Interventions for treating hyperemesis gravidarum

  • Protocol
  • Intervention



This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effectiveness and safety of all interventions for hyperemesis gravidarum.


Description of the condition

While nausea and vomiting in early pregnancy are very common, affecting approximately 80% of pregnancies, hyperemesis gravidarum is a severe form affecting 0.3% to 1.0% of pregnancies (Gadsby 1993; Niebyl 2010). The definition of hyperemesis gravidarum varies but generally includes intractable nausea/vomiting, signs of dehydration such as ketonuria, high urine specific gravity, electrolyte imbalances, and weight loss of at least 5% of pre-pregnancy weight, excluding other diagnoses (ACOG 2004; Mella 2011). The onset is generally in the first trimester at six to eight weeks, peaking by 12 weeks, with most women having resolution of symptoms by 20 weeks' gestation (Jarvis 2011). The lack of standard criteria has implications for inclusion criteria and outcome measurements of controlled studies. For example, requirement of at least 5% weight loss is not always used as an inclusion criteria in studies of interventions for hyperemesis gravidarum, but one study found that the efficacy of corticosteroids may vary depending on this criterion (Moran 2002).

It is important to exclude other causes of severe nausea and vomiting before arriving at the diagnosis of hyperemesis gravidarum. Other causes include gastrointestinal (GI) etiologies such as infection, gastritis, cholecystitis, hepatitis, appendicitis, and pancreatitis. Neurological causes include migraines or other central nervous system disease. Genitourinary etiologies include urinary tract infection/pyelonephritis. Metabolic or endocrine disturbances include hypercalcemia, Addisons's disease, thyrotoxicosis. Psychological disorders include the spectrum of eating disorders. Finally, other pregnancy associated conditions such as molar pregnancy must also be excluded (Ismail 2007; Mella 2011).

The epidemiology of hyperemesis gravidarum is generally young women, primiparous, non smokers, and non Caucasian (Bailit 2005; Klebanoff 1985; Niebyl 2010). Other risk factors include prior history of hyperemesis, pre-existing diabetes, hyperthyroid disorder, depression or psychiatric illness, asthma, and GI disorders (Fell 2006). Fetal abnormalities such as triploidy and hydrops have also been associated with hyperemesis (Kelly 2009). The etiology of hyperemesis gravidarum is poorly understood, although it is generally thought to be associated with hormonal changes associated with pregnancy. Postulated mechanisms include human chorionic gonadotropin stimulating secretory processes in the upper GI tract and/or stimulation of the thyroid stimulating hormone receptor. Estrogen levels have also been positively associated with nausea and vomiting in pregnancy, perhaps through delayed GI motility and gastric emptying. Physiological stimulation of the thyroid gland in early pregnancy causes a transient thyrotoxicosis that may lead to hyperemesis. Several studies have found a significant increase in Helicobacter pylori (H. pylori) infection in hyperemesis patients, although whether this is a cause, risk factor, or consequence of hyperemesis is not well established (Ismail 2007; Kelly 2009).

