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
Background:
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.
Pathophysiology:
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.
Infection
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.
Frequency:
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.
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.
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.
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
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 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
Nulliparity
Cigarette smoking is associated with a decreased risk for
HEG.
DIFFERENTIALS Section 4 of 10
Acute Renal Failure
Addison Disease
Appendicitis
Biliary Disease
Esophagitis
Fatty Liver
Gastroenteritis, Viral
Gastroesophageal Reflux Disease
Hepatitis, Viral
Hyperparathyroidism
Hyperthyroidism
Ileus
Nephrolithiasis
Pancreatitis, Acute
Peptic Ulcer Disease
Porphyria, Acute Intermittent
Preeclampsia (Toxemia of Pregnancy)
Other Problems to be Considered:
Intracranial lesions
Eating disorders
Gastroparesis
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.
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
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.
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 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.
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
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.
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.
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.
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
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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