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DTB | Management of hyperemesis gravidarum

DTB CME/CPD*
BNF 4.6

Management of hyperemesis gravidarum

Nausea and vomiting in pregnancy are common complaints and vary considerably in duration and severity. Hyperemesis
gravidarum represents the extreme end of the spectrum associated with dehydration and weight loss. As embryonic
organogenesis occurs during the first trimester, pharmacological intervention for any condition during this period poses
a significant clinical dilemma requiring careful assessment of risks and benefits. In the UK, there are no formal national
guidelines for the management of hyperemesis gravidarum. In addition, no high-quality evidence exists for i.v. fluid
and electrolyte replacement in hyperemesis gravidarum, and a Cochrane review on interventions for the treatment of
nausea and vomiting in pregnancy specifically excluded studies on hyperemesis gravidarum.1 In this article, we review
the evidence for the efficacy and safety of different management options for hyperemesis gravidarum.

About hyperemesis gravidarum
Although nausea and vomiting in pregnancy (NVP) is common, affecting
50–75% of pregnant women, hyperemesis gravidarum affects less than 1%.2
The pathophysiology is likely to be multifactorial with hormonal, genetic,
and gastrointestinal factors contributing. 3 Hyperemesis gravidarum is
typically associated with higher levels of human chorionic gonadotrophin,
and its onset and severity mirrors the peak levels of this hormone.
Helicobacter pylori infection is also associated with an increased risk of
hyperemesis gravidarum.4
Diagnosis
Distinguishing hyperemesis gravidarum from NVP is not always easy. Most
differentiating criteria relate to the severity and duration of symptoms.
Hyperemesis gravidarum is characterised by persistent, intractable nausea
and vomiting beginning in the first trimester and associated with a weight
loss >5% of pre-pregnancy weight, dehydration, electrolyte imbalance and
ketosis. 5,6 Diagnosis is by exclusion and other causes of severe nausea
and vomiting such as gastrointestinal conditions (e.g. appendicitis,
cholecystitis, small bowel obstruction, pancreatitis), neurological causes
(e.g. migraine, pseudotumour cerebri, vestibular lesions, tumours of the
central nervous system), metabolic and endocrine disorders (e.g.
thyrotoxicosis, hyperparathyroidism, diabetic ketoacidosis, Addison’s
disease), urinary tract infection, pyelonephritis, antibiotic use or iron
supplements must be excluded. 5,6
Potential Complications
Hyperemesis gravidarum, particularly if severe, has been associated with
fetal growth restriction, pre-term delivery, Wernicke’s encephalopathy due
to thiamine (vitamin B1) deficiency, central pontine myelinolysis due to
hyponatraemia, increased risk of venous thromboembolism (VTE) and
rarely maternal death.7–11 There is an increased risk of recurrence in
subsequent pregnancies; 15% in a woman with a previous episode of
hyperemesis gravidarum compared with 0.7% in a woman with no
prior episode.12
Management principles
There are no published studies comparing outcomes associated with
inpatient or outpatient management of hyperemesis gravidarum. Outpatient
management may have potential benefits in terms of healthcare costs and
maintaining the woman within her family environment. Suggested criteria
for referral to secondary care services include continued nausea and
vomiting associated with an inability to keep down oral antiemetics,
ketonuria or weight loss (>5% body weight) despite oral antiemetics,
or comorbidity. 5
It should be noted that none of the drugs discussed in this article are
licensed for the management of hyperemesis gravidarum. Detailed
prescribing information is available in the British National Formulary
(http://www.bnf.org) and in the summary of product characteristics for
each drug (http://medicines.org.uk/emc).
Fluid and electrolyte replacement
The most important intervention is fluid and electrolyte replacement. Current
management is based on evidence from other conditions associated with
dehydration and electrolyte imbalance. A randomised controlled trial
comparing the use of 5% dextrose and 0.9% sodium chloride with 0.9%
sodium chloride in women with hyperemesis gravidarum showed no
difference after 24 hours in persistent ketonuria, wellbeing, nausea visual
numerical rating scales, vomiting or resolution of electrolyte abnormalities.13
However, glucose containing solutions can precipitate Wernicke’s
encephalopathy in thiamine deficient states,14 and 0.9% sodium chloride is
therefore thought to be preferable. Potassium supplementation is often
necessary and should be tailored to the serum potassium concentration. 3
Thiamine (vitamin B1) supplementation
