1. Symptomatic relief
P6 acupressure versus placebo (five studies with 508 women)
Five studies compared P6 acupressure to placebo, and we have included data from four of these in the data tables. One study with 100 women showed evidence of a statistically significant effect for acupressure (Aghadam 2010), on severity of nausea (mean difference (MD) -1.70, 95% confidence interval (CI) -2.41 to -0.99, Analysis 1.1) and vomiting (MD -0.90, 95% CI -1.06 to -0.74, Analysis 1.2) after four days of treatment. Results from another study with data for 97 women (Norheim 2001) found no statistically significant difference between groups for improving (i.e. reducing) the intensity of symptoms (risk ratio (RR) 0.78, 95% CI 0.44 to 1.39, Analysis 1.3). After three days of treatment there was no strong evidence that, compared with placebo, the treatment improved nausea in the Werntoft 2001 trial, 40 women (MD 0.10, 95% CI -1.49 to 1.69, Analysis 1.4). Using scores averaged over one to three days for 60 women, results from the Belluomini 1994 study did not show that acupressure improved scores on the nausea and vomiting subscales or on the total Rhodes Index score (for nausea MD 0.39, 95% CI -0.80 to 1.58, Analysis 1.5, for vomiting MD 0.26, 95% CI -1.06 to 1.58, Analysis 1.6, for total Rhodes score MD 1.17, 95% CI -1.52 to 3.86, Analysis 1.7).
One further study (O'Brien 1996) compared P6 acupressure and placebo, but data from this study were not in a form that allowed us to enter them into RevMan tables. The authors reported no statistically significant differences between treatment and placebo groups for symptom relief.
P6 Acupressure versus vitamin B6 (one study with 66 women)
Jamigorn 2007 compared P6 acupressure with vitamin B6 and results showed no statistically significant difference between the two interventions for improvement of nausea on day three (data obtained from authors) (MD 0.20, 95% CI -2.24 to 2.64, Analysis 2.1). The authors also reported on the use of rescue medication (which may be a proxy measure for lack of symptom relief); results favoured P6 acupressure (MD -2.20, 95% CI -3.98 to -0.42, Analysis 2.2). Jamigorn 2007 also compared P6 acupressure and vitamin B6 in terms of satisfaction with the intervention (which could be considered as a proxy for its effectiveness); results suggested that women were more satisfied with acupressure but evidence of a difference between groups did not reach statistical significance (MD 0.40, 95% CI -0.04 to 0.84, Analysis 2.3). Weight gain, another possible proxy for effectiveness, was also reported by Jamigorn 2007 and results favoured the acupressure group (MD 0.70, 95% CI 0.24 to 1.16, Analysis 2.4), with higher weight gain in this group.
KID21 point (Youmen) acupressure versus sham acupressure (one study with 80 women)
One study (Rad 2012) compared Youmen acupressure with sham acupressure, but as only medians and interquartile ranges (IQRs) are reported, data could not be entered into RevMan 2012 tables.The authors reported a statistically significant difference favouring Youmen acupressure over sham acupressure, on day four.
Auricular acupressure versus placebo (one study with 91 women)
One study compared auricular acupressure (administered by participants by pressing on magnetic balls taped to an acupressure point on the ear) with placebo (no treatment) (Puangsricharern 2008). The authors reported that they used mean total Rhodes Index score and total number of vomiting episodes from days four to six to measure treatment effect. They subsequently concluded that there were no significant differences between groups (though average Rhodes scores across these days were not directly reported). The treatment started on day three (for the acupressure group) and the results for the total Rhodes score at day six (three days after treatment started) appeared to favour the treatment group, although scores were lower in this group at baseline so results are difficult to interpret (MD -3.60, 95% CI -6.62 to -0.58, Analysis 3.1). There were no differences between groups for the number of anti-emetic drugs used (MD - 0.10, 95% CI -0.37 to 0.17, Analysis 3.2).
