Review

Hyperemesis gravidarum:
pathogenesis and the use of
antiemetic agents
1. Introduction Olaleye Sanu & Ronald F Lamont†
†
2. Pathogenesis of hyperemesis Wayne State University/Hutzel Hospital, Department of Obstetrics and Gynecology, Detroit,
gravidarum Michigan, USA
3. Antiemetics Introduction: Nausea and vomiting in pregnancy remains the most common
4. Conclusion cause of hospitalization in the first half of pregnancy. Although the exact
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Connecticut on 10/28/14

5. Expert opinion cause is largely unknown, an interaction of genetic, biological and psycholog-
ical factors is plausible. An endocrine trigger for hyperemesis has been linked
with both ovarian and placental hormones, but this association requires fur-
ther clarification. The use of type-3 serotonin receptor antagonists is increas-
ing but as yet there are no convincing data to demonstrate their superiority
over the other antiemetics.
Areas covered: A computerized search was conducted using PubMed,
Embase, Cinahl, Lilacs, ISI Web of Science, the Cochrane Central Register of
Controlled Trials (all from inception or 1960 to October 2010), and Research
Registries of ongoing trials. The key words used were nausea, vomiting,
emesis, hyperemesis gravidarum, morning sickness, pregnancy, pregnancy
For personal use only.

complications, treatment, efficacy, effectiveness, antiemetics, safety

and teratogenesis.
Expert opinion: The precise mechanism underlying hyperemesis gravidarum
remains unclear, but appears to be multifactorial. As yet there is no evidence
that any antiemetic class is superior to another with respect to effectiveness.

Keywords: antiemetics, benefit, effectiveness, hyperemesis gravidarum, management,

pathogenesis, safety

Expert Opin. Pharmacother. (2011) 12(5):737-748

1. Introduction

In contrast to simple nausea and vomiting of pregnancy (NVP), hyperemesis grav-

idarum (HG) is defined as intractable nausea and vomiting during pregnancy, and
often -- but not universally -- accompanied by disturbances of serum electrolytes and
a moderate degree of ketonuria, which requires hospitalization. HG is the most
common cause of hospitalization in the first half pregnancy and the cost of care,
for hospitalization alone, is more than $500 million US annually [1]. Although
maternal deaths due to HG are now rare, failure to administer the appropriate inter-
ventions can be fatal [2]. The reduction in maternal deaths from HG is probably a
reflection of better understanding of how to treat women with this condition. Other
factors that may contribute to reduction in maternal deaths include increased accep-
tance of termination of pregnancy (TOP) and elective preterm delivery, although
many aspects of the condition require further investigation.
Simple NVP is common and can occur in 70 -- 80% of women [3]; two studies
from the Swedish birth registry reported HG prevalence of 3 -- 8/1000 deliveries [4,5].
The exact cause of HG is also unknown but low maternal age (< 20 years),