Thiamine requirements increase during pregnancy to 1.5mg/day.14 Thiamine
supplementation should be given to all pregnant women who have been
vomiting for more than 3 weeks.14 Oral thiamine can be prescribed at a dose
of 100mg daily as thiamine hydrochloride.14 For those unable to tolerate oral
tablets, thiamine can be administered intravenously.
Other considerations
Women are typically advised to eat small frequent bland meals, although
there is no evidence to support this recommendation. 3 Enteral or parenteral
nutrition should only be considered if the woman cannot maintain her weight
due to persistent vomiting and failure to respond to antiemetic therapy.15
Discontinuation of iron supplements may reduce symptoms of NVP.16
The Royal College of Obstetricians and Gynaecologists guideline on
thromboprophylaxis in pregnancy suggests the use of low molecular weight
heparin as the agent of choice for thromboprophylaxis in a pregnant woman ▶
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with three or more current or persisting risk factors that include hyperemesis,
immobility and dehydration.17 VTE prophylaxis should therefore be considered
for women admitted with hyperemesis gravidarum. Women should be
continually assessed for persistence of risk factors to determine the duration
of VTE prophylaxis.
Treatment options
Treatment options include antiemetics; herbal medications such as ginger;
vitamins particularly pyridoxine (vitamin B6); alternative therapies such as
acupressure, acupuncture, progressive muscle relaxation and hypnosis
(trance induction); and corticosteroid therapy. However, for some options
there is very limited published information available and many trials
comparing such interventions are small and have methodological limitations.
Antiemetics
Although antiemetics are the mainstay of therapy for NVP and hyperemesis
gravidarum, there are few studies assessing their safety and efficacy in
hyperemesis gravidarum. Antiemetics that have been used include
antihistamines such as cyclizine, promethazine, doxylaminei and
dimenhydrinatei; phenothiazines such as prochloperazine, chlorpromazine and
pherphenazine; dopamine antagonists such as metoclopramide and
domperidone; and more recently the 5HT3-receptor anatagonist ondansetron.18
A randomised controlled trial comparing i.v. metoclopramide (n=73) with i.v.
promethazine (n=76) in women with hyperemesis gravidarum found similar
reductions in nausea and vomiting, and improvements in wellbeing scores,
but less drowsiness (59% vs. 84%, p=0.001), dizziness (34% vs. 71%,
p<0.001), dystonia (6% vs. 19%, p=0.02) and cessation of therapy as a result
of adverse events (0% vs. 9%, p=0.014) with metoclopramide.19
A meta-analysis of 24 studies involving 200,000 women with NVP concluded
that doxylamine-pyridoxine preparations,2 antihistamines and phenothiazines
were safe and effective.20 A more recent analysis has concluded that “the
following classes of medications are, in general, not considered to be
teratogenic: antihistamine blockers, phenothiazines, other dopamine
antagonists and serotonin antagonists”.18 A safe outcome was defined as no
increased risk for congenital malformations in the newborn following first
trimester exposure to the medications.
A randomised placebo-controlled trial in 256 women from Canada found
that delayed release doxylamine combined with pyridoxine (Diclectin—
Duchesnay)ii was more effective at improving symptoms of NVP, as assessed
by the Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) scale
and quality-of-life score, than placebo.21
There is currently paucity of data supporting the superiority of any one
antiemetic over another. In some circumstances hospital specialists may use
combinations of drugs in women who do not respond to a single antiemetic.
In severe hyperemesis gravidarum other routes of administration (i.v.,
intramuscular, buccal or rectal) may be necessary and more effective.
The American College of Obstetricians and Gynecologists recommends i.v.
dimenhydrinate,ii metoclopramide and promethazine as first-line antiemetics
for treating hyperemesis gravidarum.15
Pyridoxine (vitamin B6)
A recent Cochrane review concluded that there is a lack of consistent evidence
that pyridoxine is an effective therapy for NVP.1 No improvement in nausea,
vomiting or rehospitalisation was demonstrated in women with hyperemesis
gravidarum given 20mg pyridoxine orally three times daily in addition to
standard therapy (i.v. fluids+i.v. metoclopramide+oral thiamine; n=48)
compared with the control group given placebo and standard therapy (n=46).22
Ginger
In a small double-blind randomised crossover study, 27 women admitted to
hospital with hyperemesis gravidarum were given capsules containing 250mg