Acustimulation versus placebo (one study with 230 women)
Rosen 2003 compared low-level nerve stimulation therapy over the volar aspect of the wrist at the P6 point with placebo. In this study, nausea symptoms were recorded over three weeks, with weekly assessments of changes from baseline. The author reported the "time-averaged" change in the Rhodes Index total experience scale over the entire three-week study period, and suggested that there was more improvement over time in the active treatment group (change score 6.48 (95% CI 5.31 to 7.66) versus 4.65 (95% CI 3.67 to 5.63) in the placebo group (data not shown in analysis tables). In this study, both groups experienced improved scores over the evaluation period, and data (presented in graphical form in the study report) were not simple to interpret. Results for women in the Rosen 2003 study with mild to moderate symptoms were described in an abstract by De Veciana 2001, and in another brief abstract results were reported for those women with severe symptoms (Miller 2001). However, neither abstract provided usable data for subgroup analysis.
Acupuncture versus placebo (two studies with 648 women)
One trial with data for 296 women compared traditional acupuncture, P6 acupuncture, sham acupuncture and no treatment (Smith 2002). The data tables show three comparisons: between both traditional and P6 acupuncture and sham acupuncture, and between traditional and P6 acupuncture. Most of the results show no significant differences (Analysis 5.2; Analysis 5.3; Analysis 6.1; Analysis 6.2; Analysis 6.3; Analysis 7.1; Analysis 7.2; Analysis 7.3) for relief from nausea, dry retching and vomiting. Knight 2001 also compared acupuncture to placebo but the data were not in a form that allowed us to enter them in RevMan 2012 tables; the authors used median scores because of the skewness of the data. They report no statistically significant differences between the control and intervention groups for symptom relief.
Moxibustion versus Chinese drugs (one study with 302 women)
Fan 1995 reported that in a study comparing moxibustion with Chinese drugs, symptoms for all women in both groups either "improved" or were "cured".
Ginger versus placebo (six studies with 421 women)
Ginger was compared with placebo in six studies (Keating 2002; Modares 2012; Mohammadbeigi 2011; Ozgoli 2009; Vutyavanich 2001; Willetts 2003), although one study did not provide data on symptomatic relief in a way which we could use (Willetts 2003).
In a study with data for 68 women comparing ginger versus placebo (and metoclopramide, discussed below) (Mohammadbeigi 2011) ginger was favoured over placebo for mean nausea score (MD -1.38, 95% CI -2.73 to -0.03, Analysis 8.1) and mean vomiting score (MD -1.14, 95% CI -1.91 to -0.37, Analysis 8.2) and overall Rhodes index score (MD -2.52, 95% CI -4.50 to 0.54, Analysis 8.3), all reported on day three.
Modares 2012 also compared ginger and placebo (and chamomile, discussed below), and results favoured ginger (MD -4.19, 95% CI -6.65 to -1.73, data for 70 women, Analysis 8.4) one week after treatment, using Rhodes Index overall score.
In a study with a small sample size (n = 26) (Keating 2002), results favoured ginger over placebo for improving nausea by day nine (RR 0.29, 95% CI 0.10 to 0.82, Analysis 8.5). Results also favoured ginger for stopping vomiting at day six (RR 0.42, 95% CI 0.18 to 0.98, Analysis 8.6).
In the study by Vutyavanich 2001 (n = 70), results suggested that improvement in nausea symptoms was greater in the ginger group over four days of treatment (MD 1.20, 95% CI 0.22 to 2.18, Analysis 8.7), but when ITT analysis was carried out (to include three missing patients in the placebo group counted as treatment failures), the evidence of a difference between groups was no longer statistically significant (MD 0.60 95%, CI -0.51 to 1.71, Analysis 8.8).