10.1517/14656566.2010.537655 © 2011 Informa UK, Ltd. ISSN 1465-6566 737

All rights reserved: reproduction in whole or in part not permitted
 Hyperemesis gravidarum: pathogenesis and the use of antiemetic agents
Article highlights.
. Nausea and vomiting in pregnancy remains the
commonest cause of hospitalization in the first half of
pregnancy, and the exact cause remain
largely unknown.
.
A link between genetic, ovarian, placental, and
neurobehavioural factors is possible in the aetiology of
hyperemesis gravidarum.
. There is increasing use of type-3 serotonin receptor
antagonists, but as yet there are no convincing data to
demonstrate their superiority over other antiemetics.
. Based on available evidence with respect to safety and
effectiveness of medications, treatment algorithm for
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Connecticut on 10/28/14
nausea and vomiting of pregnancy has been developed.
. Further research on the genetics and epidemiology of
hyperemesis gravidarum may yield more information
about how women with hyperemesis should
be managed.
This box summarizes key points contained in the article.
nulliparity, multiple pregnancy, lower educational attainment
and increased fetal female: male infant ratio and genetic fac-
tors have been suggested [6-10] A background maternal family
history of HG is associated with development of HG and
For personal use only.
women who suffered from HG are more likely to have had
a first-degree relative who also suffered from HG than women
who did not experience HG [10,11]. In addition, women who
experienced HG in their first pregnancy have a significant
risk of recurrence when compared to women who did not
experience the condition in their first pregnancy [12]. The
recurrence risk can be reduced by a change in paternity, sug-
gesting a paternal--fetal interaction [12], although this has
been challenged by others who have not found a recurrence
risk with a change of partner or in association with
consanguinity [13,14].
Management of women with HG involves biological, (die-
tary changes and medications), physical (bedrest, massage,
acupressure) and general/professional support [15]. Women
with persistent severe HG can be treated with parenteral
nutrition [15] and, as a last resort, elective termination of preg-
nancy due to severe maternal complications of HG has also
been reported [16]. In some women who elected to terminate
their pregnancy due to HG, an uncaring attitude of care pro-
viders, and/or their failure to recognize the severity of the con-
dition have been linked significantly with the decision to
terminate the pregnancy [16]. Professional support for women
with HG is vital throughout pregnancy.
HG usually resolves after 20 weeks of gestation; however,
in a survey of 819 women, 22% experienced symptoms of
HG, which persisted throughout pregnancy. However, their
worst symptoms occurred during the first 3 months of preg-
nancy [17]. A computerized search was conducted using
PubMed, Embase, Cinahl, Lilacs, ISI Web of Science, the
Cochrane Central Register of Controlled Trials (all from
inception or 1960 to October 2010), and Research Registries
738 Expert Opin. Pharmacother. (2011) 12(5)
of ongoing trials. The key words used were nausea, vomit-
ing, emesis, hyperemesis gravidarum, morning sickness,
pregnancy, pregnancy complications, treatment, efficacy,
effectiveness, antiemetics, safety and teratogenesis. This sys-
tematic review of the literature addresses the etiological factors
for HG, with particular emphasis on the role of antiemetics in
the treatment of women with NVP or HG.
2. Pathogenesis of hyperemesis gravidarum
NVP may be induced by several stimuli, including visual, ves-
tibular, olfactory, gustatory, gastrointestinal, psychogenic and
emetogenic. HG has been described as an obstetric syndrome
because of its multifactorial influences [18].
2.1Central nervous origins of response to emetic
stimuli
Non-pregnant animal studies demonstrate that vomiting
involves a complex reflex arc with vagal afferent and efferent
connections to a chemoreceptor trigger zone (CTZ), emetic
centre (EC) and vestibular centre (VC) in the brainstem and
medulla oblongata [19,20]. These neuroanatomical regions
(area postrema for the CTZ; nucleus tractus solitarius, dorsal
motor nucleus of the vagus, and nucleus ambiguous for the
EC, and lateral vestibular nucleus for the VC) have neurohor-
monal receptors such as dopamine, histamine, muscarine,
norepinephrine and serotonin [21-27]. Substance P, a member
of the tachykinin family of bioactive peptides, activates the
G-protein-coupled receptors (NK1, NK2 and NK3), which
are also involved in peripheral and central transmission of
emetogenic stimuli [28,29]. The involvement of these neuro-
hormonal receptors in NVP has been difficult to establish
because there are no suitable pregnant animal models, but
human studies using electroencephalograph (EEG) recordings
or functional magnetic source imaging show increased activity
in the inferior frontal gyrus of the cerebral cortex during
motion sickness and ingestion of emetogens [30,31].
The possibility of cerebral cortical involvement in HG was
highlighted by a case-control study of 35 pregnant women
(17 with HG and 18 without NVP). Six of 17 (35.3%)
with HG, compared with 1 of 18 women (5.5%) with
NVP, demonstrated non-specific abnormal EEG findings,
although the sensory input leading to these EEG abnormali-
ties was not identified. There were no differences in the visual
evoked potential and brainstem auditory evoked response
between the two groups [32].
Women with NVP/HG have been observed to have aver-
sions to certain smells and tastes, and the sight of certain kinds
of food may induce the sensation of nausea. Learned food
aversion, a neurobehavioral phenomenon linked with cortical
cholinergic neurons, has been linked with nausea of preg-
nancy but not with vomiting [33,34]. In addition, higher olfac-
tory sensitivity has not been shown to be associated with
NVP [35]. Pregnant women with a history of motion sickness
are more likely to experience NVP/HG than women with no

