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Nausea and Vomiting in Early Pregnancy

Authors:

Abstract

More than half of pregnant women suffer from nausea and vomiting, which typically begins by the fourth week and disappears by the sixteenth week of pregnancy. The cause of nausea and vomiting in pregnancy is unknown, but may be due to the rise in human chorionic gonadotrophin concentration. In 1 in 200 women, the condition progresses to hyperemesis gravidarum, which is characterised by prolonged and severe nausea and vomiting, dehydration, and weight loss. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatment for nausea and vomiting in early pregnancy? What are the effects of treatments for hyperemesis gravidarum? We searched: Medline, Embase, The Cochrane Library and other important databases up to September 2006 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 22 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupressure, acupuncture, antihistamines, corticosteroids, corticotrophins, diazepam, dietary interventions other than ginger, domperidone, ginger, metoclopramide, ondansetron, phenothiazines, and pyridoxine (vitamin B6).
Nausea and vomiting in early pregnancy
Search date May 2008
Mario Festin
ABSTRACT
INTRODUCTION: More than half of pregnant women suffer from nausea and vomiting, which typically begins by the 4th week and disappears
by the 16th week of pregnancy.The cause of nausea and vomiting in pregnancy is unknown, but may be due to the rise in human chorionic
gonadotrophin concentration. In 1 in 200 women, the condition progresses to hyperemesis gravidarum, which is characterised by prolonged
and severe nausea and vomiting, dehydration, and weight loss. METHODS AND OUTCOMES: We conducted a systematic review and
aimed to answer the following clinical questions:What are the effects of treatment for nausea and vomiting in early pregnancy? What are
the effects of treatments for hyperemesis gravidarum? We searched: Medline, Embase, The Cochrane Library, and other important
databases up to May 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of
this review).We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines
and Healthcare products Regulatory Agency (MHRA). RESULTS:We found 30 systematic reviews, RCTs, or observational studies that
met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this system-
atic review we present information relating to the effectiveness and safety of the following interventions: acupressure; acupuncture; antihis-
tamines; corticosteroids; corticotrophins; diazepam; dietary interventions other than ginger; domperidone; ginger; metoclopramide; ondansetron;
phenothiazines; and pyridoxine (vitamin B6).
QUESTIONS
What are the effects of treatment for nausea and vomiting in early pregnancy?......................... 3
What are the effects of treatments for hyperemesis gravidarum?................................... 10
INTERVENTIONS
TREATING NAUSEA AND VOMITING
Likely to be beneficial
Acupressure for treating nausea and vomiting in early
pregnancy ................................. 3
Antihistamines (H1 antagonists) ................ 5
Ginger for treating nausea and vomiting in early pregnan-
cy ....................................... 6
Pyridoxine (vitamin B6) for treating nausea and vomiting
in early pregnancy .......................... 8
Unknown effectiveness
Acupuncture for treating nausea and vomiting in early
pregnancy ................................. 8
Dietary interventions (other than ginger) for treating
nausea and vomiting in early pregnancy ......... 9
Domperidone for treating nausea and vomiting in early
pregnancy ................................. 9
Metoclopramide for treating nausea and vomiting in
early pregnancy ............................ 9
Phenothiazines for treating nausea and vomiting in early
pregnancy ................................ 10
TREATING HYPEREMESIS GRAVIDARUM
Likely to be beneficial
Acupressure for treating hyperemesis gravidarum New
......................................... 10
Unknown effectiveness
Acupuncture for treating hyperemesis gravidarum . .
11
Corticosteroids for treating hyperemesis gravidarum . .
11
Corticotrophins for treating hyperemesis gravidarum . .
13
Diazepam for treating hyperemesis gravidarum ... 13
Dietary interventions (other than ginger) for treating hy-
peremesis gravidarum ...................... 14
Ginger for treating hyperemesis gravidarum ..... 14
Ondansetron for treating hyperemesis gravidarum . .
15
Unlikely to be beneficial
Metoclopramide for treating hyperemesis gravidarum
(less effective than corticosteroids at reducing vomiting
episodes) New ............................ 14
Key points
More than half of pregnant women suffer from nausea and vomiting, which typically begins by the 4th week and
disappears by the 16th week of pregnancy.
The cause of nausea and vomiting in pregnancy is unknown, but may be due to the rise in human chorionic go-
nadotrophin concentration.
In 1 in 200 women, the condition progresses to hyperemesis gravidarum, which is characterised by prolonged
and severe nausea and vomiting, dehydration, and weight loss.
Ginger may reduce nausea and vomiting in pregnancy compared with placebo, although studies have given incon-
clusive results.
Pregnancy and childbirth
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..................................................
Pyridoxine may be as effective as ginger in reducing nausea, although studies have given inconsistent results
about reduction of vomiting.
We don't know whether dietary interventions other than ginger are beneficial.
P6 acupressure may reduce nausea and vomiting compared with sham acupressure, but wristbands can be difficult
to use.
We don't know whether acupressure is more effective than pyridoxine at reducing nausea or vomiting.
We don't know whether acupuncture is more effective than sham acupuncture at reducing nausea and vomiting.
Antihistamines may reduce nausea and vomiting compared with placebo.The antihistamine dimenhydrinate may
be as effective as ginger at improving nausea at 7 days, although it seems more effective at reducing vomiting
episodes in the first 2 days.
We don't know whether phenothiazines, metoclopramide, or domperidone reduce nausea or vomiting.
Acupressure may be more effective at reducing vomiting episodes in women with hyperemesis gravidarum compared
with placebo or control (intravenous fluid therapy).
We don't know whether acupuncture, intramuscular corticotrophin, corticosteroids, diazepam, ginger, metoclopramide,
ondansetron, or other dietary interventions, are effective in treating hyperemesis gravidarum.
Corticosteroids may be more effective than metoclopramide at reducing vomiting episodes and reducing readmission
to the intensive care unit in women with hyperemesis gravidarum.
DEFINITION Nausea and vomiting are common problems in early pregnancy. Although often called morning
sickness, nausea and vomiting can occur at any time of day and may persist throughout the day.
[1] Symptoms usually begin between 4 weeks' and 7 weeks' gestation (1 study found this to be the
case in 70% of affected women) [2] and disappear by 16 weeks' gestation in about 90% of women.
[1] [2] [3] One study found that less than 10% of affected women suffer nausea, vomiting, or both
before the first missed period. [3] Most women do not require treatment, and complete the pregnancy
without any special intervention. However, if nausea and vomiting are severe and persistent, the
condition can progress to hyperemesis, especially if the woman is unable to maintain adequate
hydration, fluid and electrolyte balance, and nutrition.Hyperemesis gravidarum is a diagnosis of
exclusion, characterised by prolonged and severe nausea and vomiting, dehydration, and weight
loss. [1] Laboratory investigation may show ketosis, hyponatraemia, hypokalaemia, hypouricaemia,
metabolic hypochloraemic alkalosis, and ketonuria.
INCIDENCE/
PREVALENCE Nausea affects about 70% and vomiting about 60% of pregnant women. [1] The true incidence of
hyperemesis gravidarum is not known. It has been documented to range from 3 in 1000 to 20 in
1000 pregnancies. However, most authors report an incidence of 1 in 200. [2]
AETIOLOGY/
RISK FACTORS The causes of nausea and vomiting in pregnancy are unknown. One theory, that they are caused
by the rise in human chorionic gonadotrophin concentration, is compatible with the natural history
of the condition, its severity in pregnancies affected by hydatidiform mole, and its good prognosis
(see prognosis below). [4] The cause of hyperemesis gravidarum is also uncertain. Again, endocrine
and psychological factors are suspected, but evidence is inconclusive. [4] Female fetal sex has
been found to be a clinical indicator of hyperemesis. [5] One prospective study found that Helicobac-
ter pylori infection was more common in pregnant women with hyperemesis gravidarum than in
pregnant women without hyperemesis gravidarum (number of women with positive serum Heli-
cobacter pylori immunoglobulin G concentrations: 95/105 [91%] with hyperemesis gravidarum v
60/129 [47%] without hyperemesis gravidarum). [6] However, it was not clear whether this link was
causal.
PROGNOSIS One systematic review (search date 1988) found that nausea and vomiting were associated with
a reduced risk of miscarriage (6 studies, 14,564 women; OR 0.36, 95% CI 0.32 to 0.42) but found
no association with perinatal mortality. [7] Hyperemesis gravidarum is thought by some to induce
nutrient partitioning in favour of the fetus, which could explain the association with improved outcome
in the fetus. [8] Nausea and vomiting and hyperemesis usually improve over the course of pregnancy,
but in one cross-sectional observational study 13% of women reported that nausea and vomiting
persisted beyond 20 weeks' gestation. [9] Although death from nausea and vomiting during preg-
nancy is rare, morbidities, including Wernicke's encephalopathy, splenic avulsion, oesophageal
rupture, pneumothorax, and acute tubular necrosis, have been reported. [10] [11]
AIMS OF
INTERVENTION To reduce the incidence and severity of nausea and vomiting in early pregnancy; to reduce the
incidence and severity of hyperemesis gravidarum; to minimise adverse effects of treatment and
possible teratogenic effects on the fetus.
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OUTCOMES Persistence, severity, or both, of nausea and vomiting episodes as measured on validated scales;
maternal mortality; rates of admission and readmission to hospital and duration of hospital stay;
incidence and severity of adverse effects of treatment; and incidence of teratogenic effects of
treatments on the fetus.
METHODS Clinical Evidence search and appraisal May 2008.The following databases were used to identify
studies for this systematic review: Medline 1966 to May 2008, Embase 1980 to May 2008, and
The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled
Clinical Trials 2008, Issue 2. Additional searches were carried out using these websites: NHS
Centre for Reviews and Dissemination (CRD) for Database of Abstracts of Reviews of Effects
(DARE) and Health Technology Assessment (HTA), and NICE.We also searched for retractions
of studies included in the review. Abstracts of the studies retrieved from the initial search were
assessed by an information specialist. Selected studies were then sent to the author for additional
assessment, using pre-determined criteria to identify relevant studies. Study design criteria for in-
clusion in this review were: published systematic reviews and RCTs in any language, at least single
blinded, and containing more than 20 individuals of whom more than 80% were followed up.There
was no minimum length of follow-up required to include studies.We excluded all studies described
as open, open label, or not blinded unless blinding was impossible (e.g. acupressure trials). In
addition, we use a regular surveillance protocol to capture harms alerts from organisations such
as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which
are added to the reviews as required.To aid readability of the numerical data in our reviews, we
round many percentages to the nearest whole number. Readers should be aware of this when re-
lating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We
have performed a GRADE evaluation of the quality of evidence for interventions included in this
review (see table, p 19 ).
QUESTION What are the effects of treatment for nausea and vomiting in early pregnancy?
OPTION ACUPRESSURE FOR TREATING NAUSEA AND VOMITING IN EARLY PREGNANCY.......
Severity of nausea and vomiting
Compared with sham acupressure or no treatment P6 acupressure may be more effective at reducing the proportion
of women who report nausea and vomiting in early pregnancy (very low-quality evidence).
Acupressure compared with pyridoxine We don't know whether acupressure is more effective at reducing nausea
or vomiting at 7 days (very low-quality evidence).
Note
More than half of women having P6 acupressure experience problems with using the wristband.
For GRADE evaluation of interventions for nausea and vomiting in early pregnancy, see table, p 19 .
Benefits: Accupressure versus placebo or control:
We found two systematic reviews (search date 2002, and search date from 1989 to 2005), [12] [13]
one additional RCT, [14] and one subsequent RCT. [15]
The first systematic review examined the effects of acupressure and acupuncture in treating nausea
or vomiting in early pregnancy, and pooled results for acupressure and acupuncture together; only
those results pertaining to acupressure alone have been included in this section. [12] The review
identified three RCTs comparing acupressure (1 RCT in finger acupressure and 2 RCTs in wrist
acupressure; 500 women) versus sham acupressure. [12] The second systematic review examined
the effects of acupressure, acupuncture, and electrical stimulation, and identified nine RCTs com-
paring acupressure (3 RCTs in finger pressure and 6 RCTs in wrist acupressure) versus control
(no treatment). [13] Two RCTs (1 in finger acupressure [16] and 1 in wrist acupressure) [17] were
identified by both reviews.