ginger (Zingiber officinale) or placebo (250mg lactose) four times a day for
i Not available as a single drug formulation in the UK.
ii  Not available in the UK.
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DTB | Management of hyperemesis gravidarum
4 days. After a 2-day washout period the women were given the other
treatment for a further 4 days. Hyperemesis relief score (degree of nausea and
vomiting, weight gain and participant-reported symptom relief) improved after
4 days in women taking ginger compared with those taking placebo (p=0.035).23
A systematic review, with four randomised controlled trials meeting the
inclusion criteria, found oral ginger to be significantly more effective than
placebo in three trials and as effective as vitamin B6 in one trial, in reducing
symptoms in NVP.24 A second systematic review analysing benefits of herbal
remedies during pregnancy included 10 randomised controlled trials
comparing ginger with either placebo (five studies), vitamin B6 (four studies)
or dimenhydrinate (one study).25 Ginger was found to be superior to placebo,
and as effective as vitamin B6 and dimenhydrinate, at improving nausea
and vomiting in pregnant women. In a randomised controlled trial in which
70 pregnant women with nausea during early pregnancy were given
capsules containing either ginger (1g/day) or vitamin B6 (40mg/day), ginger
was found to be better than vitamin B6 at relieving nausea but there was no
difference between the groups in the decrease in the number of episodes of
vomiting.26 According to the authors, ginger was also found to be significantly
superior to placebo and less effective than metoclopramide in a three-armed
randomised double-blind trial including 102 patients with NVP.27 Ginger
biscuits were also found to be significantly better than placebo at reducing
nausea in women with NVP.28
Acupuncture and acupressure
There is limited low quality evidence for acupuncture and acupressure in the
management of hyperemesis gravidarum and methodological issues relating
to the design of the trials makes evaluation difficult. A randomised
single-blind crossover study compared active (deep) versus placebo
(superficial) acupuncture given twice over 2 days in 33 women with
hyperemesis who were receiving intravenous fluid.29 The degree of nausea
was estimated using a visual analogue scale and the daily number of emesis
episodes was documented. Analyses showed that there was statistically
significantly faster reduction of nausea scores and more women stopped
vomiting after active acupuncture than after placebo acupuncture.
A study in 66 women admitted to hospital with hyperemesis gravidarum
compared the use of acupressure (Nei-Guan point) with placebo acupressure
and also included a control group that received conventional intravenous
fluid. 30 The degree of nausea and vomiting was statistically significantly
lower in the acupressure group compared with the placebo and control
groups (p≤0.001).
A more recent systematic review included six randomised controlled trials
(399 patients) examining the effect of acupressure on nausea and vomiting. 31
Indicators of efficacy included self-reported nausea, objective measurement
of emesis, total dose of antiemetic medication and hospital length of stay.
Significantly positive outcomes were reported in five studies, of which two
studies included women with hyperemesis gravidarum (102 patients).
A randomised trial of auricular acupressure did not result in improvement
in NVP compared with a control group. 32
Other therapies
Positive outcomes following hypnosis as a treatment for hyperemesis
gravidarum were reported in all six studies included in a review. 33 Studies
were mainly small case series without control groups, and the review
concluded that the evidence was not sufficient to establish whether hypnosis
is an effective treatment.
A small randomised trial compared antiemetics combined with progressive
muscle relaxation with antiemetic therapy alone in 30 women with
hyperemesis gravidarum. 34 The trial found that the group given
progressive muscle relaxation therapy needed fewer antiemetics and had
a quicker response to treatment. In addition, they had no recurrence as
compared with a 13% recurrence in the control group despite an initial
complete response.
Treatment for gastroesophageal reflux
Symptoms of gastroesophageal reflux disease are common in women with
hyperemesis gravidarum and drugs that reduce gastric acid secretion such
as H2 antagonists and proton pump inhibitors are thought to be safe and
may reduce the severity of nausea and vomiting. 35–37 A safe outcome
was defined as no increased risk of spontaneous abortions, pre-term
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DTB | Management of hyperemesis gravidarum

