REVIEW
The Obstetrician
& Gynaecologist
2003;5:204–7
Keywords
antiemetic,
hyperemesis
gravidarum,
pregnancy, vomiting.
Author details
Anne-Marie C Neill MRCOG,
Specialist Registrar, Obstetrics,
West Suffolk Hospital, Bury St
Edmund’s, Suffolk IP33 2QZ, UK.
Catherine Nelson-Piercy MA
FRCP, Consultant Obstetric
Physician, Guy’s & St Thomas’
Hospitals Trust and Whipps Cross
Hospital, 9th floor, Directorate
Office, New Guy’s House, Guy’s
Hospital, St Thomas’ Street,
London SE1 9RT, UK.
email: catherine.nelson-
piercy@gstt.sthames.nhs.uk
(corresponding author)
204
Hyperemesis gravidarum
Anne-Marie Neill, Catherine Nelson-Piercy
Nausea and vomiting in early pregnancy are common; however, in
some cases symptoms can persist, leading to maternal weight loss.
This condition is referred to as hyperemesis gravidarum (HG).
Treatment requires recognition, admission to hospital and appropriate
rehydration. All practitioners, including those managing low-risk
pregnancies, should be aware of the complications associated with
HG. To avoid substandard care a protocol for management should be
available in all obstetric units.
Introduction Investigations
Hyperemesis gravidarum (HG) is defined as Investigation may show hyponatraemia,
persistent vomiting in pregnancy, which causes hypokalaemia and low serum urea. The
weight loss (more than 5% of body mass) and haematocrit may be raised and a metabolic
ketosis. In severe cases, if inadequately or hypochloraemic alkalosis may be seen unless the
inappropriately treated hyperemesis may cause condition is severe, in which case acidaemia may
Wernicke’s encephalopathy, central pontine be encountered. Abnormal liver function tests
myelinolysis and maternal death.1 Moreover, are found in up to 50% of women.4 The usual
infants of mothers with severe HG have a higher abnormalities are elevated serum levels of
incidence of intrauterine growth restriction and aminotransferase (50–200 u/l) and raised
are significantly smaller at birth.2 HG affects 1% bilirubin; frank jaundice is rare.5 Urinalysis
of pregnant women. invariably shows an increased specific gravity and
significant ketonuria. Urine microscopy and
culture should be performed to exclude urinary
Pathophysiology tract infection. A pelvic ultrasound scan is
The pathophysiology of hyperemesis is still important to exclude molar or multiple
poorly understood. Various hormonal, pregnancy.
mechanical and psychological factors have been
implicated. The temporal relationship between
Gestational thyrotoxicosis
the level of human chorionic gonadotrophin
(hCG) (peaking between 6–12 weeks) and Biochemical evidence of hyperthyroidism is
severity of vomiting suggest hCG may have a common (found in about 60% of women with
causative role. Moreover, conditions associated HG) and self-limiting. The typical findings are
with high levels of hCG, such as multiple raised serum levels of free thyroxine (T4) and
pregnancy and hydatidiform moles, are suppressed thyroid stimulating hormone (TSH).6
associated with hyperemesis. Interestingly, The reason for increased levels of thyroid
women with HG give birth to a higher hormones in HG is largely unknown. It may be
proportion of female infants.3 related to dietary factors, in particular carbo-
hydrate deficiency.7 In women with HG, T4 is
converted to reverse tri-iodothyronine (rT3) in
Clinical features the peripheral tissues.8 The shift to rT3 is
At least 50% of women experience nausea and potentially useful because it is physiologically
vomiting in the first trimester of pregnancy. inactive and as a result the metabolic rate is
Symptoms usually begin between weeks five to stimulated to a lesser extent and energy stores are
six and peak severity is around week 11. In 90% conserved.
of women these symptoms have resolved by
week 16. Hyperemesis is diagnosed when nausea The value of routine assessment of thyroid
and vomiting become so severe that dehydration function in all women with HG is questionable
and weight loss occur. There may be ptyalism as clinical hyperthyroidism does not occur and
(inability to swallow saliva) and spitting.Vomiting treatment is not required.9 However, thyroid
may persist throughout pregnancy. The signs of function tests provide a useful index of severity
dehydration, tachycardia and postural hypo- of HG, which correlates with the degree of
tension are often present. biochemical hyperthyroidism.7 Women with HG
© 2003 Royal College of Obstetricians and Gynaecologists
and abnormal thyroid function usually require
longer hospitalisation to avoid readmission.
Resolution of biochemical hyperthyroidism
usually occurs as vomiting settles. Gestational
thyrotoxicosis is found more often in women of
Asian origin (from Bangladesh, India or
Pakistan) than in women of European origin.10
On rare occasions Graves’ disease may present for
the first time in early pregnancy and may cause
vomiting. Therefore, in women found to have
biochemical hyperthyroidism a careful history
and examination for clinical evidence of
thyrotoxicosis is required. Clinicians should be
particularly alert to symptoms predating the
pregnancy. Useful clinical signs of thyrotoxicosis
include lid lag, onycholysis and failure of
tachycardia to settle with Valsalva manoeuvre.