The reviews reported on different comparisons and outcomes.The first review found limited evidence
that acupressure reduced the proportion of women reporting morning sickness (not defined) com-
pared with sham acupressure (see table 1, p 18 ). [12] The review combined the results of finger
acupressure [16] and wrist acupressure [17] in the summary calculation. [12] The trial with the largest
sample size [16] (included in the meta-analysis) was later described in a paper that questioned the
reliability of the randomisation. [18] In the first included RCT, P6 acupressure was applied as a
band applying pressure to the P6 point. [16] Sham treatment consisted of a similar band with the
point blunted, not exerting pressure on the P6 point. Each type of band was put on each wrist in
sequence. Data for meta-analysis were taken from the third phase, when one group received active
treatment to both wrists and the other placebo treatment to both wrists for 72 hours. In the second
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included RCT, acupressure to the P6 acupoint was compared with pressure applied to a point close
to the right elbow (sham acupressure), both for 5 minutes every 4 hours on four successive mornings.
[17] A control group without treatment was asked only to complete a record form.
The second systematic review (683 women, gestational age range 811 weeks) found that both
finger and wristband acupressure significantly reduced the proportion of women reporting nausea
compared with control (see table 1, p 18 ). [13] There was also a significant reduction in the proportion
of women reporting vomiting with wristband acupressure compared with control (see table 1, p 18
). In the RCT comparing finger acupressure with control and with placebo, unilateral acupressure
was applied by finger application on P6 acupoint for 530 minutes, four times daily or as needed
for 47 days. In the RCTs comparing wristband acupressure with control or placebo, five RCTs
used bilateral wristbands and one RCT used a unilateral wristband for 314 days. However, it is
not clear whether wristbands were applied continously or whether the results of the crossover RCTs
were before or after crossover.The review also examined the placebo effects of acupressure (finger
and wrist acupressure), and found that the proportion of women reporting nausea was significantly
smaller with placebo compared with control (see table 1, p 18 ). [13] This makes the interpretation
of results of the effects of acupressure difficult.The additional RCT (138 women randomised at 13
weeks' gestation, 110 women analysed) found that acupressure given by a wristband to the P6
acupoint reduced the frequency and severity of nausea compared with a sham acupressure wrist-
band (data were not reported in a way that allowed further statistical calculation). [14]
The subsequent RCT (75 women, gestational age range 512 weeks) examined the effects of
acupressure in pregnant women suffering from nausea with or without vomiting, and who were
unable to receive conventional treatment. [15] Women were randomly allocated to acupressure (26
women), control (25 women), or placebo (24 women) groups. Acupressure bands were applied on
days 46 only, and had to be removed before going to bed and replaced in the morning.The RCT
found no significant difference in the number of women who reported nausea (P greater than 0.05;
absolute numbers not reported) or vomiting (P greater than 0.05; absolute numbers not reported)
between the acupressure and placebo groups in days 46 (treatment days).The RCT also found
a significant reduction in the number of women reporting nausea in the treatment (P less than
0.001) and placebo groups (P less than 0.05) in days 46 compared with days 13.This makes
the interpretation of results of the effects of acupressure difficult.The treatment group applied an
acupressure band to acupoint P6 on days 46; the placebo group applied the band to a sham
acupressure point on the upper side of the wrists; and women in the control group were asked to
complete a nausea and vomiting diary for 9 days. Symptoms were evaluated using visual analogue
scores (10 cm long vertical and horizontal lines with a scale ranging from 0 = no symptoms to
10 = worst possible symptom).
Acupressure versus pyridoxine (vitamin B6):
We found one RCT (66 women, gestational age range 612 weeks) comparing wristband acupres-
sure versus pyridoxine over 7 days in women with mild to moderate nausea and vomiting in early
pregnancy. [19] Acupressure was applied on the P6 acupoint and women were instructed to wear
the wristband continously from day 1 to the evening of day 5.Women in the pyridoxine group re-
ceived 50 mg of vitamin B6 twice daily for 5 days.The RCT found no significant difference in the
reduction of Rhodes index scores between both groups at the end of the evening of the 5th day
(P greater than 0.05; absolute numbers not reported).The RCT also found no significant increase
in the Rhodes index score (P greater than 0.05; absolute numbers not reported) in both the acu-
pressure group and the vitamin B6 group on the evening of the 7th day after discontinuation of
treatments.Women in both groups were advised to take the rescue drug dimenhydrinate in case
of nausea and vomiting. Symptoms were evaluated every 12 hours for 7 days using the Rhodes
index of nausea and vomiting form (8-item form: 3 items measure nausea [scores ranging from
315] and 5 items measure vomiting and retching [scores ranging from 525]), and women were
asked to record the use of the rescue drug dimenhydrinate.
Harms: Acupressure versus placebo or control:
The first systematic review [12] and other additional [14] and subsequent RCTs [15] [20] gave no in-
formation on adverse effects.The second systematic review reported adverse effects in one trial,
which included pain, numbness, and hand swelling (no further data reported). [13]
Acupressure versus pyridoxine (vitamin B6):
The RCT reported that both acupressure and vitamin B6 were well tolerated, and only one person
complained of irritation on wearing the wristband and withdrew from treatment. [19]
Comment: Conducting high-quality trials is difficult because nausea and vomiting tend to resolve spontaneously,
and interventions are difficult to mask and control with credible placebos. In the first systematic
review, results were sensitive to the method of calculation used (RR or OR), and the authors
commented that the significant relative risk calculation may be an overestimate, as two RCTs that
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did not meet Clinical Evidence criteria [21] [22] found no evidence of effect. [12] In the second sys-
tematic review, there was improvement in the proportion of women who reported nausea or vomiting
with all three groups. [13] The significant improvement in the placebo group makes it difficult to in-
terpret results and establish whether they were influenced by a placebo effect. It is possible that
the wristbands (placebo) could produce an effect by applying pressure on the P6 acupoint or in its
meridian pathway because of their uniform size and elasticity.
The subsequent RCT found acupressure had a therapeutic and placebo effect in reducing symptoms
of nausea. However, this study is limited by the small number of participants in each arm. [15] In
the RCT comparing acupressure and pyridoxine, women were also advised to take dimenhydrinate
in the event of nausea and vomiting.Women were asked to record whether they took dimenhydrinate
and, if so, how often. However, it is not clear how many women actually took dimenhydrinate or
how often it was taken. It is possible that the reduction in symptoms was largely due to the effects
of the rescue drug. [19]
OPTION ANTIHISTAMINES (H1 ANTAGONISTS) FOR TREATING NAUSEA AND VOMITING IN EARLY
PREGNANCY.................................................................
Severity of nausea and vomiting
Compared with placebo Antihistamines (buclizine, dimenhydrinate, doxylamine, hydroxyzine, and meclozine) may
be more effective at reducing nausea and vomiting (low-quality evidence).
Compared with ginger We don't know whether dimenhydrinate is more effective at reducing nausea, but ginger is
less likely to cause drowsiness (very low-quality evidence).
Compared with phenothiazines We don't know whether antihistamines are more effective at reducing nausea and
vomiting (low-quality evidence).
For GRADE evaluation of interventions for nausea and vomiting in early pregnancy, see table, p 19 .
Benefits: Antihistamines versus placebo:
We found two systematic reviews. [12] [23] The more recent systematic review (search date 2002,
6 RCTs, 571 women) found that, compared with placebo, antihistamines as a group significantly
reduced nausea (timeframes not reported; 51/355 [14%] with antihistamines v 96/216 [44%] with
placebo; OR 0.20, 95% CI 0.06 to 0.63). [12] The antihistamines included in the RCTs identified by
the review were buclizine, dimenhydrinate, hydroxyzine, and meclozine.The earlier systematic
review (search date 1998, [23] 7 RCTs [5 of which were included in the more recent systematic
review], [12] 1190 women, same antihistamines as more recent review plus doxylamine) found that
H1 antagonist antihistamines significantly reduced treatment failure (defined in the review as
treatments that provided little or no benefit in reducing vomiting) compared with untreated controls
(84/775 [11%] with antihistamines v 148/415 [36%] with untreated controls; RR 0.34, 95% CI 0.27
to 0.43). [23] However, the authors concluded that the results needed to be interpreted with care
because significant heterogeneity was found between studies. [23] The trials identified by the reviews
were old and did not provide details on randomisation or concealment strategies. [12] [23] The more
recent review combined results from trials in which different antihistamines (buclizine, dimenhydri-
nate, doxylamine, hydroxyzine, and meclozine) were compared with placebo. [12] The earlier review
found heterogeneity in the meta-analysis, which may be attributed to the variety of drugs included.
[23]
Antihistamines versus ginger:
See benefits of ginger, p 6 .
Antihistamines versus phenothiazines:
See benefits of phenothiazines, p 10 .
Harms: Antihistamines versus placebo:
The earlier review included 24 controlled studies in more than 200,000 women treated between
1960 and 1991. [23] It found a slight decrease in risk of teratogenicity with antihistamines compared
with placebo, which was of borderline significance (OR 0.76, 95% CI 0.60 to 0.94).The more recent
review included three RCTs that gathered evidence on harms from 179 women. [12] It found that
antihistamines significantly increased drowsiness (23/94 [24%] with antihistamines v 9/85 [11%]
with placebo; RR 2.3, 95% CI 1.1 to 4.7; NNH 7, 95% CI 3 to 32).
Antihistamines versus ginger:
See harms of ginger, p 6 .
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Antihistamines versus phenothiazines:
See harms of phenothiazines, p 10 .
Comment: A preparation combining doxylamine plus dicycloverine plus pyridoxine assessed in the second
review was found to reduce nausea and vomiting. However, this preparation was withdrawn from
the market in several countries after publication of papers suggesting teratogenicity, although such
claims have subsequently been found to be unreliable.
OPTION GINGER FOR TREATING NAUSEA AND VOMITING IN EARLY PREGNANCY..............
Severity of nausea and vomiting
Compared with placebo Ginger may be more effective at reducing nausea and vomiting in early pregnancy (low-
quality evidence).
Compared with pyridoxine We don't know whether ginger is more effective at improving nausea and vomiting (low-
quality evidence).
Compared with antihistamines We don't know whether ginger is more effective than dimenhydrinate at reducing
nausea, but ginger is less likely to cause drowsiness (very low-quality evidence).
Adverse effects
Ginger may cause heartburn and may be a gastric irritant (in quantities greater than 6 g). In addition, inhalation of
ginger dust may lead to immunoglobulin E-mediated allergy.
For GRADE evaluation of interventions for nausea and vomiting in early pregnancy, see table, p 19 .
Benefits: Ginger versus placebo:
We found one systematic review (search date 2004, 3 RCTs). [25] The review did not conduct a
meta-analysis.The first RCT identified by the review (70 women, over 17 weeks' gestation) compared
ginger 250 mg in oral capsules taken four times daily versus placebo. [26] It found that, compared
with placebo, ginger significantly reduced the proportion of women with vomiting after 4 days (12/32
[38%] with ginger v 23/35 [66%] with placebo; RR 0.57, 95% CI 0.34 to 0.95; NNT 4, 95% CI 2 to
12) and significantly reduced symptoms after 7 days (non-specifically described; women with im-
proved symptoms: 28/32 [88%] with ginger v 10/35 [29%] with placebo; RR 0.18, 95% CI 0.07 to
0.45).The second RCT identified by the review (26 women, less than 13 weeks' gestation) compared
ginger syrup (15 mL containing ginger 250 mg taken four times daily) versus placebo. [27] It found
that, after 6 days, significantly more women had stopped vomiting with ginger (8/12 [67%] with
ginger v 2/10 [20%] with placebo; RR 0.42, 95% CI 0.18 to 0.98).The third RCT identified by the
review (120 women, 5.518.0 weeks' gestation) compared ginger 125 mg in oral capsules taken
four times daily for 4 days versus placebo. [28] It found that ginger significantly reduced nausea
severity scores over each of the four treatment days (reported as significant, results presented
graphically). It also significantly reduced dry retching, but only on the first 2 days of treatment (re-
ported as significant, no further data reported). Ginger had no significant effect on episodes of
vomiting (reported as not significant, no further data reported).