such history [36]. Goodwin et al. demonstrated increased
abnormalities in the vestibulo-ocular reflex in pregnant
women with HG compared with those without HG,
but it remains unproven whether these abnormalities
induced the sensation of NVP [37]. As HG is peculiar to
pregnancy, many studies have also focused on the role of
the placenta.
2.2 Placental factors and hyperemesis gravidarum
In normal pregnancy, placental tissue is markedly infiltrated
with lymphocytes and mononuclear phagocytes [38,39]; one
of the main functions of the placenta is the production of
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cytokines, which are of importance in the maintenance of
pregnancy. Trophoblast-derived tumor necrosis factor
(TNF)-a, interleukin (IL)-1 and IL-6 regulate the production
and release of human chorionic gonadotrophin (hCG) [39].
Yoneyama et al. investigated the role of CD4-positive
T-helper (Th)1 and Th2 cells in the etiology of HG and con-
cluded that overproduction of Th1 leads to miscarriage and
pre-eclampsia and that Th2 production under the influence
of oestradiol (E2) and progesterone promote normal preg-
nancy. In women with HG, the proportion of IL-4 produced
by Th2 cells, as well as the plasma levels of hCG, E2 and pro-
gesterone, were statistically significantly higher than in normal
For personal use only.
pregnant controls [40]. However, within the HG group, there
was no correlation between IL-4 and trophoblastic hor-
mone levels, which might indicate that other factors are
involved [40].
Cytokines, via nociceptors, have been shown to induce
emesis through peripheral and central stimulation of the vom-
iting reflex arc [41]. Other placentally mediated mechanisms
investigated were the mean plasma levels of adenosine
(a metabolic modulator) and norepinephrine. Both factors
were significantly increased in women with HG com-
pared with normal pregnant women [42]. This is believed to
be due to over activation of the sympathetic nervous system
and enhanced production of TNF-a. It is uncertain whether
this finding is the primary event leading to HG but
catecholamines have been shown to induce emesis
through sensitization of peripheral and central adrenergic
receptors [42-44].
2.3 Hormonal factors and hyperemesis gravidarum
Another prime function of the placenta is the production of
hormones. Of the three hormones (hCG, E2, progesterone)
implicated in the pathogenesis of hyperemesis, most is
known about hCG, followed by E2 [45-50]. As pregnancy pro-
gresses, hCG levels, which appear to be genetically influ-
enced [10], plateau or decline in a similar manner to the
resolution of HG, while E2 and progesterone levels continue
to rise. An increased proportion of acidic hCG isoforms
(pH 5.2 -- 4.61 and 4.6 -- 4.01), and not the total serum
hCG, appears to play a role in HG and correlates with levels
of E2, free thyroxine (FT4) and thyroid-stimulating hormone
(TSH) [10]. The correlation of hCG with FT4 and TSH does
Expert Opin. Pharmacother. (2011) 12(5)
Sanu & Lamont
not usually lead to clinical hyperthyroidism [51] and resolution
of biochemical hyperthyroidism occurs over a period of
between one and 10 weeks. However, familial gestational
hyperthyroidism due to mutant thyrotropin receptor
hypersensitivity to hCG has been reported [52].
The concept of hCG being the trigger for HG has been
challenged by recent evidence in favor of an E2-related factor.
Three women, with a history of severe HG sufficient to need
total parenteral nutrition (TPN), opted for programmed
ovarian stimulation for IVF followed by surrogacy. They all
developed ‘HG type’ symptoms and ovarian hyperstimulation
syndrome, with high levels of E2 [53]. Their symptoms
resolved following oocyte retrieval and the three surrogate
mothers, when pregnant, reported normal levels of nausea
and vomiting during the surrogate pregnancy.
It remains unclear whether the link between trophoblastic
and ovarian hormones with HG is through central neurore-
ceptor activation or emetogenic factors. The CTZ within
the area postrema of the brain is likely to be involved with
chemical emetogenesis because it is outside the blood--brain
barrier and the cerebrospinal fluid [28]. hCG does not appear
in the CSF until a high serum threshold is reached [54];
the threshold value of hCG and/or E2 at which NVP will
inevitably occur has yet to be established.
2.4Gastrointestinal factors and hyperemesis
gravidarum
Gastrointestinal stimuli probably play a role in the pathogen-
esis of HG. Most women admitted to hospital with HG for
intravenous rehydration, and who are kept ‘nil by mouth’ in
the first 24 h, usually stop vomiting. Recurrence of vomiting
is observed in many women when they resume eating. Proges-
terone has an inhibitory effect on gastrointestinal smooth
muscle, which can lead to slower transit through the small
intestinal and colon [55-57]. However, using the C-octanoic
breath test, no abnormalities in the timing of gastric emptying
of women with HG, compared with those without HG, were
detected [58].
2.5Psychological factors and hyperemesis
gravidarum
There are unsubstantiated opinions that HG is a symbolic
rejection of pregnancy. Infantile personality, hysteria and con-
version disorder, which is a condition in which a patient dis-
plays neurological symptoms such as numbness, paralysis, or
fits, even though no neurological explanation is found and it
is determined that the symptoms are due to the patient’s psy-
chological response to stress, were once linked with HG [59,60].
This belief, when considering the management of women
with HG, can lead to psychosocial, marital and financial bur-
dens on these women [61]. In contrast, Simpson et al. demon-
strated that HG can lead to conversion disorder, as opposed to
conversion disorder being the cause of HG [62]. Overactivity
of the hypothalamic--pituitary--adrenal (HPA) axis has also
been linked with HG. Kauppila et al. showed significantly