Diagnosis
Hyperemesis is a diagnosis of exclusion. Onset is
always in the first trimester, usually weeks six to
eight. Abdominal pain is not a prominent
symptom. Other causes of vomiting, such as
urinary tract infection, should be excluded
(Table 1). Hyperemesis tends to recur, so a
previous history makes the diagnosis more likely.
It is more common in women with a past history
of eating disorder.
Table 1. Differential diagnosis of hyperemesis
gravidarum
Infection Urinary tract infection
Hepatitis
Drug induced Iron supplementation
Antibiotics
Metabolic Thyrotoxicosis
Hyperparathyroidism/hypercalcaemia
Diabetic ketoacidosis
Uraemia
Addison’s disease
Gastrointestinal Appendicitis
Cholecystitis
Small bowel obstruction
Pancreatitis
Complications
Maternal
Persistent vomiting and resultant malnutrition
may cause serious maternal morbidity. It is
associated with Mallory–Weiss tears of the
oesophagus and haematemesis, weight loss
(which may be profound, 10–20% of body
weight) and muscle wasting and consequent
weakness. Inadequate nutrition leading to
thiamine (vitamin B1) deficiency may cause
Wernicke’s encephalopathy.11 This syndrome is
© 2003 Royal College of Obstetricians and Gynaecologists
characterised by diplopia, abnormal ocular REVIEW
movements, ataxia and confusion. If thiamine is
The Obstetrician
deficient, intravenous dextrose or glucose may
& Gynaecologist
precipitate Wernicke’s encephalopathy.Thiamine
replacement may improve the symptoms of
2003;5:204–7
Wernicke’s but residual impairment is not
uncommon. If retrograde amnesia, impaired
ability to learn and confabulation (Korsakoff ’s
psychosis) have supervened, the recovery rate is
only about 50%. Hyponatraemia (plasma sodium
<120 mmol/l) causes lethargy, seizures and
respiratory arrest. Both severe hyponatraemia
and particularly its rapid reversal may precipitate
central pontine myelinolysis.12 This is character-
ised by spastic quadraparesis, pseudobulbar palsy
and impaired consciousness. Other vitamin
deficiencies occur in hyperemesis, including
cyanocobalamin (B12) and pyridoxine (B6)
causing anaemia and peripheral neuropathy.
Fetal
Infants of mothers with severe hyperemesis
associated with abnormal biochemistry have
lower birthweights compared with infants of
mother with mild hyperemesis.13 Hyperemesis
causing Wernicke’s encephalopathy is associated
with fetal death in 40% of cases.
Management
The usual natural remedies for vomiting in
pregnancy include rest, small carbohydrate meals
that should be eaten when symptoms are least
severe and carbonated drinks. If these measures
do not suffice and hyperemesis develops, active
intervention becomes necessary.
Any pregnant woman, including those with HG,
with prolonged dehydration or bed rest should
receive thromboprophylaxis (e.g. enoxaparin
40 mg/daily) and wear thromboembolic deter-
rent stockings.
Admission and rehydration
Any woman unable to maintain adequate
hydration should be admitted to hospital. On
admission the weight, pulse and lying and
standing blood pressure should be recorded.
Drugs that may cause nausea and vomiting, for
example iron supplements, should be temp-
orarily discontinued. The first-line treatment of
HG includes intravenous rehydration with
normal saline (sodium chloride 0.9%,
150 mmol/l Na) or Hartmann’s solution (sodium
chloride 0.6 %, 131 mmol/l Na). Double-
strength saline solution should be avoided even
in cases of severe hyponatraemia, as rapid
correction of sodium depletion may cause
205
 REVIEW central pontine myelinolysis. Potassium chloride
is usually required with each bag of saline,
The Obstetrician
particularly if there is continued vomiting.
& Gynaecologist
Solutions containing dextrose should be avoided
(e.g. dextrose saline) because they do not contain
2003;5:204–7
enough sodium and may precipitate Wernicke’s
encephalopathy (see above). Fluid and electrolyte
regimens must be adapted daily and titrated
against daily measurements of serum sodium and
potassium.
Thiamine therapy
Routine thiamine supplementation is advisable
for all women admitted with HG to prevent
Wernicke’s encephalopathy. If the woman is able
to tolerate tablets, thiamine can be given as
thiamine hydrochloride tablets 25–50 mg three
times daily. If intravenous treatment is required,
this is given as thiamine 100 mg diluted in
100 ml of normal saline and infused over 30–60
minutes. The intravenous preparation is only
required weekly. Treatment doses of thiamine in
established Wernicke’s are much larger.
Antiemetics
Antiemetics should be offered to women whose
condition does not improve after correction of
electrolyte imbalance and rehydration; these may
be required on a regular basis. Possible regimens
for antiemetic use are suggested in Table 2.