Ginger versus pyridoxine (vitamin B6):
We found one systematic review (search date 2004, 2 RCTs), [25] and one subsequent RCT com-
paring the effectiveness of ginger versus pyridoxine in the treatment of nausea and vomiting in
pregnancy. [29] The review did not conduct a meta-analysis.The first RCT identified by the review
(138 women, over 16 weeks' gestation) compared oral ginger 500 mg (provided in a capsule) versus
pyridoxine 10 mg three times daily for 3 days. [30] Severity of nausea was graded by the woman
using a visual analogue scale.The RCT found no significant difference in mean nausea score (1.4
with ginger v 2.0 with pyridoxine; P = 0.136) and mean vomiting score (0.7 with ginger v 0.5 with
pyridoxine; P = 0.498) after treatment between ginger and pyridoxine.The RCT found that both
ginger and pyridoxine significantly reduced nausea scores (from 5.0 to 3.6 with ginger v from 5.3
to 3.3 with pyridoxine; P less than 0.001 for either intervention v baseline) and number of vomiting
episodes (from 1.9 to 1.2 with ginger v from 1.7 to 1.2 with pyridoxine; P less than 0.001 for either
intervention v baseline) from baseline.
The second RCT identified by the review (291 women, less than 16 weeks' gestation) compared
ginger 1.05 g versus pyridoxine 75 mg daily for 3 weeks. [31] Differences from baseline in nausea
and vomiting scores were estimated for both groups at days 7, 14, and 21. The RCT found no
significant difference between ginger and pyridoxine in reducing nausea, retching, and vomiting,
averaged over time, with no evidence of different effects at the three time points (nausea: 3.6 with
ginger v 3.9 with pyridoxine; mean difference +0.2, 90% CI 0.3 to +0.8; retching: 0.5 with ginger
v 0.7 with pyridoxine; mean difference 0.3, 90% CI 0 to 0.6; vomiting: 0.9 with ginger v 0.2 with
pyridoxine; mean difference 0.5, 90% CI 0 to 0.9).When a comparison was made between the
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proportion of women reporting to be symptom free, the RCT found no significant difference between
ginger and pyridoxine at any time during the trial (no further data reported). The RCT also found
no significant difference in women's perception of an overall reduction in their symptoms between
ginger and pyridoxine (53% with ginger v 55% with pyridoxine; absolute numbers not reported; RR
0.97, 95% CI 0.77 to 1.21).
The subsequent RCT (126 women, gestational age at least 16 weeks) compared the effectiveness
of ginger (650 mg daily) and pyridoxine (25 mg three times daily) for 4 days in women with nausea
and vomiting in early pregnancy who needed antiemetics.The severity of the degree of nausea
and vomiting was assessed using a modified form of the full Rhodes score (3 physical symptoms
of Rhodes score: episodes of nausea, duration of nausea, and number of vomits measured on a
scale ranging from 3 [lowest = slight nausea] to 15 [highest = severe nausea and vomiting]).The
scores were recorded 24 hours before treatment for baselining symptoms, and then each subsequent
day of treatment.The RCT found that ginger significantly improved mean nausea and vomiting
scores compared with pyridoxine at 4 days (123 women, reduction in scores from baseline: 3.3
with ginger v 2.6 with pyridoxine; P less than 0.05).The RCT reported 3/61 [5%] women in the
ginger group and 4/62 [7%] in the vitamin B6 group took other ginger products, which may confound
the results.
Ginger versus antihistamines:
We found one RCT (170 women, gestational age less than 16 weeks) comparing ginger (0.5 g
twice daily) versus dimenhydrinate (50 mg twice daily) for 7 days. [24] The RCT found no significant
difference in daily mean nausea scores (measured on a visual analogue scale: 10 cm vertical line
with a scale ranging from 0 = no nausea to 10 = severe nausea) between the two groups on days
17 of treatment (P greater than 0.05; figures presented graphically) although mean nausea scores
decreased in both groups.The RCT found dimenhydrinate significantly reduced daily mean vomiting
episodes compared with ginger in days 12 of treatment (P less than 0.05; figures presented
graphically) but there was no significant difference at days 37 (P greater than 0.05; figures pre-
sented graphically), although the frequency of vomiting decreased in both groups.
Harms: Ginger versus placebo:
The first RCT identified by the review [25] found no significant difference in spontaneous abortions
between ginger and placebo (1/32 [3%] with ginger v 3/38 [8%] with placebo; P = 0.4), but the
sample size may have been too small to detect a clinically important difference. [26] The second
RCT identified by the review found no adverse effects associated with ginger. [27] The third RCT
identified by the review found that the most serious adverse effect was heartburn and reflux (no
data reported to establish a comparison between groups). [28]
Ginger versus pyridoxine (vitamin B6):
The first RCT identified by the review found no significant difference in drowsiness (17/64 [27%]
with ginger v 21/64 [33%] with pyridoxine; P = 0.439) or dyspepsia (6/64 [9%] with ginger v 4/64
[6%] with pyridoxine; P = 0.510) between ginger and pyridoxine. [30] The second RCT identified
by the review found that both ginger and pyridoxine caused similar rates of dry retching after
swallowing (52% with ginger v 56% with pyridoxine), vomiting after ingestion (2% with ginger v 1%
with pyridoxine), or a burning sensation (2% in each group; P values not reported). [31] It found
that women taking ginger reported belching significantly more frequently than women taking pyri-
doxine (9% with ginger v 0% with pyridoxine; P less than 0.05). There was no significant difference
between groups in pregnancy outcome. A review of the literature on the effects of ginger reported
that ginger may cause heartburn and may be a gastric irritant (in quantities greater than 6 g). In
addition, inhalation of ginger dust may lead to immunoglobulin E-mediated allergy. [32] The subse-
quent RCT reported no significant differences in adverse effects (not specified) between the two
groups (16/61 [25%] with ginger v 15/62 [24%] with pyridoxine; P = 0.795). [29] Minor adverse effects
reported included sedation, heartburn, headache, and arrhythmia.
Ginger versus antihistamines:
The RCT reported significantly fewer episodes of drowsiness in the ginger group compared with
the dimenhydrinate group (5/85 [6%] with ginger v 66/85 [78%] with dimenhydrinate; P less than
0.01).There was no significant difference between the two groups in the occurence of heartburn
(13/85 [15%] with ginger v 9/85 [11%] with dimenhydrinate; P = 0.403). [24]
Comment: Ginger versus placebo:
The ginger used in the first RCT [26] was derived from fresh ginger roots and given in capsules.
The authors of the RCT warn that different preparations of ginger may have different potencies
and therefore different magnitudes of effects.The active ingredient that improves nausea and
vomiting has not been isolated. [26]
© BMJ Publishing Group Ltd 2009. All rights reserved. ........................................................... 7
Nausea and vomiting in early pregnancy
Pregnancy and childbirth
OPTION PYRIDOXINE (VITAMIN B6) FOR TREATING NAUSEA AND VOMITING IN EARLY PREGNAN-
CY..........................................................................
Severity of nausea and vomiting
Compared wtih placebo Pyridoxine may be more effective at reducing nausea but not vomiting (low-quality evidence).
Compared with acupressure We don't know whether pyridoxine is more effective at reducing nausea or vomiting at
7 days (very low-quality evidence).
Compared with ginger We don't know whether pyridoxine is more effective at improving nausea and vomiting (low-
quality evidence).
For GRADE evaluation of interventions for nausea and vomiting in early pregnancy, see table, p 19 .
Benefits: Pyridoxine (vitamin B6) versus placebo:
We found two systematic reviews (search dates 2002 [12] and 1998). [23] The first review (3 RCTs,
949 women) found that pyridoxine had similar failure rates compared with placebo (3 RCTs, 949
women; RR 0.97, 95% CI 0.78 to 1.20). [23] However, pyridoxine significantly improved nausea
scores (2 RCTs, 395 women;WMD 0.99, 95% CI 1.47 to 0.51). This review included one RCT
in which the nature of randomisation was unclear. [23] The second systematic review (2 RCTs, 392
women) compared pyridoxine versus placebo or no treatment. [12] It found no significant difference
between pyridoxine and placebo in vomiting (timeframes not reported; RR 0.76, 95% CI 0.36 to
1.66). However, it found that pyridoxine significantly reduced nausea (change in a 10-cm visual
analogue scale;WMD 0.99 cm, 95% CI 0.51 cm to 1.47 cm). For the two RCTs included in both
reviews, failure rates were defined in various subjective ways and included failure to achieve
resolution or a clinically important improvement in symptoms. [12] [23]
Pyridoxine (vitamin B6) versus acupressure:
See benefits of acupressure, p 3 .
Pyridoxine (vitamin B6) versus ginger:
See benefits of ginger, p 6 .
Harms: Pyridoxine (vitamin B6) versus placebo:
The first review searched for evidence on harms (search date 1998, 1 cohort study, 1369 women).
[23] It found no significant increase in major fetal malformations attributable to pyridoxine (RR 1.05,
95% CI 0.60 to 1.84). [23]
Pyridoxine (vitamin B6) versus acupressure:
See harms of acupressure, p 3 .
Pyridoxine (vitamin B6) versus ginger:
See harms of ginger, p 6 .
Comment: None.
OPTION ACUPUNCTURE FOR TREATING NAUSEA AND VOMITING IN EARLY PREGNANCY.......
Severity of nausea and vomiting
Compared with sham acupuncture or no treatment We don't know whether acupuncture is more effective at reducing
nausea and retching in early pregnancy (low-quality evidence).
For GRADE evaluation of interventions for nausea and vomiting in early pregnancy, see table, p 19 .
Benefits: We found two systematic reviews (search date 2002, [12] and search date from 1989 to 2005). [13]
The first systematic review examined the effects of acupressure and acupressure in treating nausea
or vomiting in early pregnancy, and identified two RCTs comparing acupuncture versus sham
acupuncture or no treatment. [12] The second systematic review examined the effects of acupressure,
acupuncture, and electrical stimulation, and identified two RCTs comparing acupuncture versus
control (no treatment) in treating nausea or vomiting in early pregnancy. [13] Two RCTs were
identified by both reviews. [33] [34] We report the results of these RCTs separately, as the first review
pooled results for acupressure and acupuncture together in its analyses, and the second review
included studies in women with hyperemesis (which is covered as a separate question). However,
both reviews reported similar results of the effects of acupuncture in women with nausea and
vomiting in early pregnancy.
© BMJ Publishing Group Ltd 2009. All rights reserved. ........................................................... 8
Nausea and vomiting in early pregnancy
Pregnancy and childbirth
The first RCT (593 women with nausea and vomiting in early pregnancy) identified by the reviews
compared weekly traditional acupuncture for 4 weeks versus PC6 acupuncture, 8 sham acupuncture,
or no acupuncture. [33] Rates of vomiting did not differ significantly between groups (reported as
not significant; P value not reported). However, significantly more women receiving traditional,
PC6, or sham acupuncture reported improvement in nausea compared with women receiving no
acupuncture.The improvement compared with no acupuncture was noted after 1 week of treatment
with traditional acupuncture (13/135 [10%] with acupuncture v 4/127 [3%] with no acupuncture;
RR 0.93, 95% CI 0.88 to 0.99), after 2 weeks in women receiving PC6 acupuncture (P less than
0.05), and after 3 weeks in women receiving sham acupuncture (P less than 0.01).Women receiving
PC6 and sham acupuncture also reported significantly less dry retching compared with no
acupuncture (P less than 0.001).The significant improvement in all groups receiving an intervention
(traditional acupuncture, PC6 acupuncture, or sham acupuncture) makes it difficult to establish
whether the results were influenced by a placebo effect. [33] The RCT expressed only the 1 week
results as a relative risk.The second RCT (55 women, 610 weeks' gestation) found no significant
difference in the proportion of women who reported nausea between multisite acupuncture and
sham acupuncture (P = 0.9). [34]
Harms: A follow-up study of the first RCT [33] found no differences between study groups in perinatal out-
come, congenital abnormalities, pregnancy complications, or other infant outcomes. [35]
Comment: The second systematic review compared three different types of acustimulation (acupressure,
acupuncture, and electrical stimulation).The acupuncture intervention did not reduce nausea. It
may not be acceptable for studies to compare interventions as varied as these.The number of
acupuncture trials is limited for pregnant women, perhaps because it is impossible to self-administer
acupuncture, and acupunture may also be inconvenient for women experiencing chronic symptoms
of nausea and vomiting.The review reported inconsistencies in frequencies of acupuncture, which
varied from three times daily for 2 days to once weekly for 4 weeks. [13]
OPTION DIETARY INTERVENTIONS (OTHER THAN GINGER) FOR TREATING NAUSEA AND VOMITING
IN EARLY PREGNANCY........................................................
