Management of nausea and vomiting in pregnancy

National Guideline Alliance (UK)

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Management of nausea and vomiting in pregnancy

Antenatal care

Evidence review R

NICE Guideline, No. 201

National Guideline Alliance (UK).

London: National Institute for Health and Care Excellence (NICE); 2021 Aug.

ISBN-13: 978-1-4731-4227-5

Management of nausea and vomiting in pregnancy

Review question

What interventions are effective in treating nausea and vomiting during pregnancy?

Introduction

Nausea and vomiting of pregnancy (NVP) is common with around 50-80% of pregnant women experiencing these symptoms to a varying degree. Moderate to severe nausea and vomiting, is characterised by intractable vomiting which can be associated with electrolyte abnormalities, acid-base disturbance and weight loss, particularly the most severe form (hyperemesis gravidarum). Nausea and vomiting in pregnancy can impact on the woman’s physical and mental health requiring admission to hospital for rehydration and treatment which in turn will affect her family and work life. In view of this, effective treatment for nausea and vomiting in pregnancy is essential. This review aims to find out what interventions are effective in treating nausea and vomiting in pregnancy.

Summary of the protocol

See Table 1 for a summary of the Population, Intervention, Comparison and Outcome (PICO) characteristics of this review.

Table 1

Summary of the protocol (PICO table).

For full details see the review protocol in appendix A

Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A.

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

Clinical evidence

Included studies

Forty-three articles reporting 42 randomised controlled trials (RCTs) for interventions in treating nausea and vomiting were included in this review.

Mild to moderate nausea and vomiting

Twenty-seven articles reporting 26 RCTs were included in the review of treatments for mild and moderate nausea and vomiting during pregnancy (Basirat 2009, Belluomini 1994, Bsat 2003, Galeshi 2020, Geiger 1959, Ghule 2020, Keating 2002, Knight 2001, Koren 2010, Koren 2015, Mobarakabadi 2019, Mohammadbeigi 2011, Monias 1957, Oliveira 2014, Ozgoli 2009, Puangsricharem 2008, Rad 2012, Saberi 2013, Saberi 2014, Sahakian 1991, Sharifzadeh 2018, Smith 2002, Vutyavanich 1995, Vutyavanich 2001, Werntoft 2001, Willetts 2003, Zhang 2017).

The included studies are summarised in Table 2.

Eight RCTs were multi-arm trials. Six of these were 3-arm trials, 1 of which compared ginger, pyridoxine hydrochloride and placebo (Sharifzadeh 2018); 1 RCT compared ginger, a dopamine D2 receptor antagonist (metoclopramide) and placebo (Mohammadbeigi 2011); 1 RCT compared ginger, placebo, and a control (no treatment) group (Saberi 2014); 2 RCTs compared acupressure, sham acupressure, and a control (no treatment) group (Mobarakabadi 2019, Werntoft 2001); finally, 1 RCT compared ginger, acupressure and a control (no treatment) group (Saberi 2013). One RCT was a 4-arm trial that compared traditional acupuncture, P6 acupuncture, sham acupuncture and a control (no treatment) group (Smith 2002). One RCT reported an 8-arm unpublished trial from the 1970s that aimed to evaluate the efficacy of (Zhang 2017) pyridoxine hydrochloride and doxylamine succinate. The 8 arms of the trial were pyridoxine hydrochloride, a histamine H1-receptor antagonist (doxylamine succinate), a combination of pyridoxine hydrochloride and doxylamine succinate, and a placebo. The other arms of the trial were dicyclomine, a combination of dicyclomine and pyridoxine hydrochloride, a combination of dicyclomine and doxylamine succinate, and a combination of dicyclomine, pyridoxine hydrochloride, and doxylamine succinate, all of which were not interventions of interest for this review.

Five RCTs solely compared ginger to placebo (Basirat 2009, Keating 2002, Ozgoli 2009, Vutyavanich 2001, and Willetts 2003). Two of these studies were conducted in high-income countries (Keating 2002 and Willetts 2003), whilst the remaining were conducted in middle-income countries. The mean age of participants for this comparison ranged from 19 to 37 years and the gestational age ranged from 7-19 weeks. Majority of the studies for this comparison had a treatment length of 4 days. Only one study (Keating 2002) had a duration of 14 days.

Three RCTs solely compared acupressure to placebo (sham acupressure) (Belluomini 1994, Puangsricharem 2008, Rad 2012), conducted in US, Thailand, and Iran, respectively. One RCT compared P6 acupressure to KID21 acupressure (Galeshi 2020) and was conducted in Iran.

One RCT compared P6 acupuncture combined with transcutaneous electrical nerve stimulation to shame acupuncture combined with transcutaneous electrical nerve stimulation (Ghule 2020) and was conducted in India.

