• O B S T E T R I C S
Hyperemesis Gravidarum
N
ausea and vomiting
in pregnancy are
common phenome-
na, occurring in
approximately 70% of all preg-
nancies.1-4 Hyperemesis gravi-
darum, the extreme end of the
spectrum, is characterised by
severe nausea and intractable vom-
iting. It is a diagnosis of exclusion
when no other organic cause can
be identified.
Various theories have been sug-
gested for its pathogenesis and
aetiology; there is no universal
consensus but it can be a grave
condition for both the mother and
the fetus if it is not recognised and
treated early. Treatment thus
remains non-specific, although
prompt rehydration and correction
of any electrolyte imbalance
remain the cornerstone of success-
ful management. More specific
therapy may be considered if the
patient is not responding to basic
supportive therapy. Hyperemesis
gravidarum tends to be prolonged
and intractable in nature, so ade-
quate counselling and reassurance
are important to alleviate the fear
JOURNAL OF PAEDIATRICS, OBSTETRICS AND GYNAECOLOGY NOV/DEC 2001
•
Yat May Wong, MBCHB, MRCOG;
and anxiety experienced by
patients.
Many therapeutic agents, both
Western and Eastern, have been
proposed with mixed results.5-12
This review will discuss the current
knowledge of the condition, man-
agement strategies, and evidence for
an effect on pregnancy outcome.
EPIDEMIOLOGY
The incidence of hyperemesis
gravidarum has been reported as 5
per 1000 pregnancies5 with a
reported range of 1 to 20 per
1000.13 There is no clear dividing
line that dictates when the ‘normal’
nausea and vomiting of pregnancy
(morning sickness) becomes hyper-
emesis gravidarum. The condition
is poorly understood, a fact reflect-
ed by the available studies that are
generally small and non-ran-
domised. The low number of
patients obtained from these stud-
ies reflects a lack of universal
definition and diagnosis of this
condition; most studies are either
epidemiological or case reports.
Protective factors that have
Vallipuram Sivanesaratnam, MBBS, FRCOG
been proposed to reduce the inci-
dence of hyperemesis gravidarum
include advanced maternal age and
cigarette smoking; a high body
weight, nulliparity and twin preg-
nancy have been reported to be
associated with an increased risk.14
CLINICAL PRESENTATION
Hyperemesis gravidarum tends to
begin in the first trimester of preg-
nancy and resolves by 20 weeks of
gestation.15 The nausea is generally
severe and the vomiting intractable.
Dehydration is not uncommon and
hospitalisation is necessary as
ketosis and electrolyte imbalance
may occur. Patients may report
weight loss, often more than 5% of
body weight; excessive salivation
may also occur. Laboratory find-
ings include ketosis with increased
urinary specific gravity, raised
blood urea nitrogen and haema-
tocrit, and decreased serum sodi-
um, potassium and chloride.
DIFFERENTIAL DIAGNOSES
Differential diagnoses include gas-
27
 H Y P E R E M E S I S G R AV I D A R U M • OBSTETRICS •

