins

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

 

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

10-50 mg PO bid/qid (often 30-100 mg/d)

Pediatric

Not established

May decrease levodopa, phenytoin, and phenobarbital serum levels

Documented hypersensitivity

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

>200 mg/d may precipitate withdrawal effects when medication is discontinued

Herbal medications

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

 

Ginger

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

Adult

250 mg PO qid (powdered ginger root)

Pediatric

Not established

None reported

Documented hypersensitivity

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not recommended in pregnancy because no conclusive data are available; potential effect on testosterone binding and thromboxane synthetase activity are current concerns

Antiemetics

Useful in the treatment of symptomatic nausea.

 

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

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

Not established

Coadministration with other CNS depressants or anticonvulsants may cause additive effects; with epinephrine, may cause hypotension

Documented hypersensitivity; bone marrow suppression; coma; narrow-angle glaucoma; severe liver or cardiac disease

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

 

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

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

Adolescents: Administer as in adults

May have additive effects when used concurrently with other CNS depressants or anticonvulsants; coadministration with epinephrine may cause hypotension

Documented hypersensitivity; children younger than 2 y (incidences of death due to respiratory depression)

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in cardiovascular disease, impaired liver function, seizures, sleep apnea, and asthma

 

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

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

Not established

Other CNS depressants, anticholinergics, or anticonvulsants; antihypertensives may cause additive effect; coadministration with epinephrine may cause hypotension

Documented hypersensitivity; bone marrow suppression, narrow-angle glaucoma, severe liver or cardiac disease

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

 

Trimethobenzamide: (Tebamide, Tigan)

Acts centrally to inhibit the medullary chemoreceptor trigger zone.

Adult

PO: 300 mg tid/qid
IM: 200 mg, followed 1 h later by second 200 mg dose

Pediatric

Not established

Concomitant use with ethanol may increase sedative effects

Documented hypersensitivity

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May mask emesis due to Reye syndrome; may cause extrapyramidal symptoms; adverse effects (eg, EPS, seizure) may be increased in patients with acute febrile illness, dehydration, or electrolyte imbalance

 

Metoclopramide (Reglan)

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.

Adult

10 mg PO 30 min ac and hs or qid
Severe symptoms: 10 mg IV over 1-2 min prn or q4-8h

Pediatric

Not established

Anticholinergic agents antagonize metoclopramide's actions; metoclopramide may increase extrapyramidal symptoms (EPS) or risk when used concurrently with antipsychotic agents; metoclopramide may increase cyclosporine levels; opiate analgesics may increase CNS depression

Documented hypersensitivity; GI obstruction, perforation or hemorrhage; pheochromocytoma; history of seizures

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Metoclopramide often causes EPS (eg, dystonic reactions) requiring management with diphenhydramine 1-2 mg/kg (adults) up to a 50-100 mg maximum IV/IM slow push followed by a maintenance dose (25-50 mg PO q4-6h) for 48-72 h; when these reactions are unresponsive to diphenhydramine, benztropine mesylate IV 1-2 mg (adults) may be effective

 

Ondansetron: (Zofran)

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

Adult

4-8 mg PO q12h
Alternatively, 8 mg administered IV over 15 min q12h or 1 mg/h infused continuously for up to 24 h

Pediatric

Not established

Food increases extent of absorption; Cmax and Tmax do not change much; St John's wort may decrease ondansetron levels; due to reports of profound hypotension during concomitant therapy, manufacturer of apomorphine contraindicates use with ondansetron; CYP3A4 inducers may decrease levels/effects of ondansetron

Documented hypersensitivity

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May mask progressive ileus and/or gastric distension; anaphylactoid reactions may occur

Corticosteroids

These agents have profound and varied metabolic effects.

 

Methylprednisolone (Medrol, Solu-Medrol)

May improve symptoms of nausea and vomiting.

Adult

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

Not established

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

Documented hypersensitivity; viral, fungal, or tubercular skin infections

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, osteoporosis, hypokalemia, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use

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.

 

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

25-50 mg PO qid

Pediatric

Not established

May increase toxicity of CNS depressants, neuroleptics, and anticholinergics

Documented hypersensitivity

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

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

 

Diphenhydramine (Benadryl)

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

Adult

25-50 mg PO q4-6h; maximum 300 mg/d

Pediatric

Not established

Follow-up

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

  • 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.

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.

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.

Miscellaneous

Medicolegal 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 hyperemesis gravidarum 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

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