Hyperemesis gravidarum has both maternal and fetal complications. Although hyperemesis gravidarum is rarely a source of mortality, it is a significant source of morbidity. It is the most common indication for hospitalization in early pregnancy, and the second most common indication for hospitalization in pregnancy (ACOG 2004). Malnutrition and vitamin deficiencies may lead to anemia and peripheral neuropathies, or more serious, but rare, complications such as Wernicke's encephalopathy and central pontine myelinolysis. Prolonged vomiting may lead to esophageal trauma such as Mallory-Weiss tears. Nausea and vomiting in early pregnancy are associated with psychiatric morbidity. Although a causal relationship is uncertain, the severity of nausea and vomiting has been correlated with somatic symptoms, social dysfunction, anxiety, insomnia, and severe depression (Ismail 2007; Kramer 2013; Mella 2011; Swallow 2004). There may also be significant psychosocial morbidity associated with hyperemesis. Multiple studies have demonstrated an association with decreased psychosocial well being, depression, and anxiety (ACOG 2004; Munch 2011; Poursharif 2008). The physical and psychological/social burden of hyperemesis gravidarum has also been associated with elective termination of the pregnancy (ACOG 2004; Poursharif 2007). Fetal complications include preterm birth (delivery less than 37 weeks' gestation), low birthweight (generally less than 2.5 kg), and small-for-gestational age (less than 10% of expected weight for gestational age). There does not appear to be an increased risk of spontaneous abortion (usually defined as less than 20 weeks), still birth (death of a fetus >= 20 weeks' gestation or greater than 500 g), or neonatal death (death of a baby born live within 28 days of birth) (Bailit 2005; Dodds 2006). The socioeconomic costs of hyperemesis are also significant, stemming from individual expense in paying for treatment, lost job productivity from time off work, and high healthcare costs related to provision of services and hospital admissions. One study found that the cost of hyperemesis was about $200,000,000 per year for the United States (Bailit 2005). Studies in Canada have estimated that severe nausea and vomiting in pregnancy result in as many as 14 hospitalizations/1000 births, and has a cost of $653/woman/week (Neutel 2000; Piwko 2007).

Description of the interventions and how they might work

A range of interventions are commonly used for the treatment of hyperemesis gravidarum. These include dietary and lifestyle modifications, complementary therapies (i.e. acupuncture, herbal remedies), pharmaceutical therapies including a variety of classes of anti-emetics and corticosteroids, and enteral/parenteral nutrition. The goals of therapy are generally to reduce nausea and vomiting, minimize hospitalization, prevent progression of symptom severity, and improve quality of life. Prior studies examining intervention efficacy have used qualitative measures of nausea/vomiting such as visual analog scales (Sullivan 1996; Tan 2009) and the Rhodes Index of Nausea, Vomiting, and Retching (Rhodes 1984; Rhodes 1999; Rosen 2003; Shin 2007), quantitative measures such as days of hospital admission and readmission rates, and quality of life measures such as the General Health Questionnaire (Swallow 2004) and the Edinburgh Postpartum Depression Screen (Bown 2008; Cox 1987; Kramer 2013). Secondary outcomes often include adverse maternal and fetal outcomes. It can be difficult to extrapolate safety data from trials designed to examine efficacy because they may not be powered to detect such outcomes, and it is difficult to determine whether certain outcomes, such as preterm delivery, are related to the intervention or the condition of hyperemesis. However, given that some adverse outcomes, such as congenital abnormalities, are not associated with hyperemesis, data on some specific outcomes may be used to draw conclusions on safety.

Non-pharmacological interventions
Dietary and lifestyle modifications

Dietary modifications include recommendations to have small and frequent meals, avoid spicy or fatty foods, and drink fluids regularly. Lifestyle modifications include avoiding noxious sensory stimuli, eating crackers in the morning after waking, and increasing rest. Although these are common recommendations, there are few published studies evaluating the efficacy of these changes for prevention or treatment of either nausea/vomiting of pregnancy or hyperemesis gravidarum (ACOG 2004; Arsenault 2002; Matthews 2010).

Complementary therapies

There are a number of non-pharmacological therapies that have been used for the treatment of nausea and vomiting in pregnancy and hyperemesis gravidarum. Acupressure and electrical stimulation wrist bands have been associated with benefit for nausea/vomiting of early pregnancy, although the evidence is mixed and limited (Heazell 2006; Ismail 2007; Matthews 2010; Mella 2011; Rosen 2003; Shin 2007). Acupuncture has also been shown to have some benefit in the treatment of nausea and vomiting in pregnancy and in the treatment of hyperemesis gravidarum, although again the evidence is limited (ACOG 2004; Carlsson 2000; Mella 2011), and the Cochrane review evaluating its efficacy in nausea and vomiting in early pregnancy found no benefit (Matthews 2010). These methods are based on traditional Chinese medicine that specifies a point PC6 5 cm proximal to the wrist crease that is associated with decreasing nausea. Acupuncture and other stimulation at this point has been suggested to reduce opioid related post operative nausea as well as chemotherapy-associated nausea (Carlsson 2000).


