The Efficacy of Ginger for Pregnancy-Induced Nausea and Vomiting: A Systematic Review

Nausea and Vomiting (N/V) are unpalatable manifestations seen commonly during pregnancy, which impinge upon the overall well-being, the productivity and might result in hospitalization. There is growing evidence concerning the efficacy of ginger in alleviating Nausea and Vomiting in Pregnancy (NVP). Therefore, we sought to conduct a systematic review to explore the effectiveness of ginger for NVP. A comprehensive search was conducted in Google Scholar, PubMed, and Science Direct which resulted in identifying five studies. These studies showed that ginger can improve NVP in a statistically significant manner (P< 0.05). Assessing the safety profile of this agent was difficult due to the short duration of intervention, and inconsistency in the dose and dosage form of ginger used. This study helped to glean evidence about the efficacy of ginger in NVP. It also emphasized the need for conducting more studies with a better quality and that are using standardized dose and dosage forms to be able to conduct a meta-analysis.


Background
The development of Nausea and Vomiting in Pregnancy (NVP) is rife, affecting approximately 80% of pregnant females, where only 1% of these might progress to develop a severe form of NVP known as hyperemesis gravidarum 1-3 . NVP is commonly seen between the 5 th and the 18 th weeks of gestation, and affect the overall well-being of patients 4 . Importantly, the severity of the NVP varies among pregnants, and consequently, the management will vary as well. Although there are plenty of etiologies and pathophysiological theories underpinning NVP, it is still considered to be an area of controversy 5 . The importance of addressing NVP lies behind the possibility of developing dehydration, affecting the pregnancy, affecting the quality of life, productivity, and might lead to depression 6 . Treatment modalities incorporate identifying trigger factors and avoiding them, utilizing pharmacological and complementary agents and supportive therapy [7][8][9] .
Ginger (Zingiber officinale), which is a common ingredient in Asian meals, started gaining momentum as a treatment modality for NVP 10 . Noncompliance to medications and treatment plans is not uncommon among pregnant women which might be gauged by concerns related to fetus health 11 . However, herbal or complementary medicine tends to be more accepted as they are perceived to be a safer option although they might be not 12 . Hence, this systematic review aims at investigating the efficacy of ginger in relieving NVP. Although investigating the safety of this ingredient is imperative, the majority of studies included in this systematic review were conducted for a very short period (e.g. four days), and used different doses and dosage forms, therefore rendered this objective unachievable.

Search Strategy
A systematic review of the literature was performed based on the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines 13 . Three electronic databases including Google Scholar, PubMed, and Science Direct, were explored using the following terms: 'safety and efficacy of ginger in pregnancy' and 'ginger in pregnancy' .

Study Selection
We reviewed papers of studies that met the following inclusion criteria and were available as a full text or purchased by the library of the Higher Colleges of Technology: • Study design: randomized controlled trial.
• Study aim: evaluate the efficacy of ginger in NVP.
• Intervention: ginger in different doses.
• Comparator: traditional pharmaceutical products (vitamin B 6, doxylamine) , placebo, complementary medicine (wristband and acupuncture) or control. • Publication language and year: English, and between the year 2007 and 2017. • Jadad score: above or equal to 2.

Quality Assessment
Jadad scale was utilized to assess the qualities of the randomized controlled trials included in this systematic review 14,15 . A score of ≤ 2 indicates a low-quality design, while a score of ≥ 3 indicates a high-quality design 14,15 .

Review Procedure
Three researchers were involved in the process of data extraction, and a fourth researcher afterward reviewed the extracted data.

Data Extraction and Synthesis
Data was extracted from studies using a standardized document, where information such as author/s, year of publication, objectives, methodology and methods, interventions and comparator/s, study duration, and main findings were easily amalgamated. Moreover, the results of the studies were synthesized narratively with all results presented in a tabulation format.

Outcome Measures
• Symptom scores on the subjective feeling of nausea was measured by standardized scales or methods [e.g. Visual Analogue Scale (VAS)]. • Vomiting episodes were measured through a daily recording. • The general response to the treatment was measured by standardized scales or methods (e.g. the 5-point Likert-type scale and the Rhodes Index Likert-type scale).