739
 Hyperemesis gravidarum: pathogenesis and the use of antiemetic agents
higher mean levels of cortisol and adrenocorticotropic hor-
mone in women with HG than in those without HG and in
non-pregnant controls, suggesting that stress and psychologi-
cal influences may contribute to the occurrence of HG [63].
However, it could also be argued that overactivity of the
HPA axis might be secondary to HG. The link between HG
and subsequent psychosocial stress may also be inferred
from the study by Ditto et al., which demonstrated the
effectiveness of parenteral diazepam in the treatment of
hospitalized patients with HG [64].
2.6Evolutionary perspective and hyperemesis
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gravidarum
Simple NVP has been described as a protective function
against ingestion of potentially harmful substances like caf-
feinated beverages, tobacco and alcohol [65,66]. The association
of NVP with sugars, sweeteners, stimulants, meat, milk and
eggs was stronger than the association with cereals, starchy
roots and oil crops. However, the evolutionary concept of
NVP is not applicable to persistent HG, which is a potentially
debilitating condition.
2.7Vitamin B6 (pyridoxine) deficiency and
hyperemesis gravidarum
For personal use only.
Deficiency of functional vitamin B6 in the form of pyridoxal
5¢-phosphate (PLP) is recognized in pregnancy, and mothers
of higher gravidity are usually slightly more deficient than
women of lower gravidity [67]. This being the case, if pyridox-
ine deficiency was associated with HG this does not equate
with NVP becoming milder with each subsequent pregnancy.
In a study of 180 pregnant women, an increased incidence of
PLP deficiency in HG patients was not evident [68]. However,
double-blind, placebo-controlled trials have demonstrated
that pyridoxine is an effective therapy for NVP, although
the proportions of women who required hospitalization for
persistent symptoms of NVP were not included in the out-
come criteria [69,70]. If pyridoxine deficiency is indeed associ-
ated with HG then primigravid women should be more
pyridoxine deficient than women of higher gravidity.
In a placebo-controlled trial of 92 women performed to
evaluate the effectiveness of oral pyridoxine for hospitalized
HG patients receiving intravenous (IV) rehydration and IV
metoclopramide, the rate of rehospitalization was not statisti-
cally significantly different between the pyridoxine group
(37.5%) and the placebo group (21.1%) [71]. Abnormal liver
enzymes observed in women with HG are likely to be second-
ary to increased metabolic load from inactivation of tropho-
blastic hormones and possibly other emetogens associated
with pregnancy [72].
3. Antiemetics
The treatment of women with NVP/HG should be multidis-
ciplinary and should begin with dietary advice, reassurance
and support [15]. For those women with persistent vomiting,
740 Expert Opin. Pharmacother. (2011) 12(5)
IV hydration with multivitamin (pyridoxine and thiamine)
supplementation is advised [15] but may require the use of
antiemetics. A short course of corticosteroids has been shown
to be effective in women with persistent symptoms [73] and
other therapies have included the use of acupressure and pow-
dered ginger [74,75]. Antiemetics have been used to alleviate
HG/NVP symptoms for almost 60 years. A comparative
European study revealed that, in addition to dietary changes,
multivitamins, oral and/or parenteral antiemetics are often
used to treat women with NVP and HG [76]. The choice
and route of administration of antiemetics differs between
countries, suggesting that there is no evidence-based informa-
tion to guide clinical practice [76]. Although the use of antie-
metics is well established for motion sickness (histamine/
cholinergic receptor antagonists) [77], gastroparesis (dopamine
receptor antagonists) [78] and emetogenic agents (serotonin/
dopamine receptor antagonists) [79], outcome measures of
the effectiveness of antiemetics in NVP are often subjective.
In addition, there are no recent well-designed, randomized,
placebo-controlled trials to evaluate their effectiveness. It is
not known whether their effectiveness in treating NVP is
due to direct antagonism of neurotransmitter receptors in
the vomiting reflex arc in the brainstem and/or suppression
of spontaneous cortical neuronal impulses. A placebo-
controlled trial of 50 women at less than 16 weeks gestation,
using parenteral diazepam to treat HG, showed a shorter
mean hospital stay (4.5 ± 1.9 versus 6 ± 1.6 days, p < 0.05)
in favor of diazepam. The rehospitalization rate was 4% in
the diazepam group versus 27% in the placebo group
(p < 0.05) [64]. Nevertheless, studies which compared the effi-
cacy of oral antiemetics with placebo for NVP have suggested
that antiemetics are effective [80-88], though in one study, the
placebo response rate was as high as 70% [85].
3.1 Thiamine
The active form of thiamine -- thiamine diphosphate -- is a
cofactor for enzymes involved in carbohydrate metabolism.
Thiamine depletion can occur within 3 weeks of persistent
vomiting [89]. In contrast to pyridoxine, which is used to
treat NVP, thiamine supplementation is essential for hospi-
talized HG patients to prevent Wernicke--Korsakoff
encephalopathy [89].
3.2 Antihistamines
The most commonly used medication for NVP and HG is
the antihistamine class of antiemetics [90]. However, the
effectiveness of antihistamines in hospitalized HG patients,
compared with other antiemetics, is yet to be established.
The use of antihistamines may be related to the fact that
serum histamine levels are elevated in the first trimester
from the 8th to the 13th week of gestation, which
corresponds to the period of increased prevalence of NVP.
Elevated histaminuria is associated with pregnancies compli-
cated by HG compared with only traces of histaminuria in
normal pregnancies [91,92].