One RCT compared acupuncture to placebo (sham acupuncture) (Knight 2001) and was conducted in the UK, a high-income country.

One RCT compared a dopamine D2 receptor antagonist (metoclopramide) to a placebo, in a 3-arm trial (Mohammadbeigi 2011). This study was conducted in Iran over 5 days, where participants had an average age of 27 years and gestational age of 10 weeks.

One RCT compared a histamine H1-receptor antagonist (doxylamine succinate) to a placebo in an 8-arm trial (Zhang 2017). This study was conducted in US and the intervention was carried out over 7 days.

Two RCTs compared pyridoxine hydrochloride to placebo (Sahakian 1991, Vutyavanich 1995) of which the former was conducted in US and the latter in Thailand.

One RCT compared pyridoxine hydrochloride to a histamine H1-receptor antagonist (doxylamine succinate) in an 8-arm trial (Zhang 2017). This study was conducted in US and the intervention was carried out over 7 days.

One RCT (Bsat 2003), conducted in the US compared a combination of pyridoxine hydrochloride and a dopamine D2 receptor antagonist (metoclopramide) to a histamine H1-receptor antagonist only (promethazine).

Four studies reporting 3 RCTs, all conducted in the US, compared a combination of pyridoxine hydrochloride and a histamine H1-receptor antagonist to placebo. The histamine H1-receptor antagonist examined in two of the studies was doxylamine succinate (Geiger 1959, Koren 2010, 2015), with the other study using cyclizine hydrochloride (Monias 1957).

Finally, one RCT (Oliveira 2014) conducted in the US compared a combination of a serotonin 5-HT antagonist (ondansetron) and placebo to a combination of pyridoxine hydrochloride and a histamine H1-receptor antagonist (doxylamine succinate).

More than half of these studies were conducted in a high-income country (as defined by the World Bank). Ten studies reporting 9 RCTs were conducted in the US (Belluomini 1994, Bsat 2003, Geiger 1959, Keating 2002, Koren 2010, Koren 2015, Monias 1957, Oliveira 2014, Sahakian 1991, Zhang 2017), 2 RCTs were conducted in Australia (Smith 2002, Willetts 2003), 1 was conducted in the UK (Knight 2001), and 1 in Sweden (Werntoft 2001). The other 10 RCTs were conducted in low-income countries. Nine RCTs were carried out in Iran (Basirat 2009, Galeshi 2020, Mobarakabadi 2019, Mohammadbeigi 2011, Ozgoli 2009, Rad 2012, Saberi 2013, Saberi 2014, Sharifzadeh 2018) and 3 in Thailand (Puangsricharem 2008, Vutyavanich 1995, Vutyavanich 2001).

Within these studies, the mean age of the study participants ranged from 24 to 33 years and their gestational age ranged from 8 to 12 weeks. All studies specified that only participants in their first trimester or early second trimester were eligible.

Moderate to severe nausea and vomiting (including hyperemesis gravidarum)

Sixteen RCTs were included for the review on the treatment of moderate to severe nausea and vomiting during pregnancy (Abas 2014, Adlan 2017, Bondok 2006, Habek 2004, Heazell 2006, Kashifard 2013, McCarthy 2014, McParlin 2016, Nelson-Piercy 2001, Safari 1998, Sullivan 1996, Tan 2009, Tan 2010, Tan 2013, Yost 2003, Ziaei 2004). Some of the included studies involved pregnant women with hyperemesis gravidarum.

The included studies are summarised in Table 3.

Two RCTs compared acupressure + standard care to placebo (sham acupressure) (Adlan 2017, Heazell 2006), which were conducted in Malaysia and the UK, respectively. Habek 2004 conducted a 4-arm trial in Croatia comparing acupressure + standard care to placebo (sham acupressure), and also compared acupuncture + standard care to placebo (sham acupuncture).

One RCT compared pyridoxine hydrochloride to placebo (Tan 2009), whilst one RCT (Tan 2010) compared a dopamine D2-receptor antagonist (metoclopramide) to a histamine H1-receptor antagonist (promethazine). Both of these studies were conducted in Malaysia, a middle-income country.

Three RCTs compared a serotonin 5-HT antagonist (ondansetron) to either a dopamine D2 receptor antagonist (metoclopramide) (Abas 2014, Kashifard 2013), or a histamine H1-receptor antagonist (promethazine) (Sullivan 1996). These studies were conducted in Malaysia, Iran, and the US, respectively.

Five RCTs compared a corticosteroid to placebo or an alternative pharmacological intervention: two RCTs compared a corticosteroid (prednisolone and a combination of methylprednisolone and prednisolone, respectively to placebo (Nelson-Piercy 2001, Yost 2003), whilst two RCTs compared a corticosteroid (methylprednisolone and prednisolone, respectively) to a histamine H1-receptor antagonist (promethazine) (Safari 1998, Ziaei 2004); finally, one study compared corticosteroids (pulsed hydrocortisone) to dopamine D2 receptor antagonist (metoclopramide) (Bondok 2006).

