emedicine.medscape.

com

Hyperemesis Gravidarum
Updated: Jan 04, 2017
Author: Dotun A Ogunyemi, MD; Chief Editor: Christine Isaacs, MD

Overview
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 patient’s 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 12-14 weeks. In 1-10% of pregnancies, symptoms may
continue beyond 20-22 weeks.[6, 7]

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.[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 0.3-2% 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), Köşüş 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
Norway’s 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 gravidarum.

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, 40]

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.[41, 42]

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 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. A large population-based study of 999,161 women with
singleton births by Fossum et al found no association between hyperemesis gravidarum and
increased risk of long-term mortality.[43]

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.

For patient education resources, see Pregnancy Center, as well as Pregnancy and Morning
Sickness (Vomiting During Pregnancy).

Presentation
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.

DDx
Diagnostic Considerations
Important considerations
It is important to consider other diagnoses in cases of severe refractory nausea and vomiting
during pregnancy, especially if the presentation is atypical or other symptoms are present.

It is vital to fully inform patients of the available evidence regarding potential risks and benefits
of all treatments administered for hyperemesis gravidarum, 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.

Other problems to be considered

Other conditions to consider in the differential diagnosis of patients with suspected hyperemesis
gravidarum include the following:

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

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

Workup
Workup
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.

Treatment
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,
44]

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.[45]
 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.[46, 47]

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, 48]

The only FDA-approved drug for treating nausea and vomiting in pregnancy is doxylamine-
pyridoxine (Diclegis).[49, 50] 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 delayed-release 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 Quantification of Emesis and Nausea (PUQE) scores and quality of life of the trial
participants.[51]
Doxylamine-pyridoxine’s 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%).[52]

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.[53]

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.[54]

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.

Medication
Medication Summary
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
hyperemesis gravidarum.

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 exist 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
Class Summary
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.

Herbal medications
Class Summary
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.

Antiemetics
Class Summary
Useful in the treatment of symptomatic nausea.

Doxylamine/pyridoxine (Diclegis)
Mechanism of action for efficacy to treat morning sickness is unknown. It contains doxylamine,
an ethanolamine antihistamine derivative, and pyridoxine, a vitamin B6 analog. It is the only
FDA-approved medication for treatment of nausea and vomiting of pregnancy who have not
adequately responded to dietary and lifestyle changes.

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.

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.

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.

Trimethobenzamide: (Tebamide, Tigan)

Acts centrally to inhibit the medullary chemoreceptor trigger zone.
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.

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

Corticosteroids
Class Summary
These agents have profound and varied metabolic effects.

Methylprednisolone (Medrol, Solu-Medrol)

May improve symptoms of nausea and vomiting.

Antihistamines
Class Summary
Studied in nausea and vomiting during pregnancy and in small numbers of patients with
hyperemesis gravidarum, 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.

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

Contributor Information and Disclosures

Author

Dotun A Ogunyemi, MD Vice Chair of Patient Safety and Quality, William Beaumont
Hospital; Professor, Oakland University, William Beaumont School of Medicine; Clinical
Services Professor of Obstetrics and Gynecology, University of California, Los Angeles, David
Geffen School of Medicine

Dotun A Ogunyemi, MD is a member of the following medical societies: American College of

Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, American
Medical Association, National Medical Association, Society for Maternal-Fetal Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Alex Fong, MD Staff Physician, Obstetrics and Gynecology Department, Cedars-Sinai Medical
Center

Alex Fong, MD is a member of the following medical societies: American Medical Association

Disclosure: Nothing to disclose.

