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Hyperemesis Gravidarum

Author: Dotun A Ogunyemi, MD; Chief Editor: Christine Isaacs, MD

Updated: Nov 15, 2015

Practice Essentials
Hyperemesis gravidarum is the most severe form of nausea and vomiting in pregnancy, characterized by persistent
nausea and vomiting associated with ketosis and weight loss (>5% of prepregnancy weight). This condition may
cause volume depletion, electrolytes and acid-base imbalances, nutritional deficiencies, and even death. Severe
hyperemesis requiring hospital admission occurs in 0.3-2% of pregnancies.[1]

Signs and symptoms


The defining symptoms of hyperemesis gravidarum are gastrointestinal in nature and include nausea and vomiting.
Other common symptoms include ptyalism (excessive salivation), fatigue, weakness, and dizziness.
Patients may also experience the following:

Sleep disturbance

Hyperolfaction

Dysgeusia

Decreased gustatory discernment

Depression

Anxiety

Irritability

Mood changes

Decreased concentration

See Clinical Presentation for more detail.

Diagnosis
Physical examination in women with suspected hyperemesis gravidarum is usually unremarkable. Findings may be
more helpful if the patient has unusual complaints suggestive of other disorders (eg, bleeding, abdominal pain).

Examination includes the following:

Vital signs, including standing and lying blood pressure and pulse

Volume status (eg, mucous membrane condition, skin turgor, neck veins, mental status)

General appearance (eg, nutrition, weight)

Thyroid evaluation

Abdominal evaluation

Cardiac evaluation

Neurologic evaluation

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

Urinalysis for ketones and specific gravity

Serum levels of electrolytes and ketones

Liver enzymes and bilirubin levels [2]

Amylase/lipase levels

Thyroid stimulating hormone, free thyroxine levels [3]

Urine culture

Calcium level

Hematocrit level

Hepatitis panel [1]

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

Obstetric ultrasonography: Usually warranted to evaluate for multiple gestations or trophoblastic disease

Upper abdominal ultrasonography: If clinically indicated, to evaluate the pancreas and/or biliary tree

Abdominal computed tomography scanning or magnetic resonance imaging: If appendicitis is suspected as


a cause of nausea and vomiting in pregnancy

Additional imaging studies may be warranted if the patients clinical presentation is atypical (eg, nausea and/or
vomiting beginning after 9-10 wk of gestation, nausea and/or vomiting persisting after 20-22 wk, acute severe
exacerbation) or if another disorder is suggested based on the history or physical examination findings.
Procedures
In patients with abdominal pain or upper gastrointestinal bleeding, upper gastrointestinal endoscopy appears to be
safe in pregnancy, although careful monitoring is suggested.
See Workup for more detail.

Management
Initial management in pregnant women with hyperemesis gravidarum should be conservative and may include
reassurance, dietary recommendations, and support. Alternative therapies may include acupressure and hypnosis.[4]
Pharmacotherapy
The only FDA-approved drug for treating nausea and vomiting in pregnancy is doxylamine/pyridoxine. However,
antihistamines, antiemetics of the phenothiazine class, and promotility agents (eg, metoclopramide) have also been
used to manage nausea and vomiting during pregnancy. In cases refractory to standard therapy, ondansetron and
steroids may be considered.
The following medications may be used in women with hyperemesis gravidarum:

Vitamins (eg, pyridoxine)

Herbal medications (eg, ginger)

Antiemetics (eg, doxylamine-pyridoxine, prochlorperazine, promethazine, chlorpromazine,


trimethobenzamide, metoclopramide, ondansetron)

corticosteroids (eg, methylprednisolone)

Antihistamines (eg, meclizine, diphenhydramine)

Surgery
In some refractory severe cases of hyperemesis gravidarum, if maternal survival is threatened, or if hyperemesis
gravidarum is causing severe physical and psychological burden, termination of the pregnancy should be considered.
[5]

See Treatment and Medication for more detail.