Finally, three RCTs examined intravenous (IV) fluids as an intervention. Two of these examined giving IV fluids in different settings, either as a day care patient or an inpatient (McCarthy 2014, conducted in Ireland), or in a maternity assessment unit or an antenatal ward (McParlin 2016, conducted in the UK). One RCT compared IV fluid of dextrose saline to an IV fluid of normal saline rehydration (Tan 2013) and was conducted in Malaysia.

Half of these RCTs were performed in a high-income country, with three studies conducted in the UK (Heazell 2006, McParlin 2016, Nelson-Piercy 2001), three in the US (Safari 1998, Sullivan 1996, Yost 2003, one in Croatia (Habek 2004) and one in Ireland (McCarthy 2014). The remaining eight studies were conducted in middle-income countries, with five conducted in Malaysia (Abas 2014, Adlan 2017, Tan 2009, Tan 2010, Tan 2013), two in Iran (Kashifard 2013, Ziaei 2004), and one in Egypt (Bondok 2006). All the trials were 2-arm trials with one exception, a 4-arm trial that compared acupressure or acupuncture to their sham equivalents (sham acupressure, sham acupuncture) (Habek 2004). Within these studies, the mean age of the study participants ranged from 21 to 32 years and their gestational age ranged from 8 to 11 weeks. Majority of the studies investigated participants in their 9^th gestational week.

See the literature search strategy in appendix B and study selection flow chart in appendix C.

Excluded studies

Studies excluded from the review and reasons for their exclusion are provided in appendix K.

Summary of clinical studies included in the evidence review

A summary of the studies that were included in this review is presented in Table 2 and Table 3.

Mild to moderate nausea and vomiting

Table 2

Summary of included randomised trials for mild to moderate nausea and vomiting of pregnancy.

See appendix D for full evidence tables

Moderate to severe nausea and vomiting (including hyperemesis gravidarum)

Table 3

Summary of included randomised trials for moderate to severe nausea and vomiting (including hyperemesis gravidarum).

See appendix D for full evidence tables.

Quality assessment of clinical outcomes included in the evidence review

See the evidence profiles in appendix F.

Economic evidence

Included studies

One relevant study was identified in a literature review of published cost-effectiveness analyses on this topic; Murphy 2015 (see appendix H and appendix I for summary and full evidence tables). The economic evaluation, attached to the RCT in the clinical review (McCarthy 2014), considered the cost-effectiveness of day care over inpatient management of nausea and vomiting in pregnancy (NVP). The analysis conducted was a cost-utility analysis measuring effectiveness in terms of quality adjusted life years (QALYs). Studies excluded from the review and reasons for their exclusion are provided in appendix K.

Excluded studies

There was no economic evidence identified for this review question and therefore there is no excluded studies list in appendix K.

Summary of studies included in the economic evidence review

Murphy (2014) adopt a combined health care payer and patient perspective in Ireland. However, in this review only the costs concerned from a healthcare payer perspective are included, as according to the NICE guidelines manual. The resource use estimates are based on the RCT, though, the source of the unit costs are unclear. The primary outcome for the study was total number of inpatient nights related to nausea and committing of pregnancy.

The economic analysis employs a Markov model which consists of three health states: Healthy Discharged, Moderate NVP and Severe NVP, with a time horizon over 52 days. This period was divided into a series of discrete time periods referred to as cycles, which represent each episode of care for NVP.

Utilities were assigned to each state in the Markov model to generate QALYs. Trial data was used to inform quality of life for patients in the Severe NVP state. For both Moderate and Healthy states, Non-preference based data was obtained indirectly from published literature of SF-36 results and then mapped into EQ-5D estimates.

In the deterministic analysis, the mean cost per patient in day care management was €609 (95% CI: 453-860). With regards to inpatient management, the average cost per patient was €2135 (95% CI: 2124-8466). In terms of QALYs, patients receiving day care management experienced 9.49 QALYs (95% CI: 4.32-12.39) whilst patients randomised to inpatient management experienced 9.42 QALYs (95% CI: 4.19-12.25). Thus, day care management dominates inpatient management as it is both less costly and more effective. The study includes a cost effectiveness acceptability curve which, at a threshold of €45,000/per QALY, the probability that day care management is cost effective is 73% while the probability that inpatient management is cost effective is 23%.

This study is deemed as directly applicable for the following reasons: the study population is in accordance with that specified in the protocol; the interventions are appropriate to the review question; the study was conducted in a system sufficiently similar to the UK (Ireland; a healthcare payer’s perspective was undertaken for costs and the study utilises QALYs as a measure of effectiveness.