3.2.1 Placebo-controlled trials of oral antihistamines
Placebo-controlled trials of oral antihistamines such as etha-
nolamines (doxylamine and diphenhyderamine), ethylenedi-
amines (mepyramine), and piperazines (hydroxyzine and
buclizine) have recruited relatively small numbers of NVP
patients with mostly mild to moderate symptoms, not severe
enough to warrant hospitalization [80-88]. Nevertheless, these
studies demonstrated benefit with respect to symptoms and
a meta-analysis of 24 observational studies demonstrated their
safety with respect to teratogenesis [93]. The bioavailability of
orally administered antihistamines can be poor when com-
pared to the parenteral route of administration [94]. A meta-
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analysis of the effectiveness of antihistamines versus placebo
comprising 775 women with NVP compared to 415 controls
demonstrated that the treatment failure rate was 11%
(84/775) versus 36% (148/415), [relative risk (RR) 0.34,
95% confidence interval (CI) 0.27, 0.43] in favor of antihist-
amines [95]. The largest trial (597 women) included in the
meta-analysis used Bendectin (known as Debendox in
the UK), which is a combination of an antihistamine (doxyl-
amine), an anticholinergic agent (dicyclomine) and a vitamin
(pyridoxine) [96]. Ethanolamines such as doxylamine possess
more antimuscarinic effects than the other class of antihista-
minic agents (e.g., the ethylenediamines and piperazines) [97].
For personal use only.
Bendectin has been withdrawn from the market because of
an alleged teratogenic risk, although this has not been con-
firmed by meta-analysis of 15 observational studies [95]. How-
ever a meta-analysis of the effectiveness of antihistamines for
NVP excluded trials that used Bendectin and confirmed
their superiority over placebo [98].
Drowsiness is the most common side effect reported
with the use of antihistamines; it can lead to non-
compliance and affect quality of life. The ability to perform
daily routine functioning due to drowsiness was not addressed
by placebo-controlled trials involving antihistamines to
treat NVP.
There are no placebo-controlled trials of the use of oral
or parenteral antihistamines for hospitalized patients with
HG, nor are there prospective comparative trials of antihista-
mine versus any other antiemetic drug. However, we have
identified two retrospective comparative trials that used a
combination of antihistamines with another antiemetic class
of drug and compared these with other combinations of antie-
metics [99,100]. Antihistamines are often combined with other
antiemetics for hospitalized HG patients, presumably to
minimize the risk of side effects (i.e., extrapyramidal
symptoms) [100].
3.3 Phenothiazines
The use of phenothiazines for the treatment of NVP may be
linked to the fact that they have a wide range of neurotrans-
mitter receptor blocking activity, including histamine, dopa-
mine, muscarine, serotonin, and a-adrenergic receptors [94].
Activation of dopamine receptors in the stomach inhibits
gastric motility [78] but the bioavilability following oral
Expert Opin. Pharmacother. (2011) 12(5)
Sanu & Lamont
administration of phenothiazines is considered poor, com-
pared with the parenteral route. The phenothiazines have dif-
ferent neuroreceptor blocking abilities. Chlorpromazine and
triethylperazine have more anti-dopaminergic actions but
have minimal H1 receptor affinity compared with prometha-
zine, which has potent anti-H1 receptor activity and less anti-
dopaminergic activity [81,101]. All the phenothiazines have
central depressant activity but promethazine causes more
drowsiness and extrapyramidal side effects can occur with
phenothiazines that have significant anti-D2 activity [94].
Rumeau-Rouquette et al. [102] demonstrated that phenothia-
zines with a 3-carbon aliphatic side chain (chlorpromazine,
methoxy-promazine, methotrimeprazine) are associated with
a significant increase in teratogenesis but a meta-analysis of
observational studies including chlorpromazine, perphena-
zine, prochlorperazine, promethazine and trifluoperazine
demonstrated that these are not associated with an increased
risk of teratogenesis [95].
3.3.1 Placebo-controlled trials of phenothiazines
Placebo-controlled trials of phenothiazines such as prometha-
zine and triethlyperazine have demonstrated their benefits in
treating non-hospitalized NVP patients. In a meta-analysis
of three small trials, treatment failure with phenothiazines
occurred in only 43/203 (21%) of pregnant women with
NVP compared with 132/195 (68%) of those treated with
placebo (RR 0.31, 95% CI 0.24, 0.42) [95]. In one of the
included trials comprising 120 patients with NVP, treatment
with active tablets was either promethazine or mepyramine
(antihistamine). The findings were not reported according
to the type of antiemetic agent used, the proportion of
patients requiring hospital admission for treatment failure or
those who progressed to HG in the two groups. The
placebo-controlled trial of promethazine included women
who had reached 24 -- 32 weeks of gestation [87]. However,
the Cochrane review that excluded this trial, because women
in the trial had reached 24 -- 32 weeks of gestation, did not
demonstrate any significant benefit of phenothiazines
versus placebo [98]. In the trial using triethylperazine, the
side effects were judged to be similar between active treat-
ment and placebo [81]. There was no mention of side effects
in the placebo-controlled trial of promethazine [87]. There
are comparative trials of phenothiazines versus other antie-
metics for hospitalized (HG) and non-hospitalized (NVP)
patients [103,104] but there is no placebo-controlled trial of
phenothiazine versus placebo for HG patients.
Comparative trials of phenothiazines versus
3.3.2
other antiemetics
One trial of 156 women with NVP compared: i) oral meto-
clopramide (a benzamide) and intramuscular pyridoxine;
ii) rectal/oral prochlorperazine; and iii) oral promethazine.
Women in the metoclopramide/pyridoxine group had
significantly fewer emetic episodes than those in the
prochlorperazine and promethazine groups, but the
741
 Hyperemesis gravidarum: pathogenesis and the use of antiemetic agents