Ginger is another commonly recommended non-pharmacological intervention for the treatment of nausea and vomiting in pregnancy. The active ingredient in ginger responsible for its therapeutic effect is not well understood but it has long been used as a herbal medicine in Asian culture for the treatment of nausea and vomiting in pregnancy. Several randomized controlled trials have demonstrated a benefit to ginger in nausea and vomiting of pregnancy without any demonstrable adverse pregnancy outcomes. There are also studies demonstrating benefit in hyperemesis gravidarum (Arsenault 2002; Fischer-Rasmussen 1991; Matthews 2010; Mella 2011).

Intravenous fluids/enteral nutrition/parenteral nutrition

Hyperemesis gravidarum is commonly characterized by metabolic and electrolyte disturbance requiring hospital admission, with the initial therapy frequently being intravenous rehydration/repletion of electrolytes. Although intravenous rehydration is often a mainstay of treatment, there are few studies examining specific fluid regimens (ACOG 2004). One study in 2013 did compare a dextrose/saline solution with normal saline solution and found that there was no benefit in rehydration with dextrose. However, there remains a theoretical increased risk of Wernicke's encephalopathy as a result of glucose metabolism in a thiamine deficient state, which suggests that normal saline is preferable (Tan 2013).

Both enteral and parenteral nutrition are used in refractory hyperemesis gravidarum, although few studies have been done. There are case studies demonstrating that enteral nutrition is a relatively well tolerated and effective treatment strategy for refractory hyperemesis gravidarum. Complications can include infection, bleeding, tube dislodgement, preterm labor, and patient discomfort (ACOG 2004; Saha 2009). Parenteral nutrition is associated with a high incidence of complications including infection, thrombosis, and mechanical failure, and therefore is recommended only in the failure of medical management and enteral nutrition (ACOG 2004; Holmgren 2008).

Pharmacological interventions

A number of different classes of pharmaceutical agents have been evaluated for the treatment of hyperemesis gravidarum.

Vitamin B6

Vitamin B6 or pyridoxine is commonly used as a first line treatment for nausea and vomiting in pregnancy. It is a water soluble vitamin used as a cofactor in a wide array of metabolic processes and in the synthesis of nucleic acids and some neurotransmitters. Used on its own, it is associated with a decrease in nausea but not in vomiting (Mella 2011). In one study of women hospitalized with hyperemesis gravidarum, it did not seem to have any effect (Tan 2009). Vitamin B6 has not been shown to cause increased risk in major or minor congenital malformations (Arsenault 2002; Mazzotta 2000).


Antihistamines may act through different mechanisms. Doxylamine is a H-1 receptor antagonist that had been used frequently in combination with B6. When the combination B6 and doxylamine was available in the United States there was an association with decreased admissions for hyperemesis, however it was removed from the market secondary to safety concerns that were later unfounded (ACOG 2004; Ismail 2007). The combination of doxylamine/B6 has been found to be both safe, with no evidence of teratogenicity, and effective in the treatment of nausea and vomiting in pregnancy (Arsenault 2002; Mazzotta 2000; Mella 2011).

H1-receptor antagonists such as doxylamine, hydroxyzine, and diphenhydramine are thought centrally to reduce vestibular symptoms. There is one randomized controlled trial showing that diphenhydrinate is as effective as ginger in the treatment of nausea and vomiting of pregnancy (Pongrojpaw 2007). Antihistamines have not been well studied in hyperemesis (Mella 2011).

H2-receptor antagonists such as famotidine and ranitidine act peripherally in reducing reflux, which may help with reducing symptoms of nausea and vomiting, although this has not been well studied either.

A meta-analysis of antihistamines showed no increased risk of congenital malformations, risk of miscarriage, or preterm delivery (Gill 2009; Mella 2011).

Dopamine antagonists

Dopamine-2 antagonists such as metoclopramide stimulate GI motility and have been shown to be effective in decreasing vomiting. Limited studies have demonstrated its safety in pregnancy (Arsenault 2002; Mella 2011). Phenothiazines, such as promethazine, are dopamine 2-receptor antagonists that act centrally to suppress the chemoreceptor trigger zone (CTZ) that is responsible for stimulating vomiting. These have been shown to be both effective in treating hyperemesis and safe in pregnancy with regards to teratogenicity (Arsenault 2002).