The overall methodological quality of the study can be classified as having minor limitations. Despite using an RCT as a vehicle for an economic evaluation, it is not clear from where the unit cost data is derived from. there is no reported deterministic sensitivity analysis on key model parameters.

Economic model

No economic modelling was undertaken for this review because the committee agreed that other topics were higher priorities for economic evaluation.

Clinical evidence statements

Mild to moderate nausea and vomiting

Comparison 1. Ginger versus placebo

Critical outcomes

Symptomatic relief during pregnancy

Overall relief

Moderate quality evidence from 4 RCTs (N=287) showed that there is a clinically important difference favouring ginger tablets over placebo on overall symptomatic relief as assessed by the Total Rhodes Index score up to 7 days after treatment in women who experience pregnancy-related nausea and vomiting: MD −6.33 (95% CI −8.64 to −4.02).

Nausea relief

Very low quality evidence from 3 RCTs (N=219) showed that there is a clinically important difference favouring ginger tablets over placebo on relief from nausea as assessed by the Rhodes Index up to 7 days after treatment in women who experience pregnancy-related nausea and vomiting: MD −2.52 (95% CI −4.22 to −0.83).

Nausea intensity

Moderate quality evidence from 2 RCTs (N=119) showed that there is no clinically important difference favouring ginger tablets over placebo on nausea intensity as assessed by the Rhodes Index after treatment in women who experience pregnancy-related nausea and vomiting: MD −1.72 (95% CI −3.64 to 0.21).
Moderate quality evidence from 2 RCTs (N=132) showed that there is a clinically important difference favouring ginger biscuit or tablet over placebo on nausea intensity from baseline as assessed by a visual analogue scale after treatment in women who experience pregnancy-related nausea and vomiting: MD −1.52 (95% CI −2.38 to −0.67).

Nausea frequency

Low quality evidence from 1 RCT (N=51) showed that there is a clinically important difference favouring ginger tablet over placebo on nausea frequency as assessed by the Rhodes Index after treatment in women who experience pregnancy-related nausea and vomiting: MD −0.57 (95% CI −1.08 to −0.06).

Vomiting relief

Very low quality evidence from 3 RCTs (N=219) showed that there is a clinically important difference favouring ginger tablets over placebo on relief from vomiting as assessed by the Rhodes Index up to 7 days after treatment in women who experience pregnancy-related nausea and vomiting: MD −1.74 (95% CI −3.35 to −0.14).

Vomiting intensity

Low quality evidence from 2 RCTs (N=119) showed that there is no clinically important difference between ginger tablet and placebo on vomiting intensity as assessed by the Rhodes Index after treatment in women who experience pregnancy-related nausea and vomiting: MD −1.07 (95% CI −1.67 to −0.48).

Vomiting frequency

Low quality evidence from 1 RCT (N=51) showed that there is a clinically important difference favouring ginger tablet over placebo on vomiting frequency as assessed by the Rhodes Index after treatment in women who experience pregnancy-related nausea and vomiting: MD −0.9 (95% CI −1.32 to −0.48).
Very low quality evidence from 2 RCTs (N=132) showed that there is no clinically important difference between ginger biscuit or capsule and placebo on vomiting frequency as assessed by patient report in the last 24 hours up to 7 days after treatment in women who experience pregnancy-related nausea and vomiting: MD −1.02 (95% CI −2.65 to 0.60).

Retching relief

Moderate quality evidence from 2 RCTs (N=168) showed that there is a clinically important difference favouring ginger tablets over placebo on relief from retching as assessed by the Rhodes Index after treatment in women who experience pregnancy-related nausea and vomiting: MD −2.18 (95% CI −2.74 to −1.63).

Retching frequency

Low quality evidence from 1 RCT (N=51) showed that there is no clinically important difference between ginger tablet and placebo on retching frequency as assessed by the Rhodes Index after treatment in women who experience pregnancy-related nausea and vomiting: MD −0.40 (95% CI −1.00 to 0.20).

Improvement in nausea intensity

Very low quality evidence from 1 RCT (N=67) showed that there is no clinically important difference between ginger tablet and placebo on the number of women who experience pregnancy-related nausea and vomiting whose nausea intensity does not improve as assessed by a visual analogue scale score: RR 0.47 (95% CI 0.13 to 1.66).
Low quality evidence from 1 RCT (N=23) showed that there is a clinically important difference favouring ginger syrup over placebo on the number of women who experience pregnancy-related nausea and vomiting whose nausea intensity either does not improve or only improves a little as assessed by a numerical scale: Peto OR 0.04 (95% CI 0.01 to 0.24).