Tiffany Chen Herrero, MD Resident Physician, Department of Obstetrics and Gynecology,

Cedars Sinai Medical Center

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska

Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Richard S Legro, MD Professor, Department of Obstetrics and Gynecology, Division of

Reproductive Endocrinology, Pennsylvania State University College of Medicine; Consulting
Staff, Milton S Hershey Medical Center
Richard S Legro, MD is a member of the following medical societies: American College of
Obstetricians and Gynecologists, Society of Reproductive Surgeons, American Society for
Reproductive Medicine, Endocrine Society, Phi Beta Kappa

Disclosure: Received honoraria from Korea National Institute of Health and National Institute of
Health (Bethesda, MD) for speaking and teaching; Received honoraria from Greater Toronto
Area Reproductive Medicine Society (Toronto, ON, CA) for speaking and teaching; Received
honoraria from American College of Obstetrics and Gynecologists (Washington, DC) for
speaking and teaching; Received honoraria from National Institute of Child Health and Human
Development Pediatric and Adolescent Gynecology Research Thi.

Chief Editor

Christine Isaacs, MD Associate Professor, Department of Obstetrics and Gynecology, Division

Head, General Obstetrics and Gynecology, Medical Director of Midwifery Services, Virginia
Commonwealth University School of Medicine

Christine Isaacs, MD is a member of the following medical societies: American College of

Obstetricians and Gynecologists

Disclosure: Nothing to disclose.

Additional Contributors

Suzanne R Trupin, MD, FACOG Clinical Professor, Department of Obstetrics and

Gynecology, University of Illinois College of Medicine at Urbana-Champaign; CEO and Owner,
Women's Health Practice; CEO and Owner, Hada Cosmetic Medicine and Midwest Surgical
Center

Suzanne R Trupin, MD, FACOG is a member of the following medical societies: American
College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine,
International Society for Clinical Densitometry, AAGL, North American Menopause Society,
American Medical Association, Association of Reproductive Health Professionals

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Drugs & Diseases gratefully acknowledge the contributions
of previous author Giulia A Michelini, MD, to the development and writing of this article.