Table 1. Summary of prospective comparative trials of antiemetic versus antiemetic, or other pharmacological/
non-pharmacological agents for hospitalized patients with hyperemesis gravidarum.

Study design Year of study Antiemetics included Effectiveness

RCT 1996 Promethazine versus ondasetron Equally effective, but promethazine caused
more drowsiness
RCT 1998 Promethazine versus methylprednisolone Equally effective, but rehospitalization was more
in the promethazine group
RCT 2005 Metoclopramide versus acupuncture Equally effective, but improved functioning in the
and acupressure acupressure/acupuncture group
RCT 2006 Metoclopramide versus hydrocortisone Hydrocortisone was more effective
than metoclopramide
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RCT 2010 Metoclopramide versus promethazine Equally effective, but promethazine caused more
side effects (i.e., drowsiness)

RCT: randomized controlled trial.

subsequent hospitalization rate for failed treatment (i.e., HG
patients) was not significantly different between the three
groups (5.6 vs 6.0% vs 11.5%). One patient in the metoclo-
pramide group experienced an acute dystonic reaction, which
resolved spontaneously [103].
Tan et al. randomized 149 hospitalized HG patients to
For personal use only.
with promethzine, and no sedative effect [105], it may well be
the preferred antiemetic in women who have responded to
antiemetics but who experience significant sedation. This
argument can also be applied to the use of ginger because it
has no sedative side effects.