We found no clinically important results from RCTs about the effects of dietary interventions (other than
ginger) in treating women with nausea and vomiting in early pregnancy.
For GRADE evaluation of interventions for nausea and vomiting in early pregnancy, see table, p 19 .
Benefits: We found no systematic review or RCTs.
Harms: We found no RCTs.
Comment: None.
OPTION DOMPERIDONE FOR TREATING NAUSEA AND VOMITING IN EARLY PREGNANCY.......
We found no clinically important results from RCTs about the effects of domperidone in treating women
with nausea and vomiting in early pregnancy.
For GRADE evaluation of interventions for nausea and vomiting in early pregnancy, see table, p 19 .
Benefits: We found no systematic review or RCTs.
Harms: We found no RCTs.
Comment: None.
OPTION METOCLOPRAMIDE FOR TREATING NAUSEA AND VOMITING IN EARLY PREGNANCY...
We found no clinically important results from RCTs about the effects of metoclopramide in treating women
with nausea and vomiting in early pregnancy.
For GRADE evaluation of interventions for nausea and vomiting in early pregnancy, see table, p 19 .
Benefits: We found no systematic review or RCTs.
Harms: We found no RCTs.The risk of tardive dyskinesia associated with long-term or high-dose use of
metoclopramide has been highlighted by the FDA (http://www.fda.gov).
© BMJ Publishing Group Ltd 2009. All rights reserved. ........................................................... 9
Nausea and vomiting in early pregnancy
Pregnancy and childbirth
Comment: Studies of the teratogenic potential of metoclopramide are limited. One review of the safety of drugs
for the treatment of nausea and vomiting reported no malformations among four first-trimester ex-
posures to metoclopramide. [23] [36]
Clinical guide:
Metoclopramide is commonly used in clinical practice in some countries, but clinical trials are
needed to evaluate its effect on nausea and vomiting in pregnancy fully.
OPTION PHENOTHIAZINES FOR TREATING NAUSEA AND VOMITING IN EARLY PREGNANCY.....
Severity of nausea and vomiting
Compared with placebo Phenothiazines may be no more effective at reducing nausea (very low-quality evidence).
Compared with antihistamines We don't know whether phenothiazines are more effective at reducing nausea and
vomiting (low-quality evidence).
For GRADE evaluation of interventions for nausea and vomiting in early pregnancy, see table, p 19 .
Benefits: Phenothiazines versus placebo:
We found one systematic review (search date 2002, 2 RCTs, 300 women). [12] It found no significant
difference in nausea between phenothiazines and placebo using a random effects model (34/153
[22%] with phenothiazine v 97/147 [66%] with placebo; RR 0.28, 95% CI 0.06 to 1.29). [12]
Phenothiazines versus antihistamines:
We found one RCT comparing three outpatient treatments: prochlorperazine (a phenothiazine;
25 mg rectal suppositories every 12 hours as needed); promethazine (an antihistamine; 25 mg
orally every 6 hours as needed); and pyridoxine (50 mg intramuscularly) plus metoclopramide
(10 mg orally every 6 hours). [37] It found a similar number of emesis episodes and similar proportions
of people reporting no improvement or worsening of symptoms (5-point scale ranging from much
worse to much better) on the third day with prochlorperazine and promethazine, but did not report
a statistical assessment of this difference (174 women in the first trimester of a singleton pregnancy;
mean number of emesis episodes on day 3: 1.1 with prochlorperazine v 0.8 with promethazine;
self-reported symptoms displayed graphically; AR for feeling the same or worse on day 3: about
60% for both groups; significance assessments not performed). [37]
Harms: Phenothiazines versus placebo:
We found two systematic reviews (search dates 1998, [23] and 2002). [12] The earlier review as-
sessed harms in seven controlled observational trials (78,440 women), and found no evidence of
teratogenicity associated with phenothiazines (RR 1.00, 95% CI 0.84 to 1.18). [23] The second review
(1 RCT, 161 women) gave no information on teratogenicity associated with phenothiazines. [12]
However, harms associated with different phenothiazines vary, making it difficult to interpret a
summary analysis.
Phenothiazines versus antihistamines:
The RCT found one neonatal anomaly (ventricular septal defect; 1/50 [2%]) in the prochlorperazine
group, and no neonatal anomalies in the promethazine group. [37]
Comment: The trials identified by the review were old and lacked sufficient information to appraise the quality
of randomisation or allocation concealment. A more conservative (random effects) analysis was
used in the review because of significant heterogeneity between studies. Fixed-effect analysis
found a reduction in nausea with phenothiazines, but this analysis had significant heterogeneity
and should be interpreted with caution.
QUESTION What are the effects of treatments for hyperemesis gravidarum?
OPTION ACUPRESSURE FOR TREATING HYPEREMESIS GRAVIDARUM................... New
Severity of hyperemesis gravidarum
Compared with placebo or control P6 acupressure may be more effective at reducing nausea and vomiting in women
with hyperemesis gravidarum (very low-quality evidence).
For GRADE evaluation of interventions for nausea and vomiting in early pregnancy, see table, p 19 .
Benefits: Acupressure versus placebo or control:
We found one systematic review (search date from 1989 to 2005) examining the effects of acupres-
sure, acupuncture, and electrical stimulation in women with nausea and vomiting during pregnancy.
© BMJ Publishing Group Ltd 2009. All rights reserved. .......................................................... 10
Nausea and vomiting in early pregnancy
Pregnancy and childbirth
[13] The review identified one RCT for acupressure in women with hyperemesis, but pooled data
for a mixed population of women with nausea and vomiting and women with hyperemesis; hence
it is not discussed further.We found one RCT (66 women; gestational age range 530 weeks)
comparing the effects of acupressure at the Neiguan point (P6) versus placebo (acupressure applied
around the radial pulse at the wrist) and control (conventional intravenous fluid therapy) for 57
days in women diagnosed with hyperemesis gravidarum.The RCT found that nausea and vomiting
was significantly lower with acupressure compared with placebo and control on the 3rd and 4th
day after admission, and on the day of discharge (data presented graphically; reported as significant;
P value not reported).The RCT reported no significant difference in mean nausea and vomiting
scores among the three groups on the day of admission (mean nausea and vomiting scores: 26.26
with acupressure v 26.24 with placebo v 25.86 with control; P = 0.901 for all groups). It found a
significant difference among the groups in nausea and vomiting scores on the 3rd and 4th day after
admission, and on the day of discharge (mean nausea and vomiting scores: 3rd day: 17.57 with
acupressure v 22.05 with placebo v 21.59 with control; P = 0.014 for all groups; 4th day: 12.48 with
acupressure v 19.38 with placebo v 17.91 with control; P less than 0.001 for all groups; day of
discharge: 9.22 with acupressure v 14.67 with placebo v 13.05 with control; P less than 0.001 for
all groups).The RCT did not assess between-group comparisons for acupressure versus either
placebo or control. However, the RCT found no significant difference in nausea and vomiting scores
between the placebo and control groups (P = 0.802; absolute numbers not reported).The severity
of the degree of nausea and vomiting was assessed using a modified form of the full Rhodes Index
score (6 physical symptoms of Rhodes score: frequency of nausea and vomiting, amount of vomitus,
duration of nausea, and degree of discomfort caused by nausea and vomiting measured on a scale
ranging from 6 [lowest = slight nausea] to 30 [highest = severe nausea and vomiting]). Acupressure
was applied using the thumb for 10 minutes three times daily. [38] The study also reported no sig-
nificant difference in the levels of ketonuria among the three groups on discharge (P = 0.063, ab-
solute numbers not reported); however, levels of ketonuria were controlled more quickly in the P6
acupressure group compared with placebo or control groups during hospital stay.
Harms: The RCT did not report on adverse effects. [38]
Comment: Conducting high-quality trials in this area is complicated, as interventions are difficult to mask and
control with credible or appropriate placebos.
OPTION ACUPUNCTURE FOR TREATING HYPEREMESIS GRAVIDARUM.......................
Severity of hyperemesis gravidarum
Compared with sham acupuncture Active PC6 acupuncture may be more effective at reducing nausea and vomiting
in women with hyperemesis gravidarum (low-quality evidence).
For GRADE evaluation of interventions for nausea and vomiting in early pregnancy, see table, p 19 .
Benefits: We found one crossover RCT (50 women admitted to hospital with vomiting; gestational age range
616 weeks) comparing PC6 acupuncture versus sham acupuncture. [39] PC6 acupuncture was
applied 5 mm beneath the skin, whereas sham acupuncture was applied 12 mm beneath the skin
on the lateral side of the forearm. Both interventions were given three times daily for 30 minutes
on days 1 and 2 of the trial. After this, the women crossed over. The interventions were given again
on days 5 and 6. All women were assessed on day 8. All women were vomiting on the day of ran-
domisation.The RCT found that women receiving PC6 acupuncture had a significantly faster res-
olution of nausea than women receiving sham acupuncture (P = 0.032). It also found that, at day
4, PC6 acupuncture significantly reduced the proportion of women who vomited compared with
sham acupuncture (7/17 [41%] with acupuncture v 12/16 [75%] with sham acupuncture; P = 0.049).
No significant differences were found between groups with regard to food intake and the need for
intravenous fluids (reported as not significant; significance assessments not performed). [39]
Harms: The RCT found no adverse effects associated with acupuncture in any women during the study.
[39]
Comment: The placebo treatment (sham acupuncture) used in the RCT was superficial acupuncture on an
area away from a real acupuncture point. Needles were inserted only 12 mm into the skin.The
authors of the RCT state that this kind of stimulation minimises the specific effects of acupuncture.
[39] However, it may not be an entirely inert placebo, as some sensory stimulation does occur.
OPTION CORTICOSTEROIDS FOR TREATING HYPEREMESIS GRAVIDARUM...................
Severity of hyperemesis gravidarum
© BMJ Publishing Group Ltd 2009. All rights reserved. .......................................................... 11
Nausea and vomiting in early pregnancy
Pregnancy and childbirth
Compared with placebo Corticosteroids seem to be no more effective at reducing persistent vomiting in women with
hyperemesis gravidarum (moderate-quality evidence).
Compared with antihistamines We don't know whether corticosteroids are more effective at reducing nausea and
vomiting (low-quality evidence).
Compared with metoclopramide Corticosteroids seem to be more effective at reducing vomiting episodes in women
with hyperemesis gravidarum (moderate-quality evidence).
Hospital admission/readmission rates
Compared with placebo Corticosteroids may be no more effective at reducing hospital readmission rates in women
with persistent vomiting (low-quality evidence).
Compared with antihistamines Methylprednisolone seems to be more effective than promethazine at reducing rates
of subsequent admission to hospital, but may be associated with adverse effects (moderate-quality evidence).
Compared with metoclopramide Corticosteroids seem to be more effective at reducing rates of readmission to the
intensive care unit within 2 weeks of initial therapy in women with recurrent severe persistent vomiting (moderate-
quality evidence).
For GRADE evaluation of interventions for nausea and vomiting in early pregnancy, see table, p 19 .