Phenothiazines can cause drowsiness, extrapyra-
midal effects and oculogyric crisis (the latter may
also occur with metoclopramide). Emergency
treatment for oculogyric crisis and extra-
pyramidal effects is procyclidine at a dose of
5 mg by either an intramuscular or intravenous
route.There is no reported increased teratogenic
risk with standard antiemetic drugs.The selective
serotonin (5HT3) receptor antagonist ondan-
setron is effective in some women with HG.
Safety data are still being collected and routine
prescribing is not recommended. Histamine
Table 2. Antiemetic regimes for the treatment of hyperemesis gravidarum
Medication Dosage
cyclizine 50 mg three times a day
promethazine 25 mg once a day at bedtime
prochlorperazine 5 mg three times a day
12.5 mg three times a day
metoclopramide 10 mg three times a day
domperidone 10 mg four times a day
30–60 mg four times a day
chlorpromazine 10–25 mg three times a day
25 mg three times a day
206
© 2003 Royal College of Obstetricians and Gynaecologists
receptor blockers (ranitidine) and the proton
pump inhibitor omeprazole have been used
successfully.
Psychological support
Emotional support with frequent reassurance
and encouragement from nursing and medical
staff is a vital part of management. Knowledge
that symptoms will improve during the preg-
nancy is helpful in itself. Psychotherapy,
hypnotherapy and behavioural therapy have
been reported to contribute to the treatment of
hyperemesis.14
Day-care management of HG
In some countries practice nurses routinely
manage HG at home.15 Day-care management is
not standard practice in the UK but it may be
offered if a woman is keen to avoid hospital
admission. An appropriate treatment regimen is
10 mg of intravenous metoclopramide followed
by two litres of intravenous normal saline
solution given over four hours, 20 mmol/l
potassium chloride should be added to each litre
bag of saline. The investigations and medical
involvement follow the protocol for inpatient
care. If symptoms persist, home administration of
subcutaneous metoclopramide is helpful.16 For
some women admission to hospital may still be
unavoidable.
Alternative therapies
Attempts to avoid conventional pharmacological
agents in pregnancy have prompted studies
investigating the efficacy of alternative therapies.
Ginger taken in quantities of 1 g/day for four
days has been shown to significantly reduce
nausea and vomiting compared with a placebo.17
Pyridoxine (vitamin B6) may be useful for severe
nausea, although it is less effective in preventing
vomiting.18 In addition, there is evidence
Route of administration
oral, intramuscular or intravenous
oral
oral or rectal
intramuscular
oral, intramuscular or subcutaneous
oral
rectal
oral
intramuscular
suggesting that electrical stimulation at the P6
acupuncture site may improve symptoms of
nausea and vomiting and increase weight gain.19
Severe hyperemesis
The majority of women with HG improve
following rehydration and antiemetic therapy.
Symptoms may persist if antiemetics have not
been given on a regular basis or discharge to
home is premature. In some women vomiting
may continue beyond 20 weeks and it is
important not to discount the diagnosis of HG
because of advanced gestational age.
Severe HG, refractory to conventional
management is a disabling condition associated
with multiple admissions to hospital, time away
from the family and psychological morbidity. It is
difficult to treat and in extreme cases a woman
may request termination of pregnancy. In women
with severe HG20 there are data suggesting that
corticosteroid therapy may produce a dramatic
and rapid improvement.21,22 An initial regimen of
hydrocortisone 100 mg twice a day followed by
40 mg prednisolone daily is recommended.
Often the prednisolone has to be continued for
many weeks and in extreme cases until delivery. It
is usually possible to lower the dose of
prednisolone to a maintenance dose of between 5
to 10 mg/daily by 20 weeks of gestation.
Screening for the complications of steroid
treatment in pregnancy, particularly urinary tract REVIEW
infection and gestational diabetes is necessary
The Obstetrician
when prescribing long-term therapy. Predniso-
& Gynaecologist
lone is metabolised by the placenta and therefore
placental transfer is slow. The concentration of
2003;5:204–7
active compound in fetal blood is low (10% of
that in the mother) and adverse fetal effects have
not been reported.
In some women total parenteral nutrition may
be life saving. It has also been shown to produce
a rapid therapeutic effect.23 Metabolic and
infectious complications are a risk, including line
sepsis, bacterial endocarditis and pneumonia; so a
strict protocol with careful monitoring is
necessary. In view of the associated risks,
treatment with total parenteral nutrition is not
recommended until optimal rehydration,
antiemetic therapy and a trial of corticosteroids
and/or ondansetron have failed to result in
improvement.
Conclusion
Hyperemesis is a potentially life-threatening
complication of pregnancy. All practitioners
caring for pregnant women should be familiar
with the indications for hospital referral. A
protocol for the management of HG should be
available in all units to ensure accurate recog-
nition, fluid, electrolyte and vitamin replacement
and pharmacological treatment. ■

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