receive intravenous (IV) promethazine (76 patients) versus 3.5 Benzamides

IV metoclopramide (73 patients). Both drugs showed similar
therapeutic effects (vomiting episodes within 24 h of admis-
sion), but drowsiness was significantly more prevalent in the
promethazine (83.6%) than the metoclopramide (58.6%)
group [104].
In a comparative pilot study of IV ondansetron (a type-
3 serotonin receptor antagonist) versus IV promethazine
for treatment of HG, ondansetron was not superior to
promethazine with respect to treatment failure and number
of days of hospitalization, but only 15 women in each
group were tested [105]. Drowsiness, which was the only
side effect experienced, occurred in 8/15 (53%) in the
promethazine group and none in the ondansetron group,
but treatment with ondansetron was more expensive
than promethazine.
3.4 Serotonin receptor antagonists
Serotonin 5HT3 receptor antagonists (e.g., ondansetron) have
good bioavailability following oral administration. There is
limited information on the safety profile of 5HT3 receptor
antagonists with respect to teratogenesis. In a study of
176 women exposed to ondansetron in first trimester, its use
appeared to be safe for the treatment of NVP [106]. There
are no placebo-controlled trials of the effectiveness of ondan-
setron in the management of NVP/HG patients but it has
been suggested that serotonin receptor antagonists are the
most effective antiemetic drug, based on patients’ recall of
their symptoms [90]. In the United States, these agents are
used more for the treatment of HG than in other countries [90].
Bearing in mind equal effectiveness of ondasetron compared
Another example of an antiemetic agent with good bioavail-
ability following oral administration is metoclopramide. Ben-
zamides have a central dopamine receptor antagonistic effect
on the CTZ. The two benzamides used in studies involving
NVP/HG patients are trimethobenzamide (NVP patients)
and metoclopramide (HG patients). Both agents have been
shown to be free of an increased risk of congenital malforma-
tion in the fetus [107,108]. Metoclopramide has been shown to
have central serotonin 5HT3 receptor antagonism and periph-
eral serotonin 5HT4 agonism [78]. Receptors for 5HT4 exist in
several parts of the alimentary tract and act predominantly on
the motility and secretory functions of the gut [78,79]. The only
placebo-controlled trial of benzamide for NVP used
trimethobenzamide ± pyridoxine on 394 women. Treatment
failure ranged between 9 and 15% for the active group versus
57 -- 66% in the placebo group. Drowsiness was reported as
rare in the active group, and the hospitalization rate for treat-
ment failure/progression to HG between active and placebo
groups was not stated [80].
In a retrospective trial of 646 women with HG who
received at-home continuous subcutaneous metoclopramide
at a rate of 1.28 mg/h (30.8 mg/day), 192/646 (30%) experi-
enced side effects, of whom 30/646 (5%) had extrapyramidal
symptoms, and 72/646 (11%) had agitation. The hospitaliza-
tion rate (i.e., failure rate) after the use of subcutaneous
metoclopramide was less than 7% [109].
3.6Butryophenones
Other antiemetics with dopamine receptor antagonist activity
are the butryophenones. Butryophenones that have been

742 Expert Opin. Pharmacother. (2011) 12(5)

 Sanu & Lamont

Systemic emetogens –
endocrine/placental factors, Gastric, visual, olfactory,
cytokines vestibular afferents

Receptors: histamine, serotonin, dopamine and cholinergic

B
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Connecticut on 10/28/14

r Area postrema Nucleus tractus solitarius

a
i
n
s
t
e
m

Dorsal motor nucleus of vagus, nucleus ambiguous, lateral vestibular

nucleus
For personal use only.

Vagal afferents

Gastrointestinal tract – dopamine, serotonin,

cholinergic receptors

Vomiting

Figure 1. Diagram showing central nervous response to emetic stimuli.

reported to treat NVP include domperidone and droperidol.
As a dopamine and serotonin 5HT3 receptor antagonist,
and peripheral serotonin 5HT4 receptor agonist, domperi-
done is similar to metoclopramide in its mode of action but
does not easily cross the blood--brain barrier [78]. There are
no published human data on the risk of teratogenesis with
the use of these two antiemetics in pregnancy, and no
controlled trial has been reported.
3.7 Ginger
Ginger acts on the gastrointestinal tract as a dopamine and
serotonin antagonist, thus enhancing gastric motility; it has
no central nervous side effects [110]. However, there is paucity
of data on its safe use in pregnancy [111]. Ginger is effective in
treating women with NVP but we identified one double-
blind, randomized, cross-over trial of the efficacy of powdered
ginger versus placebo for HG. Ginger was more effective
(p = 0.035) than placebo with respect to relief of HG
symptoms [74].
3.8Antiemetics versus acupuncture
A randomized study of 88 hospitalized HG patients com-
pared metoclopramide infusion (20 mg/500 ml saline for
60 min) twice a week for 2 weeks and oral supplementation
with cyanocobalamin (vitamin B12), to acupuncture sessions
and acupressure. HG symptoms were equally relieved in