Fetal death

Abortion

Very low quality evidence from 2 RCTs (N=190) showed that there is no statistically significant difference between ginger capsules and placebo on abortion, up to 7 days after treatment in women who experience pregnancy-related nausea and vomiting: RR 1.09 (95% CI 0.27 to 4.39) p=0.90.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

Very low quality evidence from 4 RCTs (N=319) showed that there is no clinically important difference between ginger capsule, biscuit, or tablet, and placebo on adverse events requiring hospitalisation up to 7 days after treatment in women who experience pregnancy-related nausea and vomiting: Peto OR 1.51 (95% CI 0.25 to 9.00).
- Very low quality evidence from 1 RCT (N=120) showed that there is no clinically important difference between ginger capsules and placebo on adverse events requiring hospitalisation in high-income countries, up to 7 days after treatment in women who experience pregnancy-related nausea and vomiting: RR 1.50 (95% CI 0.26 to 8.66).
- Very low quality evidence from 3 RCTs (N=199) showed that there is no clinically important difference between ginger biscuit, tablet or capsule, and placebo on adverse events requiring hospitalisation in middle-income countries, up to 7 days after treatment in women who experience pregnancy-related nausea and vomiting: RD 0.00 (95% CI −0.03 to 0.03).

Number of days in hospital for treatment of nausea and vomiting

No evidence was identified to inform this outcome.

Women’s experience and satisfaction of care during or at end of pregnancy

No evidence was identified to inform this outcome.

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 2. Acupressure versus acupressure

Critical outcomes

Symptomatic relief during pregnancy

Nausea severity

Low quality evidence from 1 RCT (N=82) showed that there is no clinically important difference between P6 acupressure and KID21 acupressure on nausea severity on change score from baseline, as assessed by the visual analogue scale in women who experience pregnancy-related nausea and vomiting: MD −0.52 (95% CI −1.08 to 0.04).

Vomiting severity

Moderate quality evidence from 1 RCT (N=82) showed that there is no clinically important difference between P6 acupressure and KID21 acupressure on vomiting severity on change score from baseline, as assessed by the visual analogue scale in women who experience pregnancy-related nausea and vomiting: MD 0.22 (95% CI −0.26 to 0.70).

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

No evidence was identified to inform this outcome.

Number of days in hospital for treatment of nausea and vomiting

No evidence was identified to inform this outcome.

Women’s experience and satisfaction of care during or at end of pregnancy

No evidence was identified to inform this outcome.

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 3. Acupressure versus placebo

Critical outcomes

Symptomatic relief during pregnancy

Overall relief

Moderate quality evidence from 2 RCTs (N=151) showed that there is no clinically important difference between acupressure and placebo on overall relief up to 7 days after treatment, as assessed by the Rhodes Index in women who experience pregnancy-related nausea and vomiting: MD −2.23 (95% CI −4.12 to −0.34).
- Low quality evidence from 1 RCT (N=60) showed that there is no clinically important difference between acupressure and placebo on overall relief in high-income countries after treatment, as assessed by the Rhodes Index in women who experience pregnancy-related nausea and vomiting: MD −1.34 (95% CI −3.77 to 1.09).
- Low quality evidence from 1 RCT (N=91) showed that there is no clinically important difference between acupressure and placebo on overall relief in low-income countries 7 days after treatment, as assessed by the Rhodes Index in women who experience pregnancy-related nausea and vomiting: MD −3.60 (95% CI −6.62 to −0.58).

Nausea relief

Low quality evidence from 1 RCT (N=60) showed that there is no clinically important difference between acupressure and placebo on relief from nausea up to 7 days after treatment, as assessed by the Rhodes Index, in women who experience pregnancy-related nausea and vomiting: MD −1.24 (95% CI −2.63 to 0.15).

Nausea frequency

Low quality evidence from 1 RCT (N=50) showed that there is no clinically important difference between acupressure and placebo on nausea frequency up to 4 days after treatment, as assessed by an unspecified scale from 0 to 4, in women who experience pregnancy-related nausea and vomiting: MD −2.49 (95% CI −4.41 to −0.57).

Nausea intensity

Very low quality evidence from 1 RCT (N=40) showed that there is a clinically important difference favouring acupressure over placebo on nausea intensity after treatment as assessed by a visual analogue scale in women who experience pregnancy-related nausea and vomiting: MD −1.70 (95% CI −3.25 to −0.15).
Low quality evidence from 1 RCT (N=80) showed that there is a statistically significant difference favouring acupressure over placebo on nausea intensity after treatment as assessed by a visual analogue scale in women who experience pregnancy-related nausea and vomiting: difference between medians 3, p=0.001.
Low quality evidence from 1 RCT (N=50) showed that there is no clinically important difference between acupressure and placebo on nausea intensity up to 4 days after treatment, as assessed by an unspecified scale from 0 to 4, in women who experience pregnancy-related nausea and vomiting: MD −6.39 (95% CI −12.37 to −0.41).