References

1. Goodwin TM. Hyperemesis gravidarum. Obstet Gynecol Clin North Am. 2008 Sep.
35(3):401-17, viii.
2. Hay JE. Liver disease in pregnancy. Hepatology. 2008 Mar. 47(3):1067-76. [Medline].
3. Tan JY, Loh KC, Yeo GS, et al. Transient hyperthyroidism of hyperemesis gravidarum.
BJOG. 2002 Jun. 109(6):683-8. [Medline].
4. Simon EP, Schwartz J. Medical hypnosis for hyperemesis gravidarum. Birth. 1999 Dec.
26(4):248-54. [Medline].
5. Poursharif B, Korst LM, Macgibbon KW, et al. Elective pregnancy termination in a large
cohort of women with hyperemesis gravidarum. Contraception. 2007 Dec. 76(6):451-5.
[Medline].
6. Lacroix R, Eason E, Melzack R. Nausea and vomiting during pregnancy: A prospective
study of its frequency, intensity, and patterns of change. Am J Obstet Gynecol. 2000 Apr.
182(4):931-7. [Medline].
7. Bailit JL. Hyperemesis gravidarium: Epidemiologic findings from a large cohort. Am J
Obstet Gynecol. 2005 Sep. 193(3 Pt 1):811-4. [Medline].
8. Sherman PW, Flaxman SM. Nausea and vomiting of pregnancy in an evolutionary
perspective. Am J Obstet Gynecol. 2002 May. 186(5 Suppl Understanding):S190-7.
[Medline].
9. Creasy RK, Resnik R. Gastrointestinal disease in pregnancy. Creasy RK, Resnik R, eds.
Maternal-Fetal Medicine, Principles and Practice. 5th ed. Philadelphia, Pa: WB Saunders;
2004. 1109-22.
10. Kuscu NK, Koyuncu F. Hyperemesis gravidarum: current concepts and management.
Postgrad Med J. 2002 Feb. 78(916):76-9. [Medline].
11. Goodwin TM, Nwankwo OA, O'Leary LD, et al. The first demonstration that a subset of
women with hyperemesis gravidarum has abnormalities in the vestibuloocular reflex
pathway. Am J Obstet Gynecol. 2008 Oct. 199(4):417.e1-9. [Medline].
12. Rodien P, Jordan N, Lefevre A, et al. Abnormal stimulation of the thyrotrophin receptor
during gestation. Hum Reprod Update. 2004 Mar-Apr. 10(2):95-105. [Medline].
13. Panesar NS, Li CY, Rogers MS. Are thyroid hormones or hCG responsible for
hyperemesis gravidarum? A matched paired study in pregnant Chinese women. Acta
Obstet Gynecol Scand. 2001 Jun. 80(6):519-24. [Medline].
14. Murata T, Suzuki S, Takeuchi T, et al. Relation between plasma adenosine and serum
TSH levels in women with hyperemesis gravidarum. Arch Gynecol Obstet. 2006 Mar.
273(6):331-6. [Medline].
15. Leylek OA, Toyaksi M, Erselcan T, et al. Immunologic and biochemical factors in
hyperemesis gravidarum with or without hyperthyroxinemia. Gynecol Obstet Invest.
1999. 47(4):229-34. [Medline].
16. Hershman JM. Human chorionic gonadotropin and the thyroid: hyperemesis gravidarum
and trophoblastic tumors. Thyroid. 1999 Jul. 9(7):653-7. [Medline].
17. Lagiou P, Tamimi R, Mucci LA, et al. Nausea and vomiting in pregnancy in relation to
prolactin, estrogens, and progesterone: a prospective study. Obstet Gynecol. 2003 Apr.
101(4):639-44. [Medline].
18. Koch KL. Gastrointestinal factors in nausea and vomiting of pregnancy. Am J Obstet
Gynecol. 2002 May. 186(5 Suppl Understanding):S198-203. [Medline].
19. Kosus A, Kosus N, Usluogullari B, Hizli D, Namuslu M, Ayyildiz A. Gut satiety
hormones and hyperemesis gravidarum. Arch Gynecol Obstet. 2015 Dec. 292 (6):1225-
30. [Medline].
20. Shekhar S, Diddi G. Liver disease in pregnancy. Taiwan J Obstet Gynecol. 2015 Oct. 54
(5):475-82. [Medline].
21. Ergin M, Cendek BD, Neselioglu S, Avsar AF, Erel O. Dynamic thiol-disulfide
homeostasis in hyperemesis gravidarum. J Perinatol. 2015 Oct. 35 (10):788-92.
[Medline].
22. Jarnfelt-Samsioe A, Eriksson B, Waldenstrom J, et al. Serum bile acids, gamma-
glutamyltransferase and routine liver function tests in emetic and nonemetic pregnancies.
Gynecol Obstet Invest. 1986. 21(4):169-76. [Medline].
23. Ustun Y, Engin-Ustun Y, Dokmeci F, et al. Serum concentrations of lipids and