troparesis in diabetes mellitus, Hyperthyroidism Transient hyperthyroidism in

peptic ulcer, liver dysfunction, Hyperthyroidism, usually transient hyperemesis gravidarum can pose
hyperthyroidism, multiple preg- and self-limiting, has been pro- a management dilemma for the
nancy, renal dysfunction, hypercal- posed as a factor in hyperemesis attending physician as it can be dif-
caemia, hyperparathyroidism, mo- gravidarum.20-28 HCG has been sug- ficult to differentiate from Grave’s
lar pregnancy and psychological gested as a cause for this transient disease. The absence of anti-thy-
causes.15 rise in thyroid hormone levels.17-19,27 roid antibodies with no pre-gesta-
HCG is homologous to thyroid tional history of hyperthyroidism
AETIOLOGY stimulating hormone (TSH) and will favour transient hyperthy-
acts as a weak TSH agonist.19 HCG roidism rather than Grave’s dis-
The exact aetiology and patho- therefore increases the serum level ease. Recognition of the transient
physiology of hyperemesis gravi- of both free and total tri-iodothy- and self-limiting nature of hyper-
darum is unknown. (Table 1) ronine (T3) and thyroxine (T4). At thyroidism in such patients can
Oestrogen may play a role; a the same time, the serum level of avoid unnecessary treatment with
decreased level of oestrogen has TSH is generally reduced, presum- anti-thyroid drugs.28
been associated with a reduced ably because of the negative feed-
incidence of nausea and vomiting back effect of T3 and T4 on the Helicobacter pylori
in pregnancy.1 Consequently, the pituitary secretion of TSH. It is Helicobacter pylori is a gram-nega-
absence of nausea and vomiting therefore not surprising that hyper- tive bacilli that has been associated
may be a clinical marker for a fail- emesis gravidarum is more com- with the development of peptic
ing pregnancy. Human chorionic mon in pregnancies with high ulcer disease.29-30 Patients generally
gonadotropin (HCG) is also HCG levels, eg. gestational tro- present with nausea, vomiting and
thought to play a role in the aetiol- phoblastic disease and multiple heartburn, all of which are com-
ogy of hyperemesis gravidarum.16-19 pregnancy.17-18 mon symptoms in hyperemesis
gravidarum. H pylori infection has
been found in cases of persistent
Table 1. Postulated Aetiology of Hyperemesis Gravidarum
vomiting in pregnancy that has not
1. Hyperthyroidism responded to supportive treat-
- most probably because of the thyrotropic action of human chorionic ment.30 Infection can be diagnosed
gonadotrophin (HCG).
using non-invasive and invasive
2. Helicobacter pylori (H pylori) techniques. In patients who have
- worth checking for this organism in patients who are resistant to been previously infected with H
conservative treatment.
pylori and remained untreated,
3. Serotonin serological testing is the cheapest
- still awaiting larger studies to confirm its role in hyperemesis gravidarum.
method available. However, the
4. Liver dysfunction test is not so reliable when used to
- abnormal liver function is not consistently seen in patients with
confirm eradication. IgG serology
hyperemesis gravidarum.
testing has a 99% sensitivity and
5. Psychological 91% specificity.29,31-34 Serial check-
- oldest theory in the aetiology of hyperemesis gravidarum, but important to
exclude. ing of IgG antibodies post-treat-
ment is not recommended as up to