Benefits: We found two systematic reviews (search dates 1998 [23] and 2002), [12] which identified two RCTs
(65 women), [40] [41] and three subsequent RCTs. [42] [43] [44]
Corticosteroids versus placebo:
The first RCT (25 women with severe hyperemesis, mean gestational age of 10.6 weeks for pred-
nisolone and 8.3 weeks for placebo) identified by the reviews compared oral prednisolone 20 mg
twice daily versus placebo for 1 week. [40] It found that, compared with placebo, oral prednisolone
had no significant effect on persistent vomiting (5/12 [42%] with prednisolone v 7/12 [58%] with
placebo; RR 0.71, 95% CI 0.31 to 1.63) or subsequent readmission to hospital (5/12 [42%] with
prednisolone v 8/12 [67%] with placebo; RR 0.63, 95% CI 0.29 to 1.36). However, it may have
been too small to detect a clinically important effect.The first subsequent RCT (126 women, less
than 20 weeks' gestation) compared intravenous methylprednisolone 125 mg followed by an oral
prednisolone taper (40 mg for 1 day, 20 mg for 3 days, 10 mg for 3 days, 5 mg for 7 days) versus
placebo for the same regimen. [42] All women also received promethazine 25 mg and metoclo-
pramide 10 mg intravenously every 6 hours for 24 hours, followed by the same regimen given
orally as needed until discharge.The primary study outcome was the number of women requiring
readmission to hospital for hyperemesis gravidarum.The RCT found no significant difference in
hospital readmission between methylprednisolone and placebo (19/56 [34%] with methylprednisolone
v 19/54 [35%] with placebo; P = 0.89).
Corticosteroids versus antihistamines:
The second RCT (40 women admitted to hospital at less than 16 weeks' gestation) identified by
the reviews compared oral methylprednisolone versus promethazine, and found no significant dif-
ference in persistence of vomiting (OR 1.56, 95% CI 0.25 to 9.94). [41] However, it found that
methylprednisolone significantly reduced rates of subsequent admission to hospital (0/17 [0%] with
methylprednisolone v 5/18 [28%] with promethazine; OR 0.11, 95% CI 0.02 to 0.71).The second
subsequent RCT (80 pregnant women, 612 weeks' gestation) compared oral prednisolone 5 mg
daily versus oral promethazine 75 mg daily for 10 days. [43] The RCT found that prednisolone was
significantly less effective than promethazine in reducing the proportion of women with severe
nausea during the first 48 hours (20/40 [50%] with prednisolone v 10/40 [25%] with promethazine;
P = 0.02). However, it found no significant difference in severe nausea between the two groups
after the first 72 hours (at 310 days: 14/40 [35%] with prednisolone v 15/40 [38%] with promet-
hazine; P = 0.80; at day 17: 22/40 [56%] with prednisolone v 27/40 [69%] with promethazine;
P = 0.23).
Corticosteroids versus metoclopramide:
The third subsequent RCT (40 women admitted to intensive care at less than 16 weeks' gestation)
compared intravenous hydrocortisone (300 mg/day) versus intravenous metoclopramide (10 mg
three times daily) for intractable hyperemesis gravidarum for 1 week. [44] The RCT found that hy-
drocortisone significantly reduced the mean number of vomiting episodes on days 2, 3, and 7
compared with metoclopramide (reduction of mean number of vomiting episodes: 41% on day 2,
72% on day 3, 96% on day 7 with hydrocortisone v 17% on day 2, 51% on day 3, 77% on day 7
with metoclopramide; P less than 0.0001). Hydrocortisone significantly reduced the proportion of
women readmitted to the intensive care unit for recurrence of severe persistent vomiting within 2
© BMJ Publishing Group Ltd 2009. All rights reserved. .......................................................... 12
Nausea and vomiting in early pregnancy
Pregnancy and childbirth
weeks of initial treatment compared with metoclopramide (0/20 [0%] with hydrocortisone v 6/20
[30%] with metoclopramide; P less than 0.0001). [44]
Harms: The first review included controlled observational studies (8 studies, 109,602 women) and found
no evidence of teratogenicity (RR 1.24, 95% CI 0.97 to 1.60). [23]
Corticosteroids versus placebo:
The RCT identified by the reviews gave no information on adverse effects. [12] [23] The first subse-
quent RCT found no significant difference in pregnancy complications between corticosteroids and
placebo. [42]
Corticosteroids versus antihistamines:
The RCT identified by the reviews gave no information on adverse effects. [12] [23] The second
subsequent RCT found that prednisolone caused significantly less drowsiness than promethazine
(0/40 [0%] with prednisolone v 6/40 [15%] with promethazine; P = 0.026 at both 48 hours and be-
tween days 310). [43] It found no significant difference between prednisolone and promethazine
in the incidence of abdominal pain (at 48 hours: 2/40 [5%] with prednisolone v 6/40 [15%] with
promethazine; between days 30: 0/40 [0%] with prednisolone v 4/40 [10%] with promethazine;
reported as not significant for both timeframes, P values not reported).
Corticosteroids versus metoclopramide:
The RCT did not report on adverse effects. [44]
Comment: Clinical guide:
The rates of spontaneous resolution of symptoms in control groups were high.The possible benefit
of methylprednisolone in preventing subsequent admission to hospital must be balanced against
possible adverse effects of steroids given in the first trimester of pregnancy. Clinical judgment
would be more important in specific situations as there are no reports of adverse effects; however,
these may be rare but serious.
OPTION CORTICOTROPHINS FOR TREATING HYPEREMESIS GRAVIDARUM...................
Severity of hyperemesis gravidarum
Compared with placebo Intramuscular corticotrophin may be no more effective at improving nausea scores in women
with hyperemesis gravidarum (low-quality evidence).
For GRADE evaluation of interventions for nausea and vomiting in early pregnancy, see table, p 19 .
Benefits: We found two systematic reviews (search dates 1998 [23] and 2002) [12] of corticotrophins in hyper-
emesis gravidarum, which identified the same single RCT (32 women, gestational ages and
severity of hyperemesis were not reported). [45] The RCT compared intramuscular corticotrophin
(adrenocorticotrophic hormone) 0.5 mg versus placebo. [45] It found no significant difference between
intramuscular corticotrophin and placebo in nausea relief scores (measured on a scale ranging
from 15 = lack of nausea to 20 = worst possible hyperemesis;WMD relief score +0.6, 95% CI 1.65
to +2.85).There was also no difference between groups in the time from starting treatment to
stopping vomiting (significance not assessed), and all women stopped vomiting while in hospital.
Women remained in hospital for at least 10 days.There was no difference between groups in the
number of readmissions to hospital (significance not assessed).
Harms: The first systematic review gave no information on adverse effects. [12] The second systematic
review reported no adverse effects associated with corticotrophins. [23]
Comment: None.
OPTION DIAZEPAM FOR TREATING HYPEREMESIS GRAVIDARUM............................
Severity of hyperemesis gravidarum
Compared with placebo We don't know whether diazepam is more effective at reducing the severity of nausea and
vomiting in women with hyperemesis gravidarum (very low-quality evidence).
For GRADE evaluation of interventions for nausea and vomiting in early pregnancy, see table, p 19 .
Benefits: We found one systematic review (search date 2002, 1 RCT, 50 women admitted to hospital) [12]
comparing intravenous fluids containing a multivitamin preparation with or without diazepam 20 mg
daily. After symptoms settled, women were randomised to receive oral diazepam 5 mg twice daily
for 1 week or placebo.The trial found no significant difference in persistence of vomiting after 2
days of treatment (assessment not clearly reported; OR 0.64, 95% CI 0.10 to 4.19). It reported a
© BMJ Publishing Group Ltd 2009. All rights reserved. .......................................................... 13
Nausea and vomiting in early pregnancy
Pregnancy and childbirth
decrease in rates of readmission to hospital with diazepam (4% with diazepam v 27% with placebo;
detailed figures not reported). [12]
Harms: The RCT gave no information on adverse effects or acceptability of treatment. [12]
Comment: The trial was too small to draw reliable conclusions.The rate of resolution in the control group was
high, and the effects of the vitamins used in the RCT are unknown.
OPTION DIETARY INTERVENTIONS (OTHER THAN GINGER) FOR TREATING HYPEREMESIS
GRAVIDARUM................................................................
Severity of hyperemesis gravidarum
Carob seed powder compared with placebo We don't know whether dietary supplementation with carob seed flour
plus calcium lactate is more effective at relieving vomiting in women with hyperemesis gravidarum (low-quality evi-
dence).
For GRADE evaluation of interventions for nausea and vomiting in early pregnancy, see table, p 19 .
Benefits: Carob seed powder versus placebo:
We found no systematic review.We found one crossover RCT (43 women) comparing 1 g daily of
a powder containing 96.5% carob seed flour plus 3.5% calcium lactate versus placebo for 3 weeks.
[46] It found no significant difference in relief of vomiting (subjective improvement: 20/34 [59%] with
carob seed flour v 18/36 [50%] with placebo; RR 1.18, 95% CI 0.82 to 1.70). However, the trial
was conducted in 1966, so it is unclear whether the composition of carob seed flour now commer-
cially available will be the same as was used in the trial. [46]
Harms: The RCT found no adverse effects associated with carob seed flour. [46]
Comment: None.
OPTION GINGER FOR TREATING HYPEREMESIS GRAVIDARUM..............................
Severity of hyperemesis gravidarum
Compared with placebo We don't know whether ginger is more effective at reducing hyperemesis scores at 4 days
in women with hyperemesis gravidarum (very low-quality evidence).
For GRADE evaluation of interventions for nausea and vomiting in early pregnancy, see table, p 19 .
Benefits: Ginger versus placebo:
We found two systematic reviews (search dates 2002 [12] and 2004). [25] Both reviews identified
the same crossover RCT comparing ginger 250 mg in oral capsules taken four times daily versus
placebo. [47] The RCT reported that ginger reduced hyperemesis score (which evaluated degree
of nausea and vomiting, weight gain, and participant-reported symptom relief) compared with
placebo after 4 days (30 women admitted to hospital with hyperemesis gravidarum, 27 women in-
cluded in the analysis; higher hyperemesis score indicates fewer symptoms; mean score before
crossover: 4.1 with ginger v 0.9 with placebo; P = 0.035). [47] However, analysis by one of the reviews
of this outcome found no significant difference in hyperemesis score reduction (WMD +3.15, 95%
CI 0.92 to +7.22). [12] The RCT reported results before crossover, but it was too small to allow
reliable conclusions. [47]
Harms: The RCT reported no adverse effects associated with ginger. [47]
Comment: None.
OPTION METOCLOPRAMIDE FOR TREATING HYPEREMESIS GRAVIDARUM............... New
Severity of hyperemesis gravidarum
Compared with corticosteroids Metoclopramide seems to be less effective at reducing vomiting episodes in women
with hyperemesis gravidarum (moderate-quality evidence).
Hospital admission/readmission rates
Compared with corticosteroids Metoclopramide seems to be less effective at reducing rates of readmission to the
intensive care unit within 2 weeks of initial therapy in women with recurrent severe persistent vomiting (moderate-
quality evidence).
Note
© BMJ Publishing Group Ltd 2009. All rights reserved. .......................................................... 14
Nausea and vomiting in early pregnancy
Pregnancy and childbirth
We found no clinically important results from RCTs about the effects of metoclopramide in women with nausea and
vomiting in early pregnancy.
For GRADE evaluation of interventions for nausea and vomiting in early pregnancy, see table, p 19 .
Benefits: Metoclopramide versus placebo:
We found no systematic review or RCTs.
Metoclopramide versus corticosteroids:
See benefits of corticosteroids, p 11 .
Harms: Metoclopramide versus placebo:
We found no RCTs.The risk of tardive dyskinesia associated with long-term or high-dose use of
metoclopramide has been highlighted by the FDA (http://www.fda.gov).
Metoclopramide versus corticosteroids:
See harms of corticosteroids, p 11 .
Comment: Studies of the teratogenic potential of metoclopramide are limited. One review of the safety of drugs
for the treatment of nausea and vomiting reported no malformations among four first trimester ex-
posures to metoclopramide. [23] [36]
Clinical guide:
Metoclopramide is commonly used in clinical practice in some countries, but clinical trials are
needed to fully evaluate its effects on nausea and vomiting in pregnancy.