Ozgoli 2009 also compared ginger with placebo and presented the results on nausea intensity using the total number of nausea-intensity assessments per group (assessments were carried out twice daily over four days for each participant, resulting in a total of 280 assessments for treatment group and 256 assessments for control group). Apart from those results, which are not easily interpreted, and have not been included in our analysis, improvements in nausea intensity are reported in percentages per group (from which numbers have been calculated and analysed in this review). Data on overall improvements appear to have been gathered during interview (by an unblinded researcher) on day five, rather than by comparing scores over time, but this is unclear. These results show a statistically significant difference between groups, favouring the treatment group (RR 1.48, 95% CI 1.07 to 2.04, Analysis 8.9) on "nausea intensity improvement". The authors also report a reduction in the incidence of vomiting following treatment of 50% in the intervention group compared with 9% in the control group, although the original data on post-treatment vomiting are not reported, and are not included in our analyses tables.
Ginger versus chamomile (one study with 105 women)
In one study of ginger versus chamomile (Modares 2012), there was no statistically significant difference between chamomile and ginger (MD 1.55, 95% CI 95%, -0.34 to 3.44, data for 70 women, Analysis 9.1), measured using the Rhodes Index after one week of treatment.
Ginger versus vitamin B6 (four studies with 624 women)
Four trials compared ginger and vitamin B6 (Chittumma 2007; Ensiyeh 2009; Smith 2004; Sripramote 2003).
In the two trials comparing ginger to vitamin B6 that had comparable outcomes reported (Chittumma 2007; Sripramote 2003), no statistically significant difference was found between groups (standardised mean difference (SMD) -0.00, 95% CI -0.25 to 0.25, I² = 0%, data for 251 women, Analysis 10.1) for symptom scores on day three. Chittumma 2007 used the Rhodes Index to measure symptom relief, while in the Sripramote 2003 trial a 10 cm VAS was used to measure level of nausea; results from both studies were not statistically significant. Post-treatment number of vomiting episodes on day three was similar in the two intervention groups in the Sripramote 2003 trial (MD 0.00, 95% CI -0.60 to 0.60, 128 women, Analysis 10.2). Ensiyeh 2009 and Smith 2004 present results on improvement in symptoms and pooled results show no statistically significant difference between groups for the number of women reporting no relief (average RR 0.84, 95% CI 0.47 to 1.52, 360 women (random-effects), although there was moderate heterogeneity for this outcome and results should be interpreted with caution (heterogeneity: Tau² = 0.11, I² = 52%. P = 0.15; Analysis 10.3).
Ginger versus dimenhydrinate (one study with 170 women)
One study (Pongrojpaw 2007a) compared ginger and dimenhydrinate, but the results for symptomatic relief were not easily interpreted and therefore, data have not been added to data tables in RevMan 2012.
Ginger versus metoclopramide (one study with 68 women)
One study compared ginger with metoclopramide and placebo (Mohammadbeigi 2011); there was no significant difference between groups for mean nausea score (MD 1.56, 95% CI -0.22 to 3.34, Analysis 12.1), vomiting score (MD 0.33, 95% CI -0.69 to 1.35, Analysis 12.2), and overall Rhodes Index score (MD 1.89, 95% CI -0.78 to 4.56, Analysis 12.3).
Ginger versus Doxinate (doxylamine succinate plus pyridoxine hydrochloride) (one study with 63 women)
Biswas 2011 reported only medians for symptomatic data so data have not been added to tables; the authors reported no statistical differences between groups for nausea and vomiting (with symptoms improving for both groups at the end of week one, end of week two and at a follow-up visit). The authors (not contactable) concluded that therefore ginger is a safe and effective alternative therapy.
Mint oil versus placebo (one study with 60 women)
Pasha 2012 compared mint oil with placebo and there were no statistically significant differences between groups for nausea level (MD -0.88, 95% CI -1.93 to 0.17, Analysis 13.1) or vomiting level (MD -0.32, 95% CI -1.45 to 0.81, Analysis 13.2), on day four.
Lemon oil versus placebo (one study with 100 women)
One study (Kia 2013) found that while there was not a statistically significant difference on levels of symptoms on day three (using the PUQE instrument) (MD -0.46, 95% CI -1.27 to 0.35, Analysis 14.1), the group using lemon oil did show a difference in reduction of symptoms from baseline to day three (MD - 1.50, 95% CI -2.41 to -0.59, Analysis 14.2). There was no significant difference in the number of women satisfied with treatment in this study (RR 1.47, 95% CI 0.91 to 2.37, Analysis 14.3).