Vomiting relief

Moderate quality evidence from 1 RCT (N=60) showed that there is no clinically important difference between acupressure and placebo on relief from vomiting up to 7 days after treatment, as assessed by the Rhodes Index, in women who experience pregnancy-related nausea and vomiting: MD −0.35 (95% CI −1.42 to 0.72).

Vomiting frequency

Low quality evidence from 1 RCT (N=80) showed that there is a statistically significant difference favouring acupressure over placebo on vomiting intensity as assessed by patient report in women who experience pregnancy-related nausea and vomiting: difference between medians 1, p=0.001.
Moderate quality evidence from 1 RCT (N=50) showed that there is no clinically important difference between acupressure and placebo on vomiting frequency up to 4 days after treatment, as assessed by an unspecified scale from 0 to 4, in women who experience pregnancy-related nausea and vomiting: MD −0.38 (95% CI −1.57 to 0.81).

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

No evidence was identified to inform this outcome.

Number of days in hospital for treatment of nausea and vomiting

No evidence was identified to inform this outcome.

Women’s experience and satisfaction of care during or at end of pregnancy

Low quality evidence from 1 RCT (N=50) showed that there is a clinically important difference favouring acupressure over placebo on women’s experience and satisfaction of care during or at end of pregnancy for those reporting satisfaction with the intervention in women who experience pregnancy-related nausea and vomiting: RR 2.50 (95% CI 1.16 to 5.39).
Very low quality evidence from 1 RCT (N=50) showed that there is no clinically important difference between acupressure and placebo on women’s experience and satisfaction of care during or at end of pregnancy for those reporting no satisfaction with the intervention in women who experience pregnancy-related nausea and vomiting: Peto OR 7.39 (95% CI 0.15 to 372.38).
Low quality evidence from 1 RCT (N=50) showed that there is a clinically important difference favouring placebo over acupressure on women’s experience and satisfaction of care during or at end of pregnancy for those reporting they were almost satisfied with the intervention in women who experience pregnancy-related nausea and vomiting: RR 0.47 (95% CI 0.27 to 0.84).

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 4. Acupressure versus control (no treatment)

Critical outcomes

Symptomatic relief during pregnancy

Overall relief

Low quality evidence from 1 RCT (N=93) showed that there is no clinically important difference between acupressure and control (no treatment) on overall relief up to 7 days after treatment, as assessed by the Rhodes Index in women who experience pregnancy-related nausea and vomiting: MD −2.67 (95% CI −5.84 to 0.50).

Nausea relief

Low quality evidence from 1 RCT (N=93) showed that there is no clinically important difference between acupressure and control (no treatment) on relief from nausea up to 7 days after treatment, as assessed by the Rhodes Index, in women who experience pregnancy-related nausea and vomiting: MD 0.95 (95% CI −0.51 to 2.41).

Nausea frequency

Moderate quality evidence from 1 RCT (N=50) showed that there is a clinically important difference favouring P6 acupressure over control (no treatment) on change score from baseline for nausea frequency, as assessed by an unspecified scale from 0 to 4, in women who experience pregnancy-related nausea and vomiting: MD −5.50 (95% CI −7.24 to −3.76).

Nausea intensity

Very low quality evidence from 1 RCT (N=40) showed that there is a clinically important difference favouring acupressure over control (no treatment) on nausea intensity after treatment as assessed by a visual analogue scale in women who experience pregnancy-related nausea and vomiting: MD −2.30 (95% CI −3.79 to −0.81).
Moderate quality evidence from 1 RCT (N=50) showed that there is a clinically important difference favouring P6 acupressure over control (no treatment) on change score from baseline for nausea intensity, as assessed by an unspecified scale from 0 to 4, in women who experience pregnancy-related nausea and vomiting: MD −14.30 (95% CI −20.02 to −8.58).

Vomiting relief

Low quality evidence from 1 RCT (N=93) showed that there is no clinically important difference between acupressure and control (no treatment) on relief from vomiting up to 7 days after treatment, as assessed by the Rhodes Index, in women who experience pregnancy-related nausea and vomiting: MD −1.41 (95% CI −2.73 to −0.09).

Vomiting frequency

Low quality evidence from 1 RCT (N=50) showed that there is a clinically important difference favouring P6 acupressure over control (no treatment) on change score from baseline for vomiting frequency, as assessed by an unspecified scale from 0 to 4, in women who experience pregnancy-related nausea and vomiting: MD −1.39 (95% CI −2.37 to −0.41).

Retching relief

Low quality evidence from 1 RCT (N=93) showed that there is no clinically important difference between acupressure and control (no treatment) on relief from retching 7 days after treatment, as assessed by the Rhodes Index, in women who experience pregnancy-related nausea and vomiting: MD −0.82 (95% CI −1.78 to 0.14).