28 JOURNAL OF PAEDIATRICS, OBSTETRICS AND GYNAECOLOGY NOV/DEC 2001

 H Y P E R E M E S I S G R AV I D A R U M
72% of patients remain seroposi-
tive for 3.5 years after being cured.
The urea breath test has a sensi-
tivity of 95% and a specificity of
95%, with results available in 24
to 48 hours.30,35 It may be used to
confirm initial infection but is
more reliable when used to con-
firm cure. Serology and the urease
breath test are the most widely
used non-invasive tests.
Endoscopic histological diagno-
sis should be reserved for those
with a negative urea breath test, of
which 10% are false negative.30
Serotonin
Serotonin (5HT) receptors are
prevalent in the central nervous
system and in the gut,36 and play a
role in the induction of emesis;
5HT3 antagonists have been used
as antiemetics in cancer chemother-
apy.37 However, hyperemesis gravi-
darum has not been found to be
associated with an increased sero-
tonin secretion.38 Larger studies are
necessary before the role of sero-
tonin can be confirmed or disputed.
Liver dysfunction
Although abnormal liver function
has been reported in patients with
hyperemesis gravidarum39, consis-
tently abnormal test results are not
always seen.40
Psychological
This is one of the oldest theories
postulated in the pathogenesis of
hyperemesis gravidarum. Fair-
JOURNAL OF PAEDIATRICS, OBSTETRICS AND GYNAECOLOGY NOV/DEC 2001
• OBSTETRICS •
Table 2. Treatment of Hyperemesis Gravidarum
1. Supportive
- most important. Early recognition of the problem with adequate and
prompt rehydration is essential. Withhold oral feeding until vomiting is
under control.
2. Anti-emetics
- parenteral anti-emetics during the initial stage might be necessary.
3. Steroids
- oral or intravenous steroids may be useful in severe prolonged vomiting.
4. Anti-thyroid drugs
- their role is unclear and unproven as hyperthyroidism is transient in nature.
5. Vitamins and nutritional supplements
- vitamin B6 (pyridoxine) may be of use;
- the role of ACTH is still not proven.
6. Ginger
- uncertain role in the management of hyperemesis gravidarum.
7. Acupressure
- uncertain role.
8. Oral antibiotic and H2 proton pump blocker
- may have a role in intractable vomiting if H pylori is present.
9. Psychotherapy
- might be necessary if there is clinical suspicion of a psychological problem.
weather13 first reported this theory leading to electrolyte imbalance
in 1968; a variation of this theory and ultimately, maternal death.
was published in 1988.41 La Ferla42 Wernicke’s encephalopathy may
has recently suggested that hyper- arise and is generally precipitated
emesis gravidarum is primarily by the administration of glucose
psychological and behavioural in without simultaneous administra-
origin. Unfortunately, all these tion of thiamine.43-44 Liver and
studies of psychological factors are renal abnormalities may also occur
limited by their small sample size with prolonged vomiting. Persis-
and lack of a control group. tent vomiting can also lead to the
depletion of maternal nutrient
COMPLICATIONS stores and may adversely affect the
fetus if left untreated.
Complications of hyperemesis
gravidarum ensue if the condition TREATMENT
is not recognised and managed
promptly. Dehydration with keto- Treatment is a challenge and
sis will worsen if vomiting persists, includes both pharmacological and
29
 H Y P E R E M E S I S G R AV I D A R U M
non-pharmacological therapies.
(Table 2) Early diagnosis with
prompt hospital admission is nec-
essary to minimise complications.
Nutritional deficiencies have
been recorded in patients with
persistent prolonged vomiting.43
Prolonged thiamine deficiency may
lead to acute Wernicke’s encepha-
lopathy.43-44 Nasogastric feeding
with nutritional supplements may
be necessary in severe cases.45
Supportive Treatment
Intravenous rehydration and cor-
rection of any electrolyte imbal-
ance is vital.15 Oral feeding should
be stopped to allow the gut to rest
and parenteral anti-emetics pre-
scribed early on. Most patients will
respond to this therapy; an oral
diet may be gradually reintroduced
when the vomiting is under con-
trol, preferably starting with low
fat foods.46
A protracted hospital stay and
multiple hospital re-admissions are
common. A minority of patients
may elect to terminate the preg-
nancy as a treatment of symp-
toms.47 Hence, psychological, med-
ical and supportive therapies are
essential components of manage-
ment.
Anti-emetics
Metoclopramide and prochlorper-
azine are common first-line anti-
emetics. They should be adminis-
tered regularly in the first instance
and by a parenteral route. When
30
the patient is able to tolerate an
oral diet, oral anti-emetics can be
prescribed. Caution has to be exer-
cised as extrapyramidal symptoms
may occur with both these drugs
because of their anticholinergic
effects.
Droperidol, a dopamine antag-
onist, given by intravenous infusion
together with diphenhydramine, an
antihistamine, have been used with
some success in the management of
hyperemesis gravidarum that has
not responded to conventional
anti-emetics.9 The sedative and
anticholinergic effects of diphenhy-
dramine help counteract the fre-
quency of anxiety and extrapyra-
midal symptoms. However, con-
genital fetal anomalies have been
noted in a minority of patients; it is
unclear if the abnormalities were
due to a drug effect. Until larger
studies are available, this regimen
cannot be recommended as a rou-
tine management for hyperemesis
gravidarum.
Intravenous ondansetron, a
serotonin antagonist has also been
tried.8 It has been beneficial in the
treatment of chemotherapy-
induced nausea and vomiting.37
However, a preliminary study com-
paring ondansetron with prome-
thazine showed no benefit. As it is
an expensive drug, its routine use
in the management of hyperemesis
gravidarum cannot be justified.
Steroids
The successful use of steroids, both
JOURNAL OF PAEDIATRICS, OBSTETRICS AND GYNAECOLOGY NOV/DEC 2001
• OBSTETRICS •
intravenous and oral, in severe
hyperemesis gravidarum has been
reported.5-7 The exact mechanism
by which steroids suppress vomit-