Chamomile versus placebo
In one study comparing chamomile versus placebo (Modares 2012), chamomile was favoured (MD-5.74, 95% CI -8.31 to -3.17, 70 women, Analysis 15.1) for level of symptoms (using Rhodes Index) measured one week after treatment started.
Vitamin B6 versus placebo (two studies with 416 women)
In two studies comparing vitamin B6 with placebo (Sahakian 1991; Vutyavanich 1995), results favoured vitamin B6 for reduction in nausea after three days (MD 0.92, 95% CI 0.40 to 1.44, Analysis 16.1). Comparing the number of patients vomiting post-treatment, there was no strong evidence that vitamin B6 reduced vomiting (average RR 0.76, 95% CI 0.35 to 1.66, Analysis 16.2). As there was high heterogeneity for this outcome we used a random-effects model and results should be interpreted with caution (heterogeneity: I² = 77%, Tau² = 0.25, P = 0.04).
High dose vitamin B6 versus low-dose vitamin B6 (one study with 60 women)
Wibowo 2012 reported a significant difference favouring high dose over low dose vitamin B6 (MD -1.06, 95% CI -2.05 to -0.07, Analysis 17.1) for reduction in symptoms using PUQE, measured from baseline to two weeks.
Anti-emetic medication versus placebo (nine studies with 1197 women)
There were nine studies of anti-emetic medications. A range of anti-emetics (hydroxyzine, Debendox, Bendectin, Diclectin, thiethylperazine and fluphenazine-pyridoxine) were compared with placebos, and in one study, three anti-emetic medications were compared.
One study (Erez 1971) compared hydroxyzine to placebo, with the results favouring hydroxyzine for relief of nausea (RR 0.23, 95% CI 0.15 to 0.36, 150 women, Analysis 18.1).
Bsat 2003a compared three drug regimens: pyridoxine-metoclopromide, prochlorperazine and promethazine. Results were reported in graphs and we have not entered estimated figures into data tables. Approximately 65%, 38% and 40% of women in each group, respectively, responded that they felt better on the third day of treatment. The authors concluded that their results favour pyridoxine-metoclopromide over the other two regimens.
Two studies (Geiger 1959; McGuiness 1971) compared preparations of doxylamine succinate 10 mg, pyridoxine 10 mg and dicyclomine 10 mg (as Bendectin (US) and Debendox (UK) respectively) with placebo, and results for nausea relief favoured the intervention group. However, there was high heterogeneity when results from these two studies were combined and the time point at which outcome data were collected was not clear in the McGuiness 1971 study, and so in the analyses we have provided subtotals only. In the McGuiness 1971 study, while fewer women in the Debendox group had no relief in symptoms, the difference between groups was not statistically significant (RR 0.65, 95% CI 0.36 to 1.17, 81 women, Analysis 19.1). In the Geiger 1959 study, only three of 52 women receiving Debendox reported no improvement in symptoms compared with 20/57 for controls.
More recently Koren 2010 compared Diclectin (doxylamine succinate 10 mg and pyridoxine hydrochloride 10 mg) and placebo. Results favoured Diclectin for improvement in symptoms (MD -0.90, 95% CI- 1.55 to -0.25, 256 women, Analysis 20.1) from baseline to day 15 and for global-assessment of well-being (MD 1.00, 95% CI 0.38 to 1.62, Analysis 20.5), again from baseline to day 15. The authors measured the 'average change in symptoms' (measured as 'mean area under the curve for change in PUQE from baseline' as measured day-by-day) and reported a statistically significant difference favouring Dilectin (P < 0.0001) (data not shown in data and analysis tables). Requests for compassionate use of the drug after day 14 favoured Diclectin (RR 1.49, 95% CI 1.10 to 2.02, Analysis 20.2), a proxy measure for perception of effectiveness.