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

No evidence was identified to inform this outcome.

Number of days in hospital for treatment of nausea and vomiting

No evidence was identified to inform this outcome.

Women’s experience and satisfaction of care during or at end of pregnancy

Moderate quality evidence from 1 RCT (N=50) showed that there is a clinically important difference favouring acupressure over control (no treatment) on women’s experience and satisfaction of care during or at end of pregnancy for those reporting satisfaction with the intervention in women who experience pregnancy-related nausea and vomiting: RR 5.00 (95% CI 1.65 to 15.15).
Moderate quality evidence from 1 RCT (N=50) showed that there is a clinically important difference favouring acupressure over control (no treatment) on women’s experience and satisfaction of care during or at end of pregnancy for those reporting no satisfaction with the intervention in women who experience pregnancy-related nausea and vomiting: RR 0.06 (95% CI 0.01 to 0.44).
Very low quality evidence from 1 RCT (N=50) showed that there is no clinically important difference between acupressure and control (no treatment) on women’s experience and satisfaction of care during or at end of pregnancy for those reporting they were almost satisfied with the intervention in women who experience pregnancy-related nausea and vomiting: RR 1.50 (95% CI 0.63 to 3.59).

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 5. Acupressure versus ginger

Critical outcomes

Symptomatic relief during pregnancy

Overall relief

Moderate quality evidence from 1 RCT (N=98) showed that there is a clinically important difference favouring ginger over acupressure on overall relief 7 days after treatment, as assessed by the Rhodes Index, in women who experience pregnancy-related nausea and vomiting: MD 6.24 (95% CI 3.03 to 9.45).

Nausea relief

Moderate quality evidence from 1 RCT (N=98) showed that there is a clinically important difference favouring ginger over acupressure on relief from nausea 7 days after treatment, as assessed by the Rhodes Index, in women who experience pregnancy-related nausea and vomiting: MD 4.41 (95% CI 2.96 to 5.86).

Vomiting relief

Low quality evidence from 1 RCT (N=98) showed that there is a clinically important difference favouring ginger over acupressure on relief from vomiting 7 days after treatment, as assessed by the Rhodes Index, in women who experience pregnancy-related nausea and vomiting: MD 1.67 (95% CI 0.37 to 2.97).

Retching relief

Low quality evidence from 1 RCT (N=98) showed that there is a clinically important difference favouring ginger over acupressure on relief from retching 7 days after treatment, as assessed by the Rhodes Index, in women who experience pregnancy-related nausea and vomiting: MD 1.54 (95% CI 0.60 to 2.48).

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

No evidence was identified to inform this outcome.

Number of days in hospital for treatment of nausea and vomiting

No evidence was identified to inform this outcome.

Women’s experience and satisfaction of care during or at end of pregnancy

No evidence was identified to inform this outcome.

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 6. Acupuncture versus placebo

Critical outcomes

Symptomatic relief during pregnancy

Nausea relief

Moderate quality evidence from 1 RCT (N=445) showed that there is no clinically important difference favouring placebo over P6 acupuncture on relief from nausea after treatment as assessed by the Rhodes Index in women who experience pregnancy-related nausea and vomiting: MD −0.35 (95% CI −0.98 to 0.28).
Low quality evidence from 1 RCT (N=445) showed that there is no clinically important difference between traditional acupuncture and placebo on relief from nausea after treatment as assessed by the Rhodes Index in women who experience pregnancy-related nausea and vomiting: MD −0.95 (95% CI −1.54 to −0.36).

Nausea intensity

Low quality evidence from 1 RCT (N= 55) showed that there was no statistically significant difference favouring traditional acupuncture over placebo on nausea intensity after treatment as assessed by a visual analogue scale in women who experience pregnancy-related nausea and vomiting: difference between medians 0.5, p=0.9.

Vomiting relief

Moderate quality evidence from 1 RCT (N=445) showed that there is no clinically important difference between P6 acupuncture and placebo on relief from vomiting after treatment as assessed by the Rhodes Index in women who experience pregnancy-related nausea and vomiting: MD −0.30 (95% CI −0.66 to 0.06).
Moderate quality evidence from 1 RCT (N=445) showed that there is no clinically important difference between traditional acupuncture and placebo on relief from vomiting after treatment as assessed by the Rhodes Index in women who experience pregnancy-related nausea and vomiting: MD −0.30 (95% CI −0.62 to 0.02).