Benzodiazepines such as diazepam have also shown some benefit in hyperemesis gravidarum, presumably through alleviating psychosomatic symptoms such as anxiety. However, the safety of these medications in pregnancy is still controversial with some studies demonstrating a positive association between neonatal exposure to diazepam and prematurity and low birth weight (Mella 2011; Tasci 2009).

Seratonin antagonists

Seratonin antagonists such as ondansetron also act centrally to suppress the CTZ. Limited data are available on the efficacy of ondansetron in hyperemesis gravidarum; one randomized controlled trial found no benefit over promethazine (Sullivan 1996). Safety data are also limited, animal studies and small case studies have not demonstrated any teratogenic effect (Mazzotta 2000). Recently, a large retrospective cohort study in Denmark found no association between ondansetron and adverse fetal outcome (Pasternak 2013). Despite the limited safety and efficacy data, its efficacy in treating chemotherapy-associated nausea/vomiting has led to increased use of this medication (ACOG 2004).


Corticosteroids are often used as a last resort for treatment of refractory hyperemesis. They have been used for the treatment of chemotherapy-associated nausea and are postulated to modify the CTZ. Studies are conflicting regarding the efficacy of steroids in hyperemesis gravidarum. However, their use in early pregnancy is associated with oral cleft malformations, so it is generally reserved as a last resort intervention (ACOG 2004; Arsenault 2002; Ismail 2007; Mazzotta 2000).

Adrenocorticotropic hormone has also been studied but generally has not been found to be effective for hyperemesis (Mella 2011).

Why it is important to do this review

Although there has been a recent Cochrane review in 2010 examining the efficacy and safety of many of these interventions for nausea/vomiting of early pregnancy (Matthews 2010), there has not yet been a review assessing interventions for the more severe condition of hyperemesis gravidarum.


To assess the effectiveness and safety of all interventions for hyperemesis gravidarum.


Criteria for considering studies for this review

Types of studies

We will include all randomized controlled trials of any intervention for hyperemesis gravidarum. We will include studies reported in abstract, provided that there is sufficient information in the abstract or available from the author to allow us to assess eligibility and risk of bias. We will exclude quasi-randomized trials and trials using a cross-over design. We will include multi-armed trials and conduct pair-wise comparison separately, with any shared intervention group(s) divided equally among the comparisons.

Types of participants

Pregnant women with a normal intrauterine pregnancy up to 20 weeks' gestation diagnosed with hyperemesis gravidarum according to the definition of the trials.

Types of interventions

We will include all interventions for hyperemesis gravidarum. Each intervention (i.e. acupressure or ondansetron) will be analyzed separately versus placebo or no treatment and versus other interventions. Compound interventions (i.e. ondansetron and metoclopramide) will be treated as a single unique intervention.

Types of outcome measures

For the sake of comparison, some outcome measures for this study align with the outcome measures used in the previous Cochrane review on interventions for nausea and vomiting in early pregnancy (Matthews 2010).

Primary outcomes
Intervention efficacy
  • Reduction or cessation in nausea/vomiting

  • Number of episodes of emesis

  • Days of hospital admission

Secondary outcomes
Intervention efficacy
  • Hospital readmission

  • Number of antiemetics required

  • Need for enteral or parenteral nutrition

Adverse maternal outcomes
  • Pregnancy complications (i.e. antepartum hemorrhage, pre-eclampsia, gestational hypertension)

  • Weight loss

Adverse fetal/neonatal outcomes
  • Spontaneous abortion

  • Stillbirth and neonatal death

  • Congentinal abnormalities

  • Low birthweight

  • Preterm birth

Quality of life
  • Quality of life outcomes including emotional, psychological, and physical well being

  • Intervention side effects

  • Decision to terminate

Economic costs
  • Direct financial costs to women

  • Productivity costs

  • Healthcare system costs

Search methods for identification of studies

Electronic searches

We will contact the Trials Search Co-ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register. 