Thiethylperazine was compared with placebo in one study and women in the placebo group were less likely to experience symptom relief (RR 0.49, 95% CI 0.31 to 0.78, 164 women, Analysis 21.1) (Newlinds 1964). Finally, fluphenazine-pyridoxine seemed to improve symptoms compared with placebo in one trial, but results did not reach statistical significance (RR 0.52, 95% CI 0.27 to 1.01, 78 women, Analysis 22.1) (Price 1964); this is an antipsychotic drug (from the piperazine class of phenothiazines).
Metoclopramide was compared with placebo in one study (Mohammadbeigi 2011) and results favoured metoclopramide for nausea level (MD -2.94, 95% CI -4.55 to -1.33, 68 women, Analysis 23.1) and vomiting (MD -1.47, 95% CI, -2.33 to -0.61, Analysis 23.2), on day three.
Ondansetron was compared with metoclopramide in one study with data for 70 women (Ghahiri 2011), and no statistical difference was found for nausea (MD -0.12, 95% CI -0.44 to 0.20, Analysis 24.1) and vomiting (MD -0.20, 95% CI -0.57 to 0.17, Analysis 24.2) on day three, with symptoms improving for both groups.
2. Adverse maternal and fetal/neonatal outcomes
Adverse maternal and fetal outcomes were reported for some studies across several comparisons.
Acupressure versus placebo
Norheim 2001 reported that 63% of participants in the acupressure group and 90% in the placebo group reported problems (including pain, numbness, soreness and hand-swelling) using the wristband. Three women (two in the treatment group, one in the placebo group) said they felt more sick during the study period.
Acustimulation versus placebo
Rosen 2003 reported on weight gain, dehydration and ketonuria. There was significantly more weight gain and less dehydration in the treatment group (MD 1.70, 95% CI 0.23 to 3.17, Analysis 4.1; RR 0.24, 95% CI 0.07 to 0.83, Analysis 4.2, respectively) but there was no significant difference for ketonuria at the end of the trial period (RR 0.48, 95% CI 0.15 to 1.55, Analysis 4.3). The authors reported that there was no significant difference between groups on entry to the trial for ketonuria, though those most likely to withdraw from the study had ketonuria at entry (but at a non-significant level).
GInger versus placebo
Vutyavanich 2001 reported on the rates of spontaneous abortion, with no significant difference between groups (RR 0.36, 95% CI 0.04 to 3.33, Analysis 8.10). Similarly, for delivery by caesarean section, there was no difference between groups (RR 1.64, 95% CI 0.51 to 5.29, Analysis 8.11). The authors reported that there were no congenital abnormalities in either group. As with the other studies reporting such fetal outcomes, this study did not have sufficient power to show differences between groups; we will return to this in the discussion.
Willetts 2003 compared fetal adverse outcomes (such as stillbirth, neonatal death, preterm delivery, congenital abnormalities) with expected numbers based on data at one hospital in Sydney. The results were not clearly presented by randomisation group, but were shown for the overall number who completed the main study, with descriptive text about the number in the ginger group. The authors concluded that those exposed to ginger did not appear to be at greater risk of fetal abnormalities.
Also, in a study of ginger versus placebo, Keating 2002 reported weight change measured at the four-week follow-up visit, but data were not presented in a usable form; the authors commented that most women in both groups maintained or gained weight.
Modares 2012 (ginger versus chamomile versus placebo) reported one episode of 'severe nausea' and one allergic reaction in the chamomile group and one case of vomiting and another case of severe reaction and hospitalisation (though it is not clear why nausea and vomiting, the symptoms being treated, are reported as side effects).