Background
Nausea and vomiting in pregnancy is extremely common. Hyperemesis gravidarum (HEG) is the most severe form of
nausea and vomiting in pregnancy. A continuous spectrum of the severity of nausea and vomiting ranges from the
nausea and vomiting that occurs in most pregnancies to the severe disorder of hyperemesis gravidarum.
Studies estimate that nausea and vomiting occurs in 50-90% of pregnancies. The nausea and vomiting associated
with pregnancy usually begins by 9-10 weeks of gestation, peaks at 11-13 weeks, and resolves in most cases by 1214 weeks. In 1-10% of pregnancies, symptoms may continue beyond 20-22 weeks.[6, 7]
Normal nausea and vomiting may be an evolutionary protective mechanismit may protect the pregnant woman and
her embryo from harmful substances in food, such as pathogenic microorganisms in meat products and toxins in
plants, with the effect being maximal during embryogenesis (the most vulnerable period of pregnancy). This is
supported by studies showing that women who had nausea and vomiting were less likely to have miscarriages and
stillbirth.[8, 9]
Hyperemesis gravidarum is characterized by persistent nausea and vomiting associated with ketosis and weight loss
(>5% of prepregnancy weight). Hyperemesis gravidarum may cause volume depletion, electrolytes and acid-base
imbalances, nutritional deficiencies, and even death. Severe hyperemesis requiring hospital admission occurs in 0.32% of pregnancies.[1]

Pathophysiology
The physiologic basis of hyperemesis gravidarum is controversial. Hyperemesis gravidarum appears to occur as a
complex interaction of biological, psychological, and sociocultural factors. Several proposed theories are discussed
below.

Hormonal changes
Women with hyperemesis gravidarum often have high hCG levels that cause transient hyperthyroidism. hCG can
physiologically stimulate the thyroid gland thyroid-stimulating hormone (TSH) receptor. hCG levels peak in the first
trimester. Some women with hyperemesis gravidarum appear to have clinical hyperthyroidism. However, in a larger
portion (50-70%), TSH is transiently suppressed and the free thyroxine (T4) index is elevated (40-73%) with no
clinical signs of hyperthyroidism, circulating thyroid antibodies, or enlargement of the thyroid. In transient
hyperthyroidism of hyperemesis gravidarum, thyroid function normalizes by the middle of the second trimester
without antithyroid treatment. Clinically overt hyperthyroidism and thyroid antibodies are usually absent.[1, 9, 10, 11]
A report on a unique family with recurrent gestational hyperthyroidism associated with hyperemesis gravidarum
showed a mutation in the extracellular domain of the TSH receptor that made it responsive to normal levels of hCG.
Thus, cases of hyperemesis gravidarum with a normal hCG may be due to varying hCG isotypes.[12, 13]
A positive correlation between the serum hCG elevation level and free T4 levels has been found, and the severity of
nausea appears to be related to the degree of thyroid stimulation. hCG may not be independently involved in the
etiology of hyperemesis gravidarum but may be indirectly involved by its ability to stimulate the thyroid. For these
patients, hCG levels were linked to increased levels of immunoglobulin M, complement, and lymphocytes. Thus, an
immune process may be responsible for increased circulating hCG or isoforms of hCG with a higher activity for the
thyroid. Critics of this theory note that (1) nausea and vomiting are not usual symptoms of hyperthyroidism, (2) signs
of biochemical hyperthyroidism are not universal in cases of hyperemesis gravidarum, and (3) some studies have
failed to correlate the severity of symptoms with biochemical abnormalities.[14, 15, 16]

Some studies link high estradiol levels to the severity of nausea and vomiting in patients who are pregnant, while
others find no correlation between estrogen levels and the severity of nausea and vomiting in pregnant women.
Previous intolerance to oral contraceptives is associated with nausea and vomiting in pregnancy. Progesterone also
peaks in the first trimester and decreases smooth muscle activity; however, studies have failed to show any
connection between progesterone levels and symptoms of nausea and vomiting in pregnant women. Lagiou et al
studied prospectively 209 women with nausea and vomiting who showed that estradiol levels were positively
correlated while prolactin levels were inversely associated with nausea and vomiting in pregnancy and no correlation
existed with estriol, progesterone, or sex-hormone binding globulin.[17]

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.[18]
Levels of the plasma gut satiety hormones peptide YY (PYY) and pancreatic polypeptide (PP) may play a role in
hyperemesis gravidarum and pregnancy-related weight changes.[19] In a prospective case-control study of 60 women
(30 women with hyperemesis gravidarum, 30 control women), K et al found that affected women had
significantly elevated plasma PYY and PP levels relative to the control group, and that PP levels were the the most
important diagnostic and prognostic factors of hyperemesis gravidarum.[19]

Hepatic dysfunction
Abnormal liver function studies are noted in approximately 3% of pregnancies, and pregnancy-related diseases are
the most frequent causes of liver dysfunction during pregnancy.[20] There appears to be a trimester-specific
occurrence of liver disease during pregnancy.[20]
Liver disease, usually consisting of mild serum transaminase elevation, occurs in almost 50% of patients with
hyperemesis gravidarum. Impairment of mitochondrial fatty acid oxidation (FAO) has been hypothesized to play a
role in the pathogenesis of maternal liver disease associated with hyperemesis gravidarum. It has been suggested
that women heterozygous for FAO defects develop hyperemesis gravidarum associated with liver disease while
carrying fetuses with FAO defects due to accumulation of fatty acids in the placenta and subsequent generation of
reactive oxygen species. Alternatively, it is possible that starvation leading to peripheral lipolysis and increased load
of fatty acids in maternal-fetal circulation, combined with reduced capacity of the mitochondria to oxidize fatty acids in
mothers heterozygous for FAO defects, can also cause hyperemesis gravidarum and liver injury while carrying
nonaffected fetuses.