Expert Opin. Pharmacother. (2011) 12(5) 743

 Hyperemesis gravidarum: pathogenesis and the use of antiemetic agents
both groups with respect to vomiting episodes, but the
acupuncture group demonstrated significant improvement
in daily routine activity compared to metoclopramide
group [112].
3.9 Antiemetics versus steroids
Safari et al. compared the effectiveness of oral promethazine
to methylprednisolone for the treatment of HG in a random-
ized trial of 40 hospitalized patients [73]. There was no differ-
ence between the two groups with respect to therapeutic
failure. However, 5/17 (29%) patients in the promethazine
group, compared with none in the steroid group, who initially
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Connecticut on 10/28/14
responded to treatment were re-admitted within 2 weeks of
hospital discharge (p < 0.0001). Intravenous (IV) hydrocorti-
sone was compared with IV metoclopramide in 40 HG
patients admitted to the intensive care unit. Hydrocortisone
demonstrated a significant reduction in therapeutic failure
during admission and rehospitalization rates compared to
metoclopramide group (p < 0.0001) [113]. The reduction
in rehospitalization rate was not confirmed by another
randomized placebo-controlled trial of steroids, for the
treatment of HG [114]. Nevertheless, concerns have been raised
about the association of cleft lip with the use of steroids in
first trimester [115]. A summary of comparative trials of antie-
For personal use only.
metics and with steroids or acupuncture is shown in Table 1;
the emetic pathways and receptors involved are shown
in Figure 1.
4. Conclusion
The precise mechanisms underlying HG remain unknown
but appear to be multifactorial. Studies that focus on a genetic
influence in the etiology of HG may improve our understand-
ing of this condition. It is possible that genetic, endocrine
(ovarian and placental) and neurobehavioral factors are inter-
linked. The on-going study by the Hyperemesis Education
and Research Foundation into the genetics and epidemiology
of HG may reveal the association between these factors. This
study might also highlight those women likely to benefit most
from pre-emptive therapy with antiemetics [116]. As yet, there
744 Expert Opin. Pharmacother. (2011) 12(5)
is no convincing evidence that any antiemetic class is superior
to another with respect to effectiveness. However, their bene-
fit in the treatment of NVP needs to be balanced against
relative maternal side effects, fetal safety and cost.
5. Expert opinion
The possibility of a genetic component to HG was suggested
by Zhang et al. [117]. However, the mechanism linking genet-
ics with HG needs to be evaluated. We feel that HG might
also indicate an exaggerated central nervous response to
multiple emetic stimuli encountered in pregnancy.
The role of antiemetics in reducing the frequency of nausea
and vomiting episodes in non-hospitalized patients has been
established by meta-analysis of placebo-controlled trials.
Based on available evidence on safety and effectiveness of
medications, treatment algorithm for NVP has been devel-
oped [118] and adopted by the American College of Obstetri-
cians and Gynaecologists (ACOG), and the Society of
Obstetricians and Gynaecologists of Canada (SOGC). How-
ever, the impact of the use of treatment algorithm on reducing
the risk of hospitalization needs to be evaluated.
Hospitalized HG patients, who initially respond to
antiemetics but relapse after hospital discharge despite
adequate intake of medications, may reflect tolerance at the
neuroreceptor sites to the antiemetic agents.
Although the risk of hospital admission for therapeutic fail-
ure following treatment of patients with NVP with antiemet-
ics is unknown, there is indirect evidence of reduced hospital
admissions with the use of antiemetics. The voluntary with-
drawal of Bendectin in 1983 by Merrell Dow Pharmaceut-
icals, Inc. resulted in increased hospital admission and excess
hospital costs. In Canada and United States, US$16 million
and US$37 million, respectively, were incurred from hospital
admissions between 1983 and 1987 [119].
Declaration of interest
The authors state no conflict of interest and have received no
payment in preparation of this manuscript.

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Expert Opin. Pharmacother. (2011) 12(5)
Affiliation
Olaleye Sanu1 FACOG MRCOG &
Ronald F Lamont†2 BSc MB ChB MD FRCOG
†
Author for correspondence
1
Specialist Registrar in Obstetrics
and Gynaecology,
Department of Obstetrics & Gynaecology,
St Marys Imperial NHS Trust,
London, UK
2
Professor,
Reader and Consultant Obstetrician
and Gynaecologist,
Department of Obstetrics and Gynecology,
Wayne State University/Hutzel Hospital,
Detroit, Michigan, USA
Tel: +1 313 577 1342; Fax: +1 313 577 8986;
E-mail: rlamont@med.wayne.edu