Identification of Studies
The searching process went through series of phases as displayed in Figure 1. In the first phase, specific terms were used as mentioned earlier to retrieve relevant studies. This resulted in retrieving 4410 studies from Google Scholar, 147 studies from Pubmed and 647 studies from Science Direct. In phase two, the aim was to screen titles for having the relevant key terms, use the inclusion criteria to filter out irrelevant studies either by going through abstracts or full texts, and by calculating the Jadad score ( Figure 1). The outcome of this phase was identifying five studies to be incorporated in this systematic review ( Figure 1). All the studies included were exploring the efficacy of ginger in NVP [16][17][18][19][20] . The efficacy of this agent was tested using different scores as mentioned earlier including VAS, or Rhodes Index [16][17][18][19][20] . Different doses were also used in these studies, where the ginger doses ranged between 450 mg per day to 1950 mg per day [16][17][18][19][20] . Besides, the Jadad score of the studies included was either 2 or 5 [16][17][18][19][20] . Key data and findings of the randomized controlled trials are summarized in Table 1 [16][17][18][19][20] . Chittumma et al. (2007), conducted a study to compare the efficacy of ginger 1950 mg/day and vitamin B 6 75 mg/day for NVP 16 . Both medications were given for four days, and Rhodes index was utilized to assess the effectiveness of both interventions 16 . The Rhodes index of nausea and vomiting reduced among both groups "ginger and vitamin B 6 ", and this decline was found to be statistically significant compared to baseline (P<0.05) 16 . The reduction in Rhodes index (mean ± SD) was 3.3±1.5 in the ginger group, in comparison to 2.6±1.3 in the vitamin B 6 groups 16 , therefore, providing a clear indication that ginger was superior to vitamin B 6 in a statistically significant manner (P<0.05) 16 . Yet, one patient in the ginger group and four patients in the vitamin B 6 used other agents alongside the intervention and comparator agents which might have afflicted the results 16 .

Summary of Trials
Ensiyed et al. (2007), conducted a study where 70 participants were randomly assigned to receive either ginger 1000 mg/day or Vitamin B 6 40 mg/day for a period of four days 17 . The severity of nausea was assessed using VAS and Likert scales, while the vomiting was assessed by counting daily vomiting episodes 17 . Changes in nausea VAS score from baseline were 3.3±2.5 and 1.3±2.2 in the ginger and vitamin B 6 groups, respectively (P<0.05) 17 . On the other hand, the changes in the vomiting episodes from baseline in both groups was found to be statistically not significant (P>0.05) 17 . When the ginger group and vitamin B 6 were compared, it has been found that the ginger group was superior in terms of showing an improvement (82.8%) in comparison to the vitamin B 6 group (67.6%) (P>0.05) 17 . Yet, these findings were not statistically significant (Table 1). Biswas et al. (2011), studied 63 participants for three weeks to evaluate the effectiveness of ginger 450 mg/ day in alleviating NVP 18 . Participants were randomly assigned to receive either 450 mg/day of ginger or a combination of doxylamine and vitamin B 6 20 mg/30 mg per day for a period of three weeks 18 (Table 1). To assess improvement, VAS was utilized as well as counting the number of nausea spells and vomiting episodes 18 . Both groups showed a comparable and significant reduction in nausea and vomiting 18 . The median nausea VAS score dropped from 34.0 at baseline to 0, while the median vomiting VAS score dropped from 14.50 to 0 by the end of the intervention in the ginger group (P<0.05) 18 . Furthermore, the median nausea VAS score dropped from 30.0 at baseline to 0, while the median vomiting VAS score dropped from 22.00 to 0 by the end of the intervention in the doxylamine/vitamin B 6 group (P<0.05) 18 . Besides, the average number of nausea spells and vomiting episodes per day in both groups declined in a statistically significant manner (P<0.05) 18 .In fact, the median nausea spells went from 3 to 0.43 and the median vomiting episodes went from 1 to 0.14 by the end of the intervention(P<0.05) among the ginger users 18 . Additionally, the median nausea spells went from 4 to 0.60, and the median vomiting episodes went from 2 to 0 in the other group (P<0.05) 18 . Despite the fact that, there was no head to head comparison between both groups, this study managed to shed light on the efficacy of ginger 18 .
Saberi et al. (2014), conducted a study on 151 participants who were randomly assigned to one of three groups which are the ginger, acupuncture, or control groups 19 . This study was designed to compare the difference in nausea, vomiting and retching before and after the intervention using Rhodes index 19 . Overall, there was a significant improvement in nausea, vomiting and retching Rhodes index after the interventionin all groups (P<0.05) 19 . However, the ginger group showed a higher improvement in the vomiting Rhodes scale compared to the acupuncture and control groups, as the mean Rhodes index in the ginger group dropped by approximately 42% compared to about 13% reduction in the other two groups 19 . Furthermore, the reduction in the nausea Rhodes index was found to be the highest in the ginger group (47%), followed by the acupuncture (22%) and the control groups (2%) 19 . Besides, retchingRhodes index was reduced the most in the ginger group (46%) followed by the acupuncture groups (35%) ( Table 1) 19 . Nevertheless, the control group showed an increase in the retching Rhodes index by 7% after the intervention 19 . However, a determination of the significance of these comparisons was not plausible, as the level of significance was not tested. unfortunately, the significance of these comparisons was not tested statistically 19 . Saberi et al. (2014), in a different study, drew a comparison between the ginger (750 mg/day), placebo and control groups regarding their efficacy for NVP 20 . The highest reduction in the Rhodes Index for all three parameters was seen among ginger users compared to the other groups, in a statistically significant manner (P<0.05) 20 .  * A study that cannot be assessed sufficiently using abstract and is available as a full text, was assessed using the full text.