Metabolic derangement
Metabolic disturbance may have a role in the pathogenesis of hyperemesis gravidarum.[21] Ergin et al noted that
affected women had deficiencies in native and total thiol, and this deficiency was correlated with the severity of the
disease. They noted that the dynamic serum thiol-disulfide homeostasis balance shifted to the oxidative side.[21]

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.[22,
23]

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.[24, 25]

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.[26, 27]

Genetic
In studies examining the familial link of hyperemesis gravidarum, research suggests a possible genetic aspect to
hyperemesis. A study was performed looking at 544,087 pregnancies from Norways mandatory birth registry from
1967-2005. This study demonstrated that daughters born from a pregnancy complicated by hyperemesis had a 3%
risk of having hyperemesis in their own pregnancy. Women who were born after an unaffected pregnancy had a risk
of 1.1%.[28] In surveys administered to mothers who had pregnancies complicated by hyperemesis, higher rates of
hyperemesis were reported among their relatives. This was particularly so in their sisters.[29]
Overall, the data suggest that a genetic predisposition may play a role in the development of hyperemesis
gravidarium.

Biochemical research
Hyperemesis gravidarum is associated with overactivation of sympathetic nerves and enhanced production of tumor
necrosis factor (TNF)-alpha.[30] 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.[31] 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.[32, 33, 34, 35]

In a more recent study, Biberoglu et al suggest that changes in lipid peroxidation and T-cell activation may be a cause
of or compensatory reaction to hyperemesis gravidarum.[36] The investigations noted significantly elevated levels of
serum malondialdehyde (MDA) and glutathione peroxidase (GPx) in 40 pregnant women with hyperemesis
gravidarum compared to 40 unaffected, healthy pregnant women.

Psychological issues
Physiological changes associated with pregnancy interact with each woman's psychologic state and cultural values.
Psychologic responses may interact with and exacerbate the physiology of nausea and vomiting during pregnancy.
Nonetheless, hyperemesis gravidarum is typically the cause of, as opposed to the result of, psychologic stress. In
very unusual instances, cases of hyperemesis gravidarum could represent psychiatric illness, including conversion or
somatization disorder or major depression.[37, 38, 39]

Etiology
In a review of 1,301 cases of hyperemesis gravidarum from Canada, Fell et al showed that medical complications of
hyperthyroid disorders, psychiatric illness, previous molar disease, gastrointestinal disorders, pregestational
diabetes, and asthma were significantly independent risk factors for hyperemesis gravidarum, whereas maternal
smoking and maternal age older than 30 years decreased the risk. Pregnancies with female fetuses and multiple
fetuses were also at increased risk.[40, 41]
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.

Epidemiology
United States statistics

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

International statistics
Hyperemesis gravidarum appears to be more common in westernized industrialized societies and urban areas than
rural areas.

Race-, sex-, and age-related demographics


No clear racial predominance is noted for hyperemesis gravidarum, although it is less common in American Indian
and Eskimo populations, as well as less common in African and some Asian populations (but not industrialized
Japan).
Hyperemesis gravidarum affects females. The risk of hyperemesis gravidarum appears to decrease with advanced
maternal age.

Prognosis
Hyperemesis gravidarum is self-limited and, in most cases, improves by the end of the first trimester. However,
symptoms may persist through 20-22 weeks of gestation and, in some cases, until delivery.

Morbidity/mortality
Hyperemesis gravidarum was a significant cause of maternal death before 1940. In Great Britain, mortality
decreased from 159 deaths per million births from 1931-1940 to 3 deaths per million births from 1951-1960. Charlotte
Bront 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. Note the following:

Many hours of productive work are lost because of nausea and vomiting during pregnancy. Nearly 50% of
employed women believe that their work is affected, and up to 25% require time off from work.

Hyperemesis gravidarum is a debilitating illness that can cause severe suffering, which profoundly affects
both patients and their families. In about half of the women there is an adverse effect on spousal
relationships, and 55% have feelings of depression. In one study of 140 women with hyperemesis
gravidarum, 27% required multiple hospitalizations. The financial burden of hyperemesis gravidarum on the
American health system has been estimated as approximately $130 million dollars per year, excluding
physician fees.