Ginger versus vitamin B6
Smith 2004 reported on outcomes including spontaneous abortion, stillbirth, heartburn, congenital abnormality, antepartum haemorrhage/abruption or placenta praevia, pregnancy-induced hypertension, pre-eclampsia and preterm birth. There were no neonatal deaths in either group and no significant differences between the groups (Analysis 10.4 to Analysis 10.10). Similarly in Ensiyeh 2009, no significant differences were found in the maternal and fetal outcomes reported (spontaneous abortions, caesarean delivery, congenital anomaly of the baby (Analysis 10.4, Analysis 10.6, Analysis 10.15)). The authors report that 'all were discharged in good condition', though elsewhere they said that data collection and follow-up took 12 weeks; women were recruited to the trial at 17 weeks' gestation or less, implying a longer follow-up time.
Chittumma 2007 reported on arrhythmia and headache, with no evidence of a difference in effect between groups (Analysis 10.11; Analysis 10.12). Two studies (Chittumma 2007; Sripramote 2003) report results for heartburn, with no significant effect (RR 2.35, 95% CI 0.93 to 5.93, heterogeneity: I² = 3%, P = 0.31, Analysis 10.13). Chittumma 2007 reported on drowsiness, with neither ginger nor vitamin B6 favoured (RR 0.65, 95% CI 0.27 to 1.56, Analysis 10.14). Sripramote 2003 reported on sedation, with no strong evidence for either intervention (RR 0.81, 95% CI 0.47 to 1.39, Analysis 10.14).
Ginger versus dimenhydrinate
Pongrojpaw 2007a reported on the side effects of drowsiness and heartburn. More people in the dimenhydrinate group experienced drowsiness, while more in the ginger group experienced heartburn, but evidence of difference between groups was not statistically significant (drowsiness: RR 0.08, 95% CI 0.03 to 0.18, Analysis 11.1; heartburn: RR 1.44, 95% CI 0.65 to 3.20, Analysis 11.2).
Ginger versus doxylamine
Biswas 2011 reported that one (of 34) in the ginger group and two (of 29) participants in the Doxinate groups reported adverse events; body ache and loose stools for ginger and hyperacidity for the Doxinate participant. No serious adverse events were reported and all participants reported normal pregnancy outcome.
In the trials of anti-emetic drugs, fetal outcome was recorded only by Erez 1971. In that study, of the 79 cases available for follow-up in the hydroxyzine group, there were four spontaneous abortions (three in the first trimester and one in the second trimester) and one perinatal death. In the 36 cases available for follow-up from the placebo group, there were two first trimester spontaneous abortions (spontaneous abortions: RR 0.91, 95% CI 0.17 to 4.75, Analysis 18.2; perinatal mortality: RR 1.39, 95% CI 0.06 to 33.26, Analysis 18.3). In the text, the authors report that slight drowsiness was reported by 7% (n = 7) of the treatment group, but no other adverse effects were reported, and there were no hospitalisations in either group.
Bsat 2003a reported a non-significant difference in hospitalisation across the three groups receiving pyridoxine-metoclopramide, prochlorperazine and promethazine. They commented that subsequent pregnancy courses were similar and only one neonatal anomaly was seen (a cardiac defect in the prochlorperazine group).
McGuiness 1971 stated that side effects were reported by 12 patients in the Debendox group (including drowsiness for three patients, feeling weak for two, tiredness for two) compared to six adverse effects reported in the placebo group (including tiredness, sleepiness, depression and constipation). Newlinds 1964 reported that side effects occurred in 12 of the 93 patients who received thiethylperazine and 10 of the 87 in the placebo group. These adverse effects included drowsiness (four treatment, three placebo), aggravation of nausea (two treatment, three placebo), 'cerebral stimulation', described as mild in the text, and included restlessness (two in treatment group, none in placebo). Price 1964 reported that there were no side effects in the fluphenazine-pyridoxine group and one patient in the placebo group reported drowsiness. Geiger 1959 reported that one patient in the Bendectin group reported listlessness; no other adverse effects were reported.
Koren 2010 reports no significant differences between groups receiving Diclectin verus placebo for maternal side effects including headache (RR 0.81, 95% CI 0.45 to 1.48, Analysis 20.3) and somnolence (RR 1.21, 95% CI 0.64 to 2.27, Analysis 20.4); other side effects were reported by a similar and small number of participants per group and have not been added to data tables.