OPTION ONDANSETRON FOR TREATING HYPEREMESIS GRAVIDARUM.......................
Severity of hyperemesis gravidarum
Compared with antihistamines Ondansetron and promethazine seem to be equally effective at 48 hours at reducing
the proportion of women with hyperemesis gravidarum (moderate-quality evidence).
Note
We found no direct information about whether ondansetron is better than no active treatment.
For GRADE evaluation of interventions for nausea and vomiting in early pregnancy, see table, p 19 .
Benefits: Ondansetron versus placebo:
We found no systematic review or RCTs.
Ondansetron versus antihistamines:
We found one systematic review (search date 2002, 1 RCT, [48] 30 women admitted to hospital).
[12] The RCT compared ondansetron 10 mg versus promethazine 50 mg, both given by 50 mL in-
travenous solution over 30 minutes. Subsequent doses were given as needed every 8 hours until
the woman was able to eat a bland diet.The RCT found no significant difference between on-
dansetron and promethazine in the proportion of women who were vomiting at 48 hours (1/15 [7%]
with ondansetron v 3/15 [20%] with promethazine; RR 0.33, 95% CI 0.04 to 2.85). However, the
RCT was too small to draw reliable conclusions. [48]
Harms: Ondansetron versus placebo:
We found no RCTs.
Ondansetron versus antihistamines:
The review did not report on harms.The RCT identified by the review found that promethazine
significantly increased sedation compared with ondansetron (8/15 [53%] with promethazine v 0/15
[0%] with ondansetron; P = 0.002). [48] No other adverse effects were reported.
Comment: None.
GLOSSARY
Acupressure Pressure applied to a specific point of the body. It does not require needles and can be given by patients
themselves. Commercial products available include an elastic band to fit around the wrist with a plastic disc to apply
pressure at the P6 point.
Hydatidiform mole A condition in which there is abnormal cystic development of the placenta.The uterus is often
large for the duration of pregnancy and there may be vaginal bleeding, lack of fetal movement and fetal heart sounds,
and severe nausea and vomiting. Rarer, but important, complications include haemorrhage, intrauterine infection,
© BMJ Publishing Group Ltd 2009. All rights reserved. .......................................................... 15
Nausea and vomiting in early pregnancy
Pregnancy and childbirth
hypertension, and persistent gestational trophoblastic disease, which may infiltrate local tissues or metastasise to
distant sites.
Metabolic hypochloraemic alkalosis Excess base alkali in the body fluids caused by chloride loss.
P6 acupressure Pressure is applied at the P6 (Neiguan) point on the volar aspect of the wrist.
PC6 acupuncture The needle is applied at the PC6 point located near to the wrist crease.
Wernicke's encephalopathy A severe syndrome caused by a deficiency of thiamine (vitamin B1). It is usually asso-
ciated with excessive alcohol abuse and is characterised by abnormal eye movements, confusion, and loss of short
term memory and muscular coordination.
Low-quality evidence Further research is very likely to have an important impact on our confidence in the estimate
of effect and is likely to change the estimate.
Moderate-quality evidence Further research is likely to have an important impact on our confidence in the estimate
of effect and may change the estimate.
Very low-quality evidence Any estimate of effect is very uncertain.
SUBSTANTIVE CHANGES
Acupressure for treating hyperemesis gravidarum: One RCT added, which found that acupressure was more
effective at reducing nausea and vomiting episodes compared with placebo and control (conventional intravenous
fluid). [38] Categorised as Likely to be beneficial.
Metoclopramide for treating hyperemesis gravidarum: One RCT found that metoclopramide was less effective
at reducing vomiting episodes and readmission to the intensive care unit compared with corticosteroids. [44] Other
drugs and interventions may be more useful. Categorised as Unlikely to be beneficial.
Acupressure for treating nausea and vomiting in early pregnancy: One systematic review [13] and two RCTs
added. [15] [19] The systematic review found that acupressure applied as a wristband reduced the proportion of
women reporting nausea and vomiting compared with control. One RCT found no significant difference between
acupressure and placebo in the number of women who reported nausea and vomiting. [15] The RCT comparing
acupressure and pyridoxine found no significant difference between the two treatments in Rhodes index scores. [19]
Categorisation unchanged (Likely to be beneficial).
Acupuncture for treating nausea and vomiting in early pregnancy: One systematic review added. [13] The review
identified the same RCTs already reported and came to similar conclusions. Categorisation unchanged (Unknown
effectiveness).
Antihistamines (H1 antagonists) for treating nausea and vomiting in early pregnancy: One RCT added. [24]
The RCT found that the antihistamine dimenhydrinate improved vomiting for the first 2 days compared with ginger,
but there was no significant difference at days 37. It also found no significant difference in nausea scores between
the two groups. Categorisation unchanged (Likely to be beneficial).
Ginger for treating nausea and vomiting in early pregnancy:Two RCTs added. [24] [29] One RCT found that
ginger was more effective at reducing nausea and vomiting scores compared with pyridoxine. [29] One RCT comparing
ginger and antihistamines found that that dimenhydrinate improved vomiting for the first 2 days compared with ginger,
but there was no significant difference at days 37. It also found no significant difference in nausea scores between
the two groups. [24] Categorisation unchanged (Likely to be beneficial).
Pyridoxine (vitamin B6) for treating nausea and vomiting in early pregnancy: Two RCTs added. [15] [29] The
RCT comparing acupressure and pyridoxine found no significant difference between the two treatments in Rhodes
index scores.The other RCT found that pyridoxine was less effective compared with ginger at reducing nausea and
vomiting scores. Categorisation unchanged (Likely to be beneficial).
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in a randomised controlled trial of acupuncture to treat nausea and vomiting in
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36. Magee LA, Mazzotta P, Koren G. Evidence-based view of safety and effectiveness
of pharmacologic therapy for nausea and vomiting of pregnancy (NVP).Am J
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38. Shin HS, Song YA, Seo S. Effect of Nei-Guan point (P6) acupressure on ketonuria
levels, nausea and vomiting in women with hyperemesis gravidarum. J Adv Nurs
2007;59:510519.[PubMed]
39. Carlsson CP, Axemo P, Bodin A, et al. Manual acupuncture reduces hyperemesis
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Pain Symptom Manage 2000;20:273279.[PubMed]
40. Nelson-Piercy C, Fayers P, de Swiet M. Randomised, double-blind, placebo-
controlled trial of corticosteroids for the treatment of hyperemesis gravidarum.
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41. Safari HR, Fassett MJ, Souter IC, et al.The efficacy of methylprednisolone in
the treatment of hyperemesis gravidarum: a randomized, double-blind, controlled
study.Am J Obstet Gynecol 1998;179:921924.[PubMed]
42. Yost NP, McIntire DD, Wians FH Jr, et al. A randomized, placebo-controlled trial
of corticosteroids for hyperemesis due to pregnancy.Obstet Gynecol
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treatment for intractable hyperemesis gravidarum. Crit Care Med
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45. Ylikorkala O, Kauppila A, Ollanketo ML. Intramuscular ACTH or placebo in the
treatment of hyperemesis gravidarum. Acta Obstet Gynecol Scand
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46. General Practitioner's Research Group. Hyperemesis treated with a pharmaco-
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for hyperemesis gravidarum.Am J Obstet Gynecol 1996;174:15651568.[PubMed]
49. Norheim AJ, Pedersen EJ, Fønnebø V, et al. Acupressure treatment of morning
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Mario Festin
Obstetrician Gynaecologist, University of the Philippines Manila
College of Medicine
Philippine General Hospital
Manila
Philippines
Competing interests: MRF declares that he has no competing interests.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a
judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and
harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices.
Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research
we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the
categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately
it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest
extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any
person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, inci-
dental or consequential, resulting from the application of the information in this publication.
© BMJ Publishing Group Ltd 2009. All rights reserved. .......................................................... 17
Nausea and vomiting in early pregnancy
Pregnancy and childbirth
TABLE 1 Acupressure in women with nausea and vomiting in pregnancy: results of systematic reviews. [12] [13]
ResultsMethodsRef
Episodes of morning sickness:
37/145 (25%) with acupressure v 61/140 (43%) with sham acupressure; RR 0.57, 95% CI 0.38 to 0.86
Systematic review, 2 RCTs, 285 women included in the meta-analysis
[12]
Duration of nausea and vomiting (active wristband acupressure v sham wristband acupressure):
WMD 1.89 hours/12-hour cycle, 95% CI 3.45 hours/12-hour cycle to 0.33 hours/12-hour cycle
RCT (randomised block design), [49] 97 women, 812 weeks' gestation
[12]
Intensity of nausea and vomiting:
WMD 0.25, 95% CI 0.62 to +0.12
[12]
Intensity of nausea (P6 acupressure v no treatment): mean nausea score:
At day 1:WMD 2.40, 95% CI 3.78 to 1.02; P = 0.0006
At day 6:WMD 2.00, 95% CI 3.37 to 0.63; P = 0.004
At day 14:WMD 2.30, 95% CI 3.79 to 0.81; P = 0.003
RCT (women drew envelopes from box), [20] 60 women, mean gesta-
tional ages of 9.8 weeks in the P6 group v 9.6 weeks in the sham
acupressure group v 10.8 weeks in the no treatment group
[12]
Intensity of nausea (P6 acupressure v sham acupressure): mean nausea score:
At day 1:WMD 0.40, 95% CI 2.01 to +1.21; P = 0.63
At day 6:WMD 1.4, 95% CI 2.89 to 0.09; P = 0.07
At day 14:WMD 1.7, 95% CI 3.25 to 0.15; P = 0.03
All WMDs calculated by Clinical Evidence contributor
Proportion of women reporting nausea (finger acupressure v control):
23/119 (19%) with finger acupressure v 108/231 (47%) with control; RR 0.41, 95% CI 0.28 to 0.60; P = 0.005
1 RCT, 350 women, mean gestational ages 7.210.0 weeks
[13]
Proportion of women reporting nausea (wristband acupressure v control):
32/102 (31%) with wristband accupressure v 60/106 (57%) with control; RR 0.55, 95% CI 0.38 to 0.77; P = 0.007
2 RCTs (4 crossover), 273 women, mean gestational ages 811 weeks
[13]
Proportion of women reporting vomiting (wristband acupressure v control): 29/107 (27%) with wristband acu-
pressure v 58/131 (44%) with control; RR 0.45, 95% CI 0.32 to 0.63; P less than 0.001
5 RCTs (3 crossover), 250 women, mean gestational ages 811 weeks
[13]
Proportion of women reporting nausea (placebo v control):
41/112 (37%) with placebo v 77/133 (58%) with control; RR 0.63, 95% CI 0.39 to 1.02; P = 0.0479
3 RCTs (2 crossover) 421 women, mean gestational ages 811 weeks
[13]
© BMJ Publishing Group Ltd 2009. All rights reserved. ............................................................................................................ 18
Nausea and vomiting in early pregnancy
Pregnancy and childbirth
TABLE GRADE evaluation of interventions for nausea and vomiting in early pregnancy
Severity of nausea/vomiting, severity of hyperemesis gravidarum, hospital admission/readmission rates, adverse effects
Important out-
comes
CommentGRADE
Effect
size
Direct-
ness
Consis-
tencyQuality
Type of
evi-
denceComparisonOutcome
Number of studies
(participants)
What are the effects of treatment for nausea and vomiting in early pregnancy?
Quality points deducted for randomisation flaws and
other methodological flaws. Consistency point deduct-
Very low01124Acupressure v sham acu-
pressure/no treatment
Severity of nausea or vomitingAt least 14 RCTs (at
least 1853 wom-
en) [12] [13] [14]
[15] ed for conflicting results. Directness point deducted
for inclusion of different interventions
Quality point deducted for sparse data and incom-
plete reporting of results. Directness point deducted
for inclusion of other interventions
Very low01024Acupressure v pyridoxineSeverity of nausea or vomiting1 (66) [19]
Quality points deducted for randomisation flaws.
Consistency point deducted for heterogeneity among
studies
Low00114Antihistamines v placeboSeverity of nausea and vomit-
ing
At least 7 RCTs (at
least 1190 women)
[12] [23]
Consistency point deducted for conflicting results.