delivery, small for gestational age babies or congenital malformations with severe hyperemesis gravidarum demonstrated that daily i.v. 300mg
in the newborn. 35 hydrocortisone was superior to i.v. metoclopramide in reducing vomiting and
recurrence.41

Corticosteroids Corticosteroids should not be considered until conventional treatment (i.v.

Case series of women with severe refractory hyperemesis gravidarum have
reported dramatic and rapid improvement with corticosteroids. However,
results of randomised studies are conflicting,38–40 and the largest double-
blind placebo-controlled study of corticosteroid (i.v. methylprednisolone
followed by oral prednisone) failed to show improvement in the primary
outcome of rehospitalisation; both groups also received i.v. fluid,
metoclopramide and promethazine.40 Case selection, and route and dose of
corticosteroid administration, may explain the conflicting results; beneficial
results were observed in more severe cases of hyperemesis gravidarum. A
prospective double-blind study of 40 women admitted to intensive care
fluid replacement and regular antiemetics) has failed. There are no
established guidelines for their use in hyperemesis gravidarum.
Suggested regimes are i.v. or oral methylprednisolone at a dose of 48mg
daily for 3 days,15 or i.v. hydrocortisone at a dose of 100mg twice daily
followed by oral prednisolone 40–50mg daily once clinical improvement
occurs. 5 If no response to therapy is seen at the end of 3 days, it is
common practice to discontinue corticosteroid treatment as response
is unlikely thereafter.42 The regimes suggest that treatment should be
continued in those who respond using the lowest effective dose until
the gestation at which hyperemesis gravidarum would have
resolved spontaneously. 5

Conclusion
Most cases of nausea and vomiting in pregnancy (NVP) are mild, resolving by the 20th week of gestation. Hyperemesis gravidarum, characterised by
persistent nausea and vomiting, weight loss, electrolyte imbalance, dehydration and ketosis can be debilitating and have a significant effect on the
woman’s physical, psychological, social and professional wellbeing. Aetiology is multifactorial and hyperemesis gravidarum can result in both fetal and
life-threatening maternal complications. Evidence from randomised controlled trials in hyperemesis gravidarum is limited and most current treatment
options are largely based on evidence from patients with NVP. Treatment may require hospital admission and fluid and electrolyte replacement.
Antiemetics (antihistamines, phenothiazines, dopamine antagonists) are thought to be safe in pregnancy and form the mainstay of therapy. There is no
clear evidence recommending one antiemetic over another. There is very limited low quality evidence that ginger may be beneficial in hyperemesis
gravidarum. Current evidence suggests little benefit from the routine use of pyridoxine or alternative therapies such as hypnosis, acupressure and
acupuncture, electrical stimulation and progressive muscle relaxation. The effectiveness of corticosteroid therapy is not established; it may be considered
by specialists in severe cases of hyperemesis gravidarum if conventional treatments fail. Thiamine supplements, gastric acid suppression and prophylaxis
for venous thromoboembolism may be considered for women with prolonged vomiting.

[R=randomised controlled trial; M=meta-analysis]

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DOI: 10.1136/dtb.2013.11.0215
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Management of hyperemesis gravidarum

DTB 2013 51: 126-129

doi: 10.1136/dtb.2013.11.0215

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