The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from:

  1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

  2. weekly searches of MEDLINE;

  3. weekly searches of EMBASE;

  4. handsearches of 30 journals and the proceedings of major conferences;

  5. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL, MEDLINE and EMBASE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.

Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co-ordinator searches the register for each review using the topic list rather than keywords. 

In addition, we will contact the Cochrane Complementary Medicine Field to search their Trials Register.

Searching other resources

We will search the reference lists of retrieved studies.

We will not apply any language restrictions.  

Data collection and analysis

Selection of studies

Two review authors will independently assess for inclusion all the potential studies we identify as a result of the search strategy. We will resolve any disagreement through discussion or, if required, we will consult a third person.

Data extraction and management

We will design a form to extract data. For eligible studies, at least two review authors will extract the data using the agreed form. We will resolve discrepancies through discussion or, if required, we will consult a third person. We will enter data into Review Manager software (RevMan 2011) and check for accuracy.

When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies

Two review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreement by discussion or by involving an additional assessor.

(1) Random sequence generation (checking for possible selection bias)

We will describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We will assess the method as:

  • low risk of bias (any truly random process, e.g. random number table; computer random number generator);

  • high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number);

  • unclear risk of bias.   

(2) Allocation concealment (checking for possible selection bias)

We will describe for each included study the method used to conceal allocation to interventions prior to assignment and will assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We will assess the methods as:

  • low risk of bias (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes);

  • high risk of bias (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);

  • unclear risk of bias.   

(3.1) Blinding of participants and personnel (checking for possible performance bias)

We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will consider that studies are at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess the methods as:

  • low, high or unclear risk of bias for participants;

  • low, high or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We will describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess methods used to blind outcome assessment as:

  • low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported, or can be supplied by the trial authors, we will re-include missing data in the analyses which we undertake.

We will assess methods as:

  • low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);

  • high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomization);

  • unclear risk of bias.

(5) Selective reporting (checking for reporting bias)

We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We will assess the methods as:

  • low risk of bias (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);

  • high risk of bias (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

  • unclear risk of bias.

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

We will describe for each included study any important concerns we have about other possible sources of bias.

We will assess whether each study was free of other problems that could put it at risk of bias:

  • low risk of other bias;

  • high risk of other bias;

  • unclear whether there is risk of other bias.

(7) Overall risk of bias

We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings.  We will exclude studies with high or unclear risk of performance or selection bias. We will explore the impact of the level of bias through undertaking sensitivity analyses - see Sensitivity analysis

Measures of treatment effect

Dichotomous data

For dichotomous data, we will present results as summary risk ratio with 95% confidence intervals. 

Continuous data

For continuous data, we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardized mean difference to combine trials that measure the same outcome, but use different methods.  

Unit of analysis issues

Cluster-randomized trials

We will include cluster-randomized trials in the analyses along with individually-randomized trials. We will adjust their standard errors using the methods described in the Cochrane Handbook using an estimate of the intracluster correlation co-efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster-randomized trials and individually-randomized trials, we plan to synthesize the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomization unit is considered to be unlikely.

We will also acknowledge heterogeneity in the randomization unit and perform a subgroup analysis to investigate the effects of the randomization unit.

Dealing with missing data

For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis. Studies that are deemed to have high risk of attrition bias will be included in a sensitivity analysis.

For all outcomes, we will carry out analyses, as far as possible, on an intention-to-treat basis, i.e. we will attempt to include all participants randomized to each group in the analyses, and all participants will be analyzed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial will be the number randomized minus any participants whose outcomes are known to be missing.

Assessment of heterogeneity

We will assess statistical heterogeneity in each meta-analysis using the T², I² and Chi² statistics. We will regard heterogeneity as substantial if an I² is greater than 30% and either the T² is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity. 

Assessment of reporting biases

If there are 10 or more studies in the meta-analysis we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually.  If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.