ing is unclear; it may be via a direct
effect upon the vomiting centre in
the brain.7
Steroid therapy may be used in
these patients when other causes of
vomiting have been excluded,
when vomiting has persisted for
more than 4 weeks and is associat-
ed with dehydration, and when the
risks and benefits of treatment
have been clearly explained to the
patient. As there is mixed data con-
cerning the safety of steroids in
pregnancy, both to the mother
and fetus,48-50 the use of steroids
should be confined to refractory
cases.
Anti-thyroid drugs
As hyperthyroidism has been noted
in patients with hyperemesis gravi-
darum, it is tempting to prescribe
anti-thyroid medication in an
attempt to suppress symptoms.
However, the role of anti-thyroid
drugs in management remains
unclear. A short course of anti-thy-
roid drugs may be beneficial and
can be discontinued once the vom-
iting has settled.51 Other researchers
however, have reported no benefits
with anti-thyroid drugs as the
hyperthyroidism is transient and
self limiting.28,52 Until more evi-
dence is available, anti-thyroid
drugs should not be routinely pre-
scribed.
 H Y P E R E M E S I S G R AV I D A R U M
Vitamins and Nutritional
Supplements
Vitamin B6 (pyridoxine) has been
shown to be effective in the man-
agement of nausea in early preg-
nancy.10 However, its use in the
management of intractable vomit-
ing is unknown. Adrenocorti-
cotropic hormone (ACTH) has
been used in the management of
hyperemesis gravidarum, but is not
superior to placebo; it is not rou-
tinely recommended as a treatment
for hyperemesis gravidarum.10
Ginger
Ginger is a common food in Asian
countries and has been used as an
anti-emetic in early pregnancy.
Fischer-Rasmussen12 reported that
powdered root ginger may be an
effective treatment for hyperemesis
gravidarum, possibly due to its
aromatic, carminative and absor-
bent properties.
Although ginger has been
proven as an effective anti-emetic53,
there are known possible adverse
effects that can arise from its use in
pregnancy; ginger is a potential
emmenagogue, a traditional reme-
dy that ‘brings on a period’.11
However, as emmenagogues are
not strong enough to act as an
abortifacient, caution rather than
contraindication is advised when
ginger is used in pregnancy.
Ginger is also a potent throm-
boxane synthetase inhibitor54 that
may theoretically increase the risk
of bleeding. An effect of ginger on
JOURNAL OF PAEDIATRICS, OBSTETRICS AND GYNAECOLOGY NOV/DEC 2001
testosterone receptor binding in
the fetus has been reported and
may affect sex steroid differentia-
tion in the fetus.55 Therefore, it is
currently not advisable to recom-
mend the routine use of ginger as
an anti-emetic in pregnancy until
larger trials have further assessed
its side effect profile.
H pylori Treatment
H pylori testing has been recom-
mended in the presence of unremit-
ting vomiting.29-30 Good results
have been reported following treat-
ment with an oral antibiotic and
H2 proton pump inhibitor/H2
antagonist.30,56 Screening for H
pylori is thus beneficial.
Acupressure
Trials of P6 acupressure at the
Neiguan point have been assessed
in the Cochrane database but
showed equivocal results as a
treatment of nausea in pregnan-
cy.10 The available trials are small
and of poor quality. It is difficult to
confidently judge its benefits at
present.
Psychotherapy
Psychological factors have long
been proposed in persistent severe
vomiting in pregnancy.13,41-42 The
patient’s social and family history
should be further explored if a psy-
chological/psychiatric problem is
suspected. Psychotherapy and
behavioural therapy have been
reported to be effective.57-58
• OBSTETRICS •
OUTCOME OF PREGNANCY
The presence of nausea and vomit-
ing in pregnancy has been associat-
ed with a favourable outcome in
pregnancy, such as decreased risk
of miscarriage and perinatal
death.1,3,14 Rapidly increasing oes-
trogen was thought to play a role
in causing these symptoms.4,59-60
Some studies have shown a neg-
ative association between nausea
and vomiting in pregnancy and
adverse pregnancy outcome, for
example, increased risk for fetal
anomalies61 and low birthweight.62
Others have found no such associ-
ations.13,63 These inconsistent find-
ings can be explained by popula-
tion differences, differences in the
methodology used, sample size and
variation in the classification of
pregnancy outcome measures.
Ultimately, the effect of nausea and
vomiting in pregnancy on the out-
come of pregnancy remains a mat-
ter for debate.
CONCLUSION
Hyperemesis gravidarum is a diag-
nosis of exclusion. It carries a risk
of maternal and fetal death if not
diagnosed and treated promptly.
However, management remains a
challenge to the attending clinician
as its aetiology and pathogenesis
are still unclear. Supportive therapy
remains the cornerstone of success-
ful management. Various pharma-
cological and non-pharmacological
31
 H Y P E R E M E S I S G R AV I D A R U M
therapies have been found to be
useful, but the results of these stud-
ies must be cautiously interpreted.
A multidisciplinary approach
might be necessary in certain cases
to ensure an optimal outcome for
these patients.
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About the Authors
Dr Wong is a Lecturer and Dr Sivanesaratnam is a
Professor and Head of Department. Both are in
the Department of Obstetrics and Gynaecology
at the University Malaya Medical Centre, Kuala
Lumpur, Malaysia.

Journal of Paediatrics, Obstetrics & Gynaecology

Call for Papers

JPOG welcomes papers from doctors anywhere in Asia, on all aspects of paediatrics, obstetrics and gynaecology,
with a focus on therapeutics and patient management. Our criteria for acceptance are simple: quality and
relevance to Asia. All articles undergo an independent peer-review process.
For more information, please contact:

The Editor, JPOG,

35/F, Two Chinachem Exchange Square, 338 King’s Road, North Point, Hong Kong.
Tel: (852) 2559 5888, Fax: (852) 2559 6910, E-mail: nrodrig@medimedia.com.hk

JOURNAL OF PAEDIATRICS, OBSTETRICS AND GYNAECOLOGY NOV/DEC 2001 33