apolipoproteins in normal and hyperemetic pregnancies. J Matern Fetal Neonatal Med.
2004 May. 15(5):287-90. [Medline].
24. Kocak I, Akcan Y, Ustun C, Demirel C, Cengiz L, Yanik FF. Helicobacter pylori
seropositivity in patients with hyperemesis gravidarum. Int J Gynaecol Obstet. 1999 Sep.
66(3):251-4. [Medline].
25. Lee RH, Pan VL, Wing DA. The prevalence of Helicobacter pylori in the Hispanic
population affected by hyperemesis gravidarum. Am J Obstet Gynecol. 2005 Sep. 193(3
Pt 2):1024-7. [Medline].
26. Black FO. Maternal susceptibility to nausea and vomiting of pregnancy: is the vestibular
system involved?. Am J Obstet Gynecol. 2002 May. 186(5 Suppl Understanding):S204-9.
[Medline].
27. Heinrichs L. Linking olfaction with nausea and vomiting of pregnancy, recurrent
abortion, hyperemesis gravidarum, and migraine headache. Am J Obstet Gynecol. 2002
May. 186(5 Suppl Understanding):S215-9. [Medline].
28. Vikanes A, Skjaerven R, Grjibovski AM, et al. Recurrence of hyperemesis gravidarum
across generations: population based cohort study. BMJ. 2010 Apr 29. 340:c2050.
[Medline]. [Full Text].
29. Zhang Y, Cantor RM, MacGibbon K, et al. Familial aggregation of hyperemesis
gravidarum. Am J Obstet Gynecol. 2011 Mar. 204(3):230.e1-7. [Medline].
30. Kaplan PB, Gucer F, Sayin NC, et al. Maternal serum cytokine levels in women with
hyperemesis gravidarum in the first trimester of pregnancy. Fertil Steril. 2003 Mar.
79(3):498-502. [Medline].
31. Kiyokawa Y, Yoneyama Y. Relationship between adenosine and T-helper 1/T-helper 2
balance in hyperemesis gravidarum. Clin Chim Acta. 2006 Aug. 370(1-2):137-42.
[Medline].
32. Sekizawa A, Sugito Y, Iwasaki M, et al. Cell-free fetal DNA is increased in plasma of
women with hyperemesis gravidarum. Clin Chem. 2001 Dec. 47(12):2164-5. [Medline].
33. Sugito Y, Sekizawa A, Farina A, et al. Relationship between severity of hyperemesis
gravidarum and fetal DNA concentration in maternal plasma. Clin Chem. 2003 Oct.
49(10):1667-9. [Medline].
34. Yoneyama Y, Suzuki S, Sawa R, et al. Plasma adenosine concentrations increase in
women with hyperemesis gravidarum. Clin Chim Acta. 2005 Feb. 352(1-2):75-9.
[Medline].
35. Yoneyama Y, Suzuki S, Sawa R, et al. The T-helper 1/T-helper 2 balance in peripheral
blood of women with hyperemesis gravidarum. Am J Obstet Gynecol. 2002 Dec.
187(6):1631-5. [Medline].
36. Biberoglu EH, Kirbas A, Dirican AO, et al. Alterations in lipid peroxidation and T-cell
function in women with hyperemesis gravidarum. J Obstet Gynaecol. 2015 Sep 14. 1-4.
[Medline].
37. Simpson SW, Goodwin TM, Robins SB, et al. Psychological factors and hyperemesis
gravidarum. J Womens Health Gend Based Med. 2001 Jun. 10(5):471-7. [Medline].
38. Buckwalter JG, Simpson SW. Psychological factors in the etiology and treatment of
severe nausea and vomiting in pregnancy. Am J Obstet Gynecol. 2002 May. 186(5 Suppl
Understanding):S210-4. [Medline].
39. Morrow GR, Roscoe JA, Hickok JT, et al. Nausea and emesis: evidence for a
biobehavioral perspective. Support Care Cancer. 2002 Mar. 10(2):96-105. [Medline].
40. Mitchell-Jones N, Gallos I, Farren J, Tobias A, Bottomley C, Bourne T. Psychological
morbidity associated with hyperemesis gravidarum: a systematic review and meta-
analysis. BJOG. 2017 Jan. 124 (1):20-30. [Medline].
41. Fell DB, Dodds L, Joseph KS, et al. Risk factors for hyperemesis gravidarum requiring
hospital admission during pregnancy. Obstet Gynecol. 2006 Feb. 107(2 Pt 1):277-84.
[Medline].
42. Dodds L, Fell DB, Joseph KS, et al. Outcomes of pregnancies complicated by
hyperemesis gravidarum. Obstet Gynecol. 2006 Feb. 107(2 Pt 1):285-92. [Medline].
43. Fossum S, Vikanes ÅV, Naess Ø, Vos L, Grotmol T, Halvorsen S. Hyperemesis
gravidarum and long-term mortality: a population-based cohort study. BJOG. 2016 Dec