Discussion
The majority of the studies included in this systematic review brought to light that ginger powder a dose of 450 mg to 1950 mg per day is effective in alleviating nausea and vomiting seen during pregnancy in a statistically significant manner [16][17][18][19][20] . In fact, some studies found that participants whom received ginger had a superior control over symptoms compared to the comparator groups (vitamin B 6 , placebo, control) 16,17,19,20 . These findings go in synchrony with some studies that demonstrated the efficacy of ginger in alleviating NVP, using a dose of 1 gram which is considered to be the most commonly used and tested dose 10,21-23 . Several mechanisms have been proposed with regards to the antiemetic effect produced by ginger including the carminative effect which breaks up the intestinal gas 24 . This mechanism was supported by the results of a randomized, double-blind trial which demonstrated the ability of the ginger to accelerate gastric emptying and stimulated antral contractions 24 . Some asserted that the antiemetic effect results from the inhibition of serotonin receptors in the gastrointestinal system and the central nervous system 'vomiting center' , as well as the inhibition of vasopressin which causes a reduction in tachygastric activity [25][26][27][28][29] .
There are various active ingredients found in the ginger including gingerol, shogaol, and galanolactone, which produce antiemetic effects using difference mechanisms [30][31][32] . The ginger used for NVP should be obtained from Zingiber officinale, and not from other types of ginger with a different Latin name such as the ones that come from African or Thailand, due to the differences in the balance of chemical constituents 30 . Furthermore, the balance between these components varies between fresh, semi-dried and dried forms, therefore expecting to havevariations in responses produced by these forms 30 .

Ginger group:
The difference in nausea and vomiting scores improved from baseline in a statistically significant manner (P<0.05).

Vitamin B 6 group:
The difference in nausea and vomiting scores improved from baseline in a statistically significant manner (P<0.05). Three days without intervention, followed by four days of intervention.

Ginger group vs. Vitamin
Rhodes score 1 for nausea and vomiting twice a day for seven days.

Ginger group:
The Rhodes index (mean) for nausea, vomiting, and retching reduced significantly after the introducing ginger (P<0.05).

Acupressure Group:
The Rhodes index (mean) for nausea, vomiting, and retching reduced significantly after the introducing acupuncture (P<0.05). Differentiation between nausea and vomiting is of paramount importance to be able to derive accurate conclusions 30 . From a medical perspective, vomiting received more attention when measuring outcomes due to the concerns with regards to progressing tohyperemesis gravidarum 30 .On the other hand, nausea is considered to be more distressing, therefore paying attention to this component is imperative 30 . The vast majority of studies included in this systematic review looked into nausea as well as vomiting in a separated manner. Yet, the participants' understanding and their ability to differentiate between both concepts was not assessed or confirmed, which might impinge upon the accuracy of findings.
Using a natural product does not ensure safety which is a common misconception seen among lay public. Indeed, it has been found that Ginger might interact with anticoagulants and anti-platelets as ginger itself has an anticoagulant effect 29,[32][33][34][35][36] . Furthermore, it is known to cause gastrointestinal irritation and is contraindicated in patients with or have a history of gallstones as it stimulates secreting bile 37 . Moreover, ginger is known to cause hypotension, and the possibility of cardiac arrhythmias, hence, cardiac patients should be warned 30 .
The correct dosage should be prescribed, although there is currently no consensus agreement on the maximum dose 30 . In Europe and North America, the maximum dose does not go beyond 2 gram per day, while in China, it may go up to 9 grams per day (although it is rarely used in pregnancy) 30 . Hence, more research entailing ginger pharmacodynamics (effective and toxic doses) should be conducted to be able to have a unified guideline.

Limitations
Having a rudimentary understanding with regards to the limitation of this design is imperative. Publication bias will always be a concern in systematic review as it might lead to false positive overall conclusions. In fact, one of the major limitations of this systematic review is having limited access to certain studies that were not purchased by the academic institution. Furthermore, some studies might have still been in the publication process and not yet available on the web to encompass their findings in this review. With regards to the studies included in this systematic review, the inconsistencies in the comparators, the dose and the dosage form used, the outcome measures (tools) and the duration of the intervention made it difficult to perform a metaanalysis 16-20 .

Conclusion
In conclusion, the findings of this systematic review decipher the efficacy of ginger in alleviating NVP. In fact, this review found that ginger is as effective if not superior to the comparators. Besides, it is considered to be an attractive alternative as it is readily available in every house, yet ensuring a proper dosing is crucial. Although it is anatural product, it is still associated with some adverse effects and interacts with other medications. More consistent studies need to be conducted to enable performing a meta-analysis, identify safe and effective dose ranges, appropriate duration of treatment, and consequences of overdosing.

Authors Contributions
All authors contributed to the study design. All authors were involved in the literature review and data extraction process. Besides, all participated in the writing and revision of the manuscript.

Declaration of Conflicting Interests
The authors have no conflict of interest to declare.

Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.