Directness point deducted for uncertainty about inter-
vention
Low01104Ginger v placeboSeverity of nausea and vomit-
ing
3 (216) [25]
Directness points deducted for uncertainty about in-
tervention and uncertainty about effects of taking
additional ginger products
Low02004Ginger v pyridoxine (vitamin
B6)
Severity of nausea and vomit-
ing
3 (552) [25] [29]
Quality points deducted for sparse data and incom-
plete reporting of results. Consistency point deducted
for different results at different endpoints
Very low00124Ginger v antihistaminesSeverity of nausea and vomit-
ing
1 (170) [24]
Quality points deducted for randomisation issues and
uncertain diagnosis or outcome
Low00024Pyridoxine v placeboSeverity of nausea and vomit-
ing
5 (787) [12] [23]
Quality point deducted for incomplete reporting of
results. Directness point deducted for uncertainty
about benefit
Low01014Acupuncture v sham
acupuncture/no treatment
Severity of nausea and vomit-
ing
2 (648) [12]
Quality points deducted for uncertainty about randomi-
sation and allocation. Consistency point deducted
for heterogeneity among studies
Very low00124Phenothiazines v placeboSeverity of nausea and vomit-
ing
2 (300) [12]
Quality points deducted for sparse data and incom-
plete reporting of results
Low00024Antihistamines v phenoth-
iazines
Severity of nausea and vomit-
ing
1 (174) [37]
What are the effects of treatments for hyperemesis gravidarum?
Quality points deducted for sparse data and incom-
plete reporting of results. Directness point deducted
for no direct comparison between interventions
Very low01024Acupressure v placebo/con-
trol
Severity of hyperemesis
gravidarum
1 (66) [38]
Quality points deducted for sparse data and incom-
plete reporting of results
Low00024Acupuncture v sham
acupuncture
Severity of hyperemesis
gravidarum
1 (50) [39]
© BMJ Publishing Group Ltd 2009. All rights reserved. ............................................................................................................ 19
Nausea and vomiting in early pregnancy
Pregnancy and childbirth
Severity of nausea/vomiting, severity of hyperemesis gravidarum, hospital admission/readmission rates, adverse effects
Important out-
comes
CommentGRADE
Effect
size
Direct-
ness
Consis-
tencyQuality
Type of
evi-
denceComparisonOutcome
Number of studies
(participants)
Quality point deducted for sparse dataModerate00014Corticosteroids v placeboSeverity of hyperemesis
gravidarum
1 (24) [40]
Quality point deducted for sparse data. Directness
point deducted for inclusion of other interventions
Low01014Corticosteroids v placeboHospital admission/readmis-
sion rates
2 (150) [40] [42]
Quality point deducted for sparse data. Consistency
point deducted for conflicting results at different
endpoints
Low00114Corticosteroids v antihis-
tamines
Severity of hyperemesis
gravidarum
2 (120) [41] [43]
Quality point deducted for sparse dataModerate00014Corticosteroids v antihis-
tamines
Hospital admission/readmis-
sion rates
1 (40) [41]
Quality point deducted for sparse dataModerate00014Corticosteroids v metoclo-
pramide
Severity of hyperemesis
gravidarum
1 (40) [44]
Quality point deducted for sparse dataModerate00014Corticosteroids v metoclo-
pramide
Hospital admission/readmis-
sion rates
1 (40) [44]
Quality points deducted for sparse data and incom-
plete reporting
Low00024Corticotrophins v placeboSeverity of hyperemesis
gravidarum
1 (32) [45]
Quality points deducted for sparse data and incom-
plete reporting . Directness point deducted for uncer-
tainty about effect of other interventions
Very low01024Diazepam v placeboSeverity of hyperemesis
gravidarum
1 (50) [12]
Quality point deducted for sparse data. Directness
point deducted for uncertainty about composition of
intervention
Low01014Carob seed powder plus
calcium lactate v placebo
Severity of hyperemesis
gravidarum
1 (43) [46]
Quality point deducted for sparse data. Consistency
point deducted for conflicting results on analysis. Di-
rectness point deducted for composite outcome
Very low01114Ginger v placeboSeverity of hyperemesis
gravidarum
1 (30) [47]
Quality point deducted for sparse dataModerate00014Ondansetron v antihis-
tamines
Severity of hyperemesis
gravidarum
1 (30) [48]
Type of evidence: 4 = RCT; 2 = Observational
Consistency: similarity of results across studies
Directness: generalisability of population or outcomes
Effect size: based on relative risk or odds ratio
© BMJ Publishing Group Ltd 2009. All rights reserved. ............................................................................................................ 20
Nausea and vomiting in early pregnancy
Pregnancy and childbirth
... [12,13] This varied finding in olfaction in pregnancy may be due to the fact that the effect is more cognitive (central) than sensory (peripheral). [26,28] It may also be because the effect of pregnancy on olfaction is little and may vary with individuals, hence more sensitive tests are required to reveal any appreciable change in olfaction. [28] Olfaction is linked to important cognitive and emotional domains such as the orbitofrontal cortex and the dorsomedial nucleus of the thalamus in the brain. ...
... Human chorionic gonadotropin level peaks during the first trimester and match the profile of selfreported changes. [26] In this study, the prevalence of hyposmia in pregnant women was higher than in the non-pregnant women. Although the participants in this study were not progressively monitored in pregnancy, the five hyposmic pregnant women were identified at their second trimester of pregnancy. ...
Article
Background: Pregnant women require normal olfactory function in order to develop good appetite for healthy living and normal fetal development. This study was carried out to investigate and compare olfactory function of pregnant women with non-pregnant women. Methods: This was a case control study of women in reproductive age group at the University College Hospital, Ibadan, Nigeria from July 2014 to February 2015. Consecutive 70 pregnant women and 70 non-pregnant women (controls) without rhinologic symptoms were studied. A structured questionnaire was administered to obtain participants' information on socio-demographics, pregnancy history, and ability to perceive smell. They subjectively rated their olfactory function on a visual analogue scale of 0 - 100. Olfactory threshold (OT), discrimination (OD), identification (OI) scores and TDI of both groups were determined with"Sniffin' sticks"kits and compared. The level of significance was P<0.05. Results: The mean age of the pregnant women was 30.5±3.9years and control was 28.5±6.6years. There were more pregnant women (7.1%) with hyposmia than the non-pregnant women (2.9%). The subjective rating of olfactory function was 68.2±24.9 (median 70) and 72.3±21.6 (median 69) in pregnant women and controls respectively. The mean OT, OD, OI, TDI scores were higher in pregnant women than the controls. However, it was only in OI (P=0.000) and TDI (P=0.012) that the differences were significant. Conclusions: Pregnant women have olfactory dysfunction more than the non-pregnant women of reproductive age group. Also, they have tendency to develop loss of cognitive olfactory information more than the non-pregnant women.
... In addition, increased amounts of vitamin B6 are needed during pregnancy to ensure fetal brain development, 46 and pyridoxine supplementation may even reduce nausea during early pregnancy. 47 In summary, pyridoxine strongly contributes to the proper functioning of the nervous system by facilitating neurotransmitter and myelin synthesis, and also controlling glutamate excitability and neuronal metabolism. ...
Article
Full-text available
Background: Neurotropic B vitamins play crucial roles as coenzymes and beyond in the nervous system. Particularly vitamin B1 (thiamine), B6 (pyridoxine), and B12 (cobalamin) contribute essentially to the maintenance of a healthy nervous system. Their importance is highlighted by many neurological diseases related to deficiencies in one or more of these vitamins, but they can improve certain neurological conditions even without a (proven) deficiency. Aim: This review focuses on the most important biochemical mechanisms, how they are linked with neurological functions and what deficits arise from malfunctioning of these pathways. Discussion: We discussed the main role of B Vitamins on several functions in the peripheral and central nervous system (PNS and CNS) including cellular energetic processes, antioxidative and neuroprotective effects, and both myelin and neurotransmitter synthesis. We also provide an overview of possible biochemical synergies between thiamine, pyridoxine, and cobalamin and discuss by which major roles each of them may contribute to the synergy and how these functions are inter-related and complement each other. Conclusion: Taking into account the current knowledge on the neurotropic vitamins B1, B6, and B12, we conclude that a biochemical synergy becomes apparent in many different pathways in the nervous system, particularly in the PNS as exemplified by their combined use in the treatment of peripheral neuropathy.
... Increasing of HCG (human chorionic gonadotrophin) concentrations can cause nausea and vomiting. When the condition continued, characterized by severe nausea and vomiting, dehydration, and weight loss it is called hyperemesis gravidarum (Festin 2014). This study found, the prevalence nausea and vomiting in the DG and NG were 70.6% and 53.1%, respectively. ...
... This disorder is less common and affecting between 0.3% and 3% of pregnant women (3). These patients are usually hospitalised and rehydration therapy with pharmacological drugs are used for controlling this ominous condition which may be life threatening in some circumtances like electrolyte imbalance, encephalopaty, ketonaemia and weight loss (4). The exact etiology of EG and HG is not wellestablished and believed to be multi-factorial involving hormonal, immunological and psychosocial factors (5). ...
Article
Full-text available
This prospective, randomized study included 77 women divided randomly into two groups. To investigate the effect of Kinesio taping on nausea and vomiting in women with Emesis Gravidarum. The study group received standard medications as metaclopramide(10 mg) twice in a day and vitamin B6(30 mg) single dose in a day and was performed Kinesio taping on the stomach region over the abdomen, while the control group received only the standard medications for treatment of emesis gravidarum. The degree of nausea and vomiting was evaluated by a 10-cm visual analogue scale (VAS) and Pregnancy unique quantification of emesis (PUQE) scoring. There was no statistically significant difference between the two groups regarding mean of age, gravidity, parity, body mass index, gestational weeks at admission. Both groups showed a significant reduction in nausea and vomiting after the treatments. However, when considering the decrease in PUQE scores and VAS scores in groups from baseline at admission to the fifth day of treatment, the Kinesio tape group was significantly superior than the control group (p=0.048). This randomized, preliminary study demonstrates that Kinesio taping can be a useful and novel treatment option as supplement to the standard medication in the management of emesis gravidarum. © 2018, Yuzuncu Yil Universitesi Tip Fakultesi. All rights reserved.
... Various ailments affecting pregnant women can lead not only to bad mood but also frequent hospitalizations [1]. What is often referred to as the "morning sickness" might occur and prevail at any time during the day [2]. A research conducted by Jewell and Young [3] revealed that around 2% of women are affected by NVP in the morning, whereas up to 80% of women reported some discomfort during the day. ...
Article
Full-text available
Introduction. It is estimated that 90% of pregnant women suffer from nausea and vomiting (NVP). The severity of NVP may vary and the first symptoms tend to appear between the 4th and 9th week of pregnancy, reaching their peak around 7th-12th week and disappear around 16th-20th week of pregnancy. The etiology of both nausea and vomiting is yet to be discovered, yet there is a number of factors that may contribute to it. These symptoms usually accompany the increase of human chorionic gonadotropin (hCG) and most intensive ailments associated to the highest rate of this hormone appear around the 10th week of pregnancy.
Chapter
Nausea and vomiting of pregnancy is a common disorder, affecting up to 80% of pregnancies. The etiology is thought to relate to both hormonal and hereditary factors. Symptom onset typically occurs early in pregnancy, between 6 and 8 weeks’ gestation. In the absence of concerning clinical findings or features suggestive of another etiology, the diagnosis is one of exclusion. Therapeutic approaches are tailored based on severity of symptoms and adverse effects of treatment; therapy is escalated depending on persistence of symptoms and presence of dehydration.