Women with hyperemesis gravidarum who have a low pregnancy weight gain (< 15.4 lb or 7 kg) have
increased risk for delivering neonates of low birth weight, delivering neonates who are small for gestational
age, preterm delivery, and a 5-minute Apgar score of less than 7.

Complications
Case reports describe the following maternal complications of hyperemesis gravidarum:

Esophageal rupture or perforation

Pneumothorax and pneumomediastinum

Wernicke encephalopathy or blindness

Hepatic disease

Seizures, coma, or death

Others complications include renal failure, pancreatitis, deep venous thrombosis, pulmonary embolism, central
pontine myelinolysis, rhabdomyolysis, vitamin K deficiency and coagulopathy, and splenic avulsion.
Complications associated with central hyperalimentation include sepsis, fungemia, tamponade, local infection,
venous thrombosis, fatty infiltration of the placenta, and transaminitis.

Patient Education
Early patient education about the signs and symptoms of pregnancy may be beneficial. One study found an
association between nausea and vomiting and insufficient knowledge about pregnancy, stress, doubts regarding the
pregnancy, and poor communication with the doctor and spouse.
Early interventions may include reassurance and dietary counseling, including directing the patient to eat small
meals, to avoid high-fat or spicy foods, to follow hunger cues, and to increase the intake of dry carbohydrates and
carbonated beverages.

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 also 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.

Laboratory Studies
Initial laboratory 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. [2]

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. [3]

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. [1]

Imaging Studies
Ultrasonography
Obstetric ultrasonography is usually warranted in patients with hyperemesis gravidarum 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.

Other imaging modalities


In patients with abdominal pain or upper gastrointestinal bleeding, upper gastrointestinal endoscopy appears to be
safe in pregnancy, although careful monitoring is suggested.
In rare cases, abdominal computed tomography (CT) scanning or even magnetic resonance imaging (MRI) may be
indicated if appendicitis is under consideration as a cause of nausea and vomiting in pregnancy.

Approach Considerations
If the patient is being treated on an outpatient bases, monitor her regularly, paying attention to symptoms and to the
state of mind of the patient and family. Monitor weight and urinary ketones at each visit.
Some patients note improvement of nausea and vomiting with decreased activity and increased rest. Other patients
suggest that fresh outdoor air may improve symptoms.
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).
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.
[5]

Medical Care
Initial management should be conservative and may include reassurance, dietary recommendations, and support.
Alternative therapies may include acupressure and hypnosis.[4]
Note the following:

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. [42]

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. [4]

Outpatient or home intravenous (IV) hydration should be considered. If medications and outpatient hydration
fail or if severe electrolyte disturbances persist, inpatient admission for IV hydration may be necessary.

Pharmacologic therapy
If pharmacologic therapy is necessary, treatment may be initiated by giving vitamin B-6 10-25 mg 3-4 times daily;
doxylamine 12.5 mg 3-4 times daily can be used in addition. Ginger capsules 250 mg 4 times daily can be added at
this point if the patient is still vomiting; this has been shown to be effective in randomized trials.[43]
Metoclopramide 5-10 mg orally every 8 hours 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, tapered to the 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.[1, 44]
The only FDA-approved drug for treating nausea and vomiting in pregnancy is doxylamine-pyridoxine (Diclegis).[45, 46]
Originally sold between 1956 and 1983 under a different brand name, it was pulled from the market because of
safety concerns, which have since been disproved. The new dosage form approved in April 2013 is a delayedrelease tablet that, when taken at bedtime, is at its peak serum concentrations in the morning, when nausea and
vomiting may be worse.
Approval of the new formulation of doxylamine-pyridoxine was based on a study of pregnant women between 7 and
14 weeks' gestation who were suffering from nausea and vomiting. Compared with placebo, doxylamine-pyridoxine
significantly improved both the Pregnancy-Unique Quantication of Emesis and Nausea (PUQE) scores and quality
of life of the trial participants.[47]
Doxylamine-pyridoxines approval did not include hyperemesis gravidarum, but a study by Koren and Maltepe
showed that the drug may work best when administered before the onset of symptoms. A greater reduction in the
recurrence of hyperemesis gravidarum was observed in those who used the doxylamine-pyridoxine combination
preemptively compared to those who took the drug at symptom onset (43% vs 17%).[48]

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.[49]
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 IV
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.[50]

Consultations
Patients with hyperemesis gravidarum 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 hyperemesis gravidarum .
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.

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