15. [Medline].
44. Boelig RC, Barton SJ, Saccone G, Kelly AJ, Edwards SJ, Berghella V. Interventions for
treating hyperemesis gravidarum. Cochrane Database Syst Rev. 2016 May 11.
CD010607. [Medline].
45. Rosen T, de Veciana M, Miller HS, et al. A randomized controlled trial of nerve
stimulation for relief of nausea and vomiting in pregnancy. Obstet Gynecol. 2003 Jul.
102(1):129-35. [Medline].
46. Borrelli F, Capasso R, Aviello G, et al. Effectiveness and safety of ginger in the treatment
of pregnancy-induced nausea and vomiting. Obstet Gynecol. 2005 Apr. 105(4):849-56.
[Medline].
47. McParlin C, O'Donnell A, Robson SC, Beyer F, Moloney E, Bryant A, et al. Treatments
for Hyperemesis Gravidarum and Nausea and Vomiting in Pregnancy: A Systematic
Review. JAMA. 2016 Oct 4. 316 (13):1392-1401. [Medline].
48. Safari HR, Alsulyman OM, Gherman RB, et al. Experience with oral methylprednisolone
in the treatment of refractory hyperemesis gravidarum. Am J Obstet Gynecol. 1998 May.
178(5):1054-8. [Medline].
49. US Food and Drug Administration. FDA approves Diclegis for pregnant women
experiencing nausea and vomiting. April 8, 2013. Available at
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm347087.htm.
Accessed: April 15, 2013.
50. Lowes R. FDA approves Diclegis as first morning sickness drug in 30 years. Medscape
Medical News. April 9, 2013. Available at
http://www.medscape.com/viewarticle/782212. Accessed: April 15, 2013.
51. Koren G, Clark S, Hankins GD, et al. Effectiveness of delayed-release doxylamine and
pyridoxine for nausea and vomiting of pregnancy: a randomized placebo controlled trial.
Am J Obstet Gynecol. 2010 Dec. 203(6):571.e1-7. [Medline].
52. Koren G, Maltepe C. Preemptive Diclectin therapy for the management of nausea and
vomiting of pregnancy and hyperemesis gravidarum (abstract). ClinicalTrials.gov.
Available at http://clinicaltrials.gov/show/NCT00293644. Accessed: April 10, 2013.
53. Matok I, Gorodischer R, Koren G, Sheiner E, Wiznitzer A, Levy A. The safety of
metoclopramide use in the first trimester of pregnancy. N Engl J Med. 2009 Jun 11.
360(24):2528-35. [Medline].
54. Holmgren C, Aagaard-Tillery KM, Silver RM, et al. Hyperemesis in pregnancy: an
evaluation of treatment strategies with maternal and neonatal outcomes. Am J Obstet
Gynecol. 2008 Jan. 198(1):56.e1-4. [Medline].
55. ACOG. ACOG (American College of Obstetrics and Gynecology) Practice Bulletin:
nausea and vomiting of pregnancy. Obstet Gynecol. 2004 Apr. 103(4):803-14. [Medline].
56. Fejzo MS, Magtira A, Schoenberg FP, et al. Antihistamines and other prognostic factors
for adverse outcome in hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol.
2013 Sep. 170(1):71-6. [Medline].
57. Fox S. Morning sickness: antihistamines linked to poor outcomes. Medscape Medical
News from WebMD. June 14, 2013. Available at
http://www.medscape.com/viewarticle/806282. Accessed: June 19, 2013.
58. Goodwin TM. Nausea and vomiting of pregnancy: an obstetric syndrome. Am J Obstet
Gynecol. 2002 May. 186(5 Suppl Understanding):S184-9. [Medline].
59. Hsu JJ, Clark-Glena R, Nelson DK, et al. Nasogastric enteral feeding in the management
of hyperemesis gravidarum. Obstet Gynecol. 1996 Sep. 88(3):343-6. [Medline].
60. Jarnfelt-Samsioe A, Eriksson B, Mattsson LA, et al. Serum lipids and lipoproteins in
pregnancies associated with emesis gravidarum. Gynecol Endocrinol. 1987 Mar. 1(1):51-
60. [Medline].
61. Larimore WL, Petrie KA. Drug use during pregnancy and lactation. Prim Care. 2000
Mar. 27(1):35-53. [Medline].
62. Scott JR. Medical and surgical complications of pregnancy. Danforth DN, De Saia PJ,
Hammond CB, Scott JR, eds. Danforth's Obstetrics and Gynecology. 10th ed.
Philadelphia, Pa: Lippincott Williams & Wilkins; 2008. 282-6.