Article
Background Hyperemesis gravidarum (HG) is a major health burden affecting between 1-2% of all pregnancies. The sequelae of the condition can be fatal. There is current equipoise as to how best to manage the condition; that is inpatient versus outpatient management. Objective This study investigated the total length of stay for patients diagnosed with HG, comparing those who were managed as inpatients as opposed to those managed in a day case setting. A case control methodology was utilized. Two tertiary referral centres for HG of similar size and demographic were selected. One preferentially used day case management. The other uses inpatient management. Results In total 61 day, case managed patients and 91 inpatient managed patients were recruited to the study. Adjusting for readmission, total length of stay was 4.08 days for inpatient managed patients compared to 0.39 days for day case managed patients (p=0.0002). Conclusion Day case managed patients for HG have a significantly shorter length of stay. There is no predictive value in the reviewed serum biomarkers as to the likelihood of re-admission.
Article
Background: Nausea and vomiting affect up to 90% of pregnant women. Granisetron is a potent and highly selective serotonin receptor antagonist and is an effective antiemetic. Findings from a prior study in pregnant women demonstrated a large iner-individual variability in granisetron exposure. Granisetron is primarily metabolized by the cytochrome P450 (CYP) enzymes CYP1A1 and CYP3A and is likely a substrate of the ABCB1 transporter. Single-nucleotide polymorphisms (SNPs) in CYP3A, CYP1A1 and ABCB1 can alter drug metabolism. Objective: This study evaluated the influence of polymorphisms in CYP3A4, CYP3A5, CYP1A1 and ABCB1 on the pharmacokinetic properties of granisetron in pregnant women. Methods: The study enrolled 16 pregnant women (gestational age of 12 to 19 weeks). All patients had nausea and vomiting and were treated with granisetron 1 mg. Granisetron plasma concentrations were determined using liquid chromatography tandem-mass spectrometry (LC-MS/MS). The patients' genotype was determined using TaqMan SNP Genotyping Assays. The Hardy-Weinberg equilibrium was assessed by comparing observed and expected genotype frequencies, using the exact test. Intravenous granisetron clearance was used as the dependent variable for analysis of associations. Results: Of 16 patients, 25% were homozygous for the allele variant CYP3A5*3 and had a significantly lower granisetron clearance and increased area under the plasma concentration vs time curve (AUC) compared with non-homozygous patients. Approximately one-third of patients (n=5) were carriers for the allele variant CYP1A1*2A and had a significantly higher granisetron clearance and decreased AUC. We did not find significant differences in the AUC or clearance for any SNP's in CYP3A4 and ABCB1 genes. Conclusions: Polymorphisms in CYP3A5 and CYP1A1 account for some of the variability in systemic clearance and exposure of granisetron in pregnant women. This article is protected by copyright. All rights reserved.
Article
The production of a medical research paper is beset with problems from inception to publication. If the subject involves acupuncture, the problems can seem surprisingly great even for an established university research department. Most acupuncture reports from China are anecdotal in nature and reviewing the Western literature shows that difficulty in definition of techniques has allowed invasive and non-invasive acupuncture to be used interchangeably, with consequent inaccuracy in the reported results. Because of the physical nature of the treatment, not all accepted criteria for clinical trials are achievable and ethical committees may therefore be reluctant to grant approval. Even publication has been made difficult by scepticism from peer reviewers, although a more enlightened attitude is now gaining ground. If acupuncture is to become an accepted treatment, scientific evaluation by experienced research teams and perseverance in gaining publication for the results is vital.
Article
Thirty-two women with hyperemesis gravidarum were treated with intramuscular ACTH (0.5 mg) or placebo for 4 days in a randomized double-blind trial. The two treatments were equally effective in relieving hyperemesis, although the function of the adrenal cortex was stimulated only during the ACTH therapy. The administration of ACTH thus appears useless for the treatment of severe vomiting in early pregnancy.
Article
The generalizability of the apparent decreased risk of miscarriage and perinatal mortality associated with early pregnancy nausea and vomiting was investigated by examining data available from 11 previous studies. Statistical reanalyses of these studies indicated a strong significant association of nausea and vomiting of pregnancy with decreased risk of miscarriage, and no consistent associations with perinatal mortality. A statistical meta-analysis confirmed the decreased risk of miscarriage associated with gestational nausea and vomiting (common odds ratio = 0·36, 95% CI 0·32 to 0·42) and indicated that the association with decreased fetal mortality was restricted to the first 20 weeks gestation. The meta-analysis also revealed that over 150 additional possibly unreported studies with contradictory evidence would be required to refute this observed association.
Article
Background: Nausea and vomiting in early pregnancy are troublesome symptoms for some women. We undertook a single blind randomized controlled trial to determine whether acupuncture reduced nausea, dry retching, and vomiting, and improved the health status of women in pregnancy. Methods: The trial was undertaken at a maternity teaching hospital in Adelaide, Australia, where 593 women less than 14 weeks' pregnant with symptoms of nausea or vomiting were randomized into 4 groups: traditional acupuncture, pericardium 6 (p6) acupuncture, sham acupuncture, or no acupuncture (control). Treatment was administered weekly for 4 weeks. The primary outcomes were nausea, dry retching, vomiting, and health status. Comparisons were made between groups over 4 consecutive weeks. Results: Women receiving traditional acupuncture reported less nausea (p < 0.01) throughout the trial and less dry retching (p < 0.01) from the second week compared with women in the no acupuncture control group. Women who received p6 acupuncture (p < 0.05) reported less nausea from the second week of the trial, and less dry retching (p < 0.001) from the third week compared with women in the no acupuncture control group. Women in the sham acupuncture group (p < 0.01) reported less nausea and dry retching (p < 0.001) from the third week compared with women in the no acupuncture group. No differences in vomiting were found among the groups at any time. Conclusion: Acupuncture is an effective treatment for women who experience nausea and dry retching in early pregnancy. A time-related placebo effect was found for some women.
To determine the effect of continuous acupressure at P, applied by Sea-Bands with acupressure buttons on the frequency and severity of nausea and vomiting of pregnancy during the 1 st trimester. A two-group, quasi-experimental, posttest-only and posttest-repeated measure. Seventeen medical clinics or offices in southern Michigan. Convenience sample of English-speaking, healthy pregnant women in their 1 st trimester, who had at least one episode of nausea, vomiting, or both before their prenatal clinic/office visit where they were recruited. After being accepted for the study, the women were randomly assigned to treatment or placebo groups. Treatment group 1 applied Sea-Bands with acupressure buttons to both wrists for 4 days and removed the Sea-Bands for 3 subsequent days. Placebo group 2 applied the Sea-Bands without acupressure buttons to both wrists on the same time schedule as group 1. Self-report daily diaries of the number of times per day that participants experienced nausea, the severity of nausea, the number of vomiting episodes per day, and the severity of vomiting. Mann-Whitney U procedures revealed that the treatment group had significantly less frequency and severity of nausea and vomiting of pregnancy while wearing the Sea-Bands than did the placebo group. The treatment group also had significantly less frequency and severity of nausea and vomiting of pregnancy while wearing the Sea-Bands than when not wearing the Sea-Bands. Sea-Bands with acupressure buttons are a noninvasive, inexpensive, safe, and effective treatment for the nausea and vomiting of pregnancy.
Article
To evaluate the antiemetic effect of acupressure at the Neiguan point. Sixty women in early pregnancy were entered into a randomized, double-blind, cross-over, placebo-controlled trial. During a 12-day period, organized in four steps of 3 days each, the women were divided into two homogeneous groups to test the effectiveness of unilateral and bilateral acupressure. Use of acupressure resulted in a significantly lower frequency of morning sickness compared with placebo treatment. More than a 60% positive effect was found with unilateral and bilateral acupressure, compared with an approximately 30% positive effect of placebo acupressure. Changing from unilateral to bilateral pressure on the Neiguan point caused no significant statistical difference. No noteworthy side effects occurred. Acupressure on the Neiguan point relieves morning sickness.
Article
Thirty women participated in a double-blind randomized cross-over trial of the efficacy of a natural product, the powdered root of ginger (Zingiber officinale), and placebo in hyperemesis gravidarum. Three patients had to be withdrawn. Each woman swallowed capsules containing either 250 mg ginger or lactose q.i.d. during the first 4 days of the treatment period. Interrupted by a 2 days wash-out period the alternative medication was given in the second 4-day period. The severity and relief of symptoms before and after each period were evaluated by two scoring systems. The scores were used for statistical analyses of possible differences. Subjectively assessed, 19 women (70.4%) stated preference to the period in which ginger, as was later disclosed, had been given (P = 0.003). More objectively assessed by relief scores a significantly greater relief of the symptoms was found after ginger treatment compared to placebo (P = 0.035). No side effects were observed. The possible mutagenic and antimutagenic characters of ginger reported in a study of E. coli have not been evaluated with respect to any significance in humans. Powdered root of ginger in daily doses of 1 g during 4 days was better than placebo in diminishing or eliminating the symptoms of hyperemesis gravidarum.
Article
A prospective study was designed to test the efficacy of pressure at the P6 (Neiguan) acupuncture point, in preventing morning sickness. Three groups of patients in early pregnancy recorded the severity and frequency of sickness over a period of 4 consecutive days following daily pressure at P6 point, pressure at a point near the right elbow and with no treatment. Troublesome sickness was significantly less in both the genuine (23/119) and dummy (41/112) pressure groups as compared with the control series (67/119). When the data are adversely 'weighted' to compensate for the lower incidence of fully completed returns in the active treatment groups, only the P6 group show a significant reduction in sickness. No side effects occurred in either group and while anticipation of benefit may offer a partial explanation for the findings, pressure at the Neiguan point appears to have a specific therapeutic effect.
Article
To evaluate the effectiveness of acupressure in reducing nausea and vomiting of pregnancy. Symptomatic pregnant women were randomized to one of two acupressure groups: one treatment group using an acupressure point (PC-6) and one sham control group using a placebo point. Subjects were blind to the group assignment. Each evening for 10 consecutive days, the subjects completed an assessment scale describing the severity and frequency of symptoms that occurred. Data from the first 3 days were used as pre-treatment scores. Beginning on the morning of the fourth day, each subject used acupressure at her assigned point for 10 minutes four times a day. Data from day 4 were discarded to allow 24 hours for the treatment to take effect. Data from days 5-7 were used to measure treatment effect. Sixty women completed the study. There were no differences between groups in attrition, parity, fetal number, maternal age, gestational age at entry, or pre-treatment nausea and emesis scores. Analysis of variance indicated that both groups improved significantly over time, but that nausea improved significantly more in the treatment group than in the sham control group (F1,58 = 10.4, P = .0021). There were no differences in the severity or frequency of emesis between the groups. There was a significant positive correlation (r = 0.261, P = .044) between maternal age and severity of nausea. Our results indicate that acupressure at the PC-6 anatomical site is effective in reducing symptoms of nausea but not frequency of vomiting in pregnant women.
Article
To review the pathophysiology of gastrointestinal motility disorders during pregnancy, their clinical manifestations, and their management. Studies published from 1963 to 1992 identified by computerized literature searches of Index Medicus and MEDLINE; hand searches; contact with pharmaceutical representatives for information on drug therapy during pregnancy; and selected texts on drugs and obstetrics. Selected studies were those involving controlled design of physiology related to pregnancy or to hormonal effects on the gastrointestinal tract or both, and clinical studies or previous reviews that contributed to the understanding of the gastrointestinal effects of pregnancy. Data concerning the epidemiology, causes, clinical manifestations, and complications of altered gastrointestinal motility during pregnancy as well as the strength of association between gastrointestinal disorders of pregnancy and hormonal changes were evaluated and used to develop a practical approach to evaluate and manage these patients. Effects on the gastrointestinal tract during pregnancy are caused primarily by hormonal changes and not the physical effects of the gravid uterus. Motility changes occur throughout the gastrointestinal tract, including a reduction in lower esophageal sphincter pressure and its physiologic function with resulting gastroesophageal reflux and the risk for aspiration; alterations in gastric motor function associated with nausea and vomiting; and a decrease in the rate of small-bowel and colonic transit manifested primarily as abdominal bloating and constipation. These effects are mediated by progesterone, with estrogen probably acting as a primer. Given the large number of pregnancies each year complicated by gastrointestinal motility disorders, many physicians (including internists and gastroenterologists) must manage these problems. Knowledge of the underlying physiologic alterations in gastrointestinal motility during pregnancy and of safe treatment options is essential to the care of the pregnant patient.