Data synthesis

We will carry out statistical analysis using the Review Manager software ( RevMan 2011). We will use fixed-effect meta-analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect: i.e. where trials are examining the same intervention, and the trials’ populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will use random-effects meta-analysis to produce an overall summary if an average treatment effect across trials is considered clinically meaningful. The random-effects summary will be treated as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful, we will not combine trials.

If we use random-effects analyses, the results will be presented as the average treatment effect with 95% confidence intervals, and the estimates of  T² and I².

Subgroup analysis and investigation of heterogeneity

If we identify substantial heterogeneity, we will investigate it using subgroup analyses and sensitivity analyses. We will consider whether an overall summary is meaningful, and if it is, use random-effects analysis to produce it.

We plan to carry out the following subgroup analyses:

  1. patients with weight loss of at least 5% of pre-pregnancy weight versus patients with weight loss of less than 5% of pre-pregnancy weight;

  2. singleton gestation versus twin gestations;

  3. primiparous versus multiparous.

The primary outcomes will be used in subgroup analysis.

  • Reduction or cessation in nausea/vomiting. We will examine outcomes measured by all commonly used instruments to assess nausea and vomiting.

  • Number of episodes of emesis.

  • Days of hospital admission.

We will assess subgroup differences by interaction tests available within RevMan (RevMan 2011).  We will report the results of subgroup analyses quoting the χ2 statistic and P value, and the interaction test I² value.

Sensitivity analysis

We will perform sensitivity analysis in trials found to have a high or unclear risk of attrition bias, and high or unclear risk of other biases. Outcomes included will be restricted to primary outcomes.

  • Reduction or cessation in nausea/vomiting.

  • Number of episodes of emesis.

  • Days of hospital admission.


As part of the pre-publication editorial process, this protocol has been commented on by three peers (an editor and two referees who are external to the editorial team) and the Group's Statistical Adviser.

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Pregnancy and Childbirth Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.


O'Hara, 19 January 2015


This protocol states in the background section that previous studies have found that ginger helps with hyperemesis gravidarum, and gives four references. One of these is another Cochrane Review of interventions for nausea and vomiting in pregnancy (1). This second review lists gives hyperemesis gravidarum as an exclusion criterion, i.e. it is specifically about nausea and vomiting in pregnancy, excluding hyperemesis gravidarum. Two others of the four references are review papers summarising guidance on treatment protocols (2,3). So only one of these four references reports on an original study (4). Could you confirm whether the two review papers reference any other original studies of the efficacy of ginger in hyperemesis gravidarum, as to my knowledge there is only the one but I am very interested to know if there are others.

Comment submitted by Margaret O'Hara, January 2015


1. Matthews A, Dowswell T, Haas DM, Doyle M, O'Mathuna DP. Interventions for nausea and vomiting in early pregnancy. Cochrane Database of Systematic Reviews 2010, Issue 9. [DOI: 10.1002/14651858.CD007575.pub2]

2. Arsenault M, Lane CA. The management of nausea and vomiting of pregnancy. Journal of Obsetrics and Gynaecology Canada2002;24(10):817-23.

3. Mella MT. Nausea/vomiting of pregnancy and hyperemesis gravidarum. In: Berghella V editor(s). Maternal-fetal Evidence Based Guidelines. 2. New York City, New York USA: Informa Healthcare, 2011:72-80.

4. Fischer-Rasmussen W, Kjaer SK, Dahl C, Asping U. Ginger treatment of hyperemesis gravidarum. European Journal of Obstetrics & Gynecology and Reproductive Biology 1991;38:19-24.

What's new

19 January 2015Feedback has been incorporated Feedback 1 submitted by Margaret O'Hara.

Contributions of authors

Rupsa C Boelig: contact person and guarantor of review, drafted initial protocol.

Vincenzo Berghella: helped to initiate this review, edited protocol, provided both methodological and clinical perspective.

Anthony J Kelly: helped to initiate this review, provided both methodological and clinical perspective.

Steven J Edwards: provided methodological perspective.

Samantha J Barton: provided methodological perspective.

Declarations of interest

None known.