Retching relief

Moderate quality evidence from 1 RCT (N=445) showed that there is no clinically important difference between P6 acupuncture and placebo on relief from retching after treatment as assessed by the Rhodes Index in women who experience pregnancy-related nausea and vomiting: MD −0.35 (95% CI −0.63 to −0.07).
Moderate quality evidence from 1 RCT (N=445) showed that there is no clinically important difference between traditional acupuncture and placebo on relief from retching after treatment as assessed by the Rhodes Index in women who experience pregnancy-related nausea and vomiting: MD −0.45 (95% CI −0.74 to −0.16).

Fetal death

Low quality evidence from 1 RCT (N=445) showed that there is no statistically significant difference between P6 acupuncture and placebo on fetal death after treatment in women who experience pregnancy-related nausea and vomiting: RR 0.50 (95% CI 0.21 to 1.20) p=0.12.
Low quality evidence from 1 RCT (N=445) showed that there is no statistically significant difference between traditional acupuncture and placebo on fetal death after treatment in women who experience pregnancy-related nausea and vomiting: RR 0.50 (95% CI 0.21 to 1.20) p=0.12.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

Low quality evidence from 1 RCT (N=55) showed that there was no clinically important difference between traditional acupuncture and placebo for adverse events requiring hospitalisation in women who experience pregnancy-related nausea and vomiting: RD 0.00 (95% CI −0.07 to 0.07).

Number of days in hospital for treatment of nausea and vomiting

No evidence was identified to inform this outcome.

Women’s experience and satisfaction of care during or at end of pregnancy

No evidence was identified to inform this outcome.

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 7. Acupuncture + component versus sham acupuncture + placebo component

Critical outcomes

Symptomatic relief during pregnancy

Overall relief

Low quality evidence from 1 RCT (N=107) showed that there is a clinically important difference favouring P6 acupuncture and transcutaneous electrical nerve stimulation over sham acupuncture and placebo transcutaneous electrical nerve stimulation on overall relief as assessed by the Rhodes Index in women who experience pregnancy-related nausea and vomiting: MD −6.32 (95% CI −8.21 to −4.43).

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

No evidence was identified to inform this outcome.

Number of days in hospital for treatment of nausea and vomiting

No evidence was identified to inform this outcome.

Women’s experience and satisfaction of care during or at end of pregnancy

Low quality evidence from 1 RCT (N=107) showed that there was a clinically important difference favouring P6 acupuncture and transcutaneous electrical nerve stimulation over sham acupuncture and placebo transcutaneous electrical nerve stimulation on quality of life as assessed by the Nausea Vomiting of Pregnancy Quality of Life questionnaire in women who experience pregnancy-related nausea and vomiting: MD −34.65 (95% CI −40.64 to −28.66).

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 8. Dopamine D2-receptor antagonist versus placebo

Critical outcomes

Symptomatic relief during pregnancy

Overall relief

High quality evidence from 1 RCT (N=68) showed that there is a clinically important difference favouring dopamine D2-receptor antagonist (metoclopramide hydrochloride) over placebo on overall relief after treatment as assessed by the Rhodes Index in women who experience pregnancy-related nausea and vomiting: MD −4.62 (95% CI −6.83 to −2.41).

Nausea intensity

High quality evidence from 1 RCT (N=68) showed that there is a clinically important difference favouring dopamine D2-receptor antagonist (metoclopramide hydrochloride) over placebo on overall relief after treatment as assessed by the Rhodes Index in women who experience pregnancy-related nausea and vomiting: MD −3.05 (95% CI −4.50 to −1.60).

Vomiting intensity

Moderate quality evidence from 1 RCT (N=68) showed that there is a clinically important difference favouring dopamine D2-receptor antagonist (metoclopramide hydrochloride) over placebo on overall relief after treatment as assessed by the Rhodes Index in women who experience pregnancy-related nausea and vomiting: MD −1.06 (95% CI −1.82 to −0.30).

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

No evidence was identified to inform this outcome.

Number of days in hospital for treatment of nausea and vomiting

No evidence was identified to inform this outcome.

Women’s experience and satisfaction of care during or at end of pregnancy

No evidence was identified to inform this outcome.

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 9. Histamine H1-receptor antagonist versus placebo

Critical outcomes

Symptomatic relief during pregnancy

Improvement on symptoms

Very low quality evidence from 1 RCT (N=390) showed that there is a clinically important difference favouring histamine H1-receptor antagonist (doxylamine succinate) over placebo on number of women with improvement in nausea after treatment as assessed by physician evaluations in women who experience pregnancy-related nausea and vomiting: RR 1.33 (95% CI 1.12 to 1.57).
Very low quality evidence from 1 RCT (N=390) showed that there is no clinically important difference between histamine H1-receptor antagonist (doxylamine succinate) and placebo on number of women with improvement in vomiting after treatment as assessed by physician evaluations in women who experience pregnancy-related nausea and vomiting: RR 1.19 (95% CI 1.04 to 1.35).

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

No evidence was identified to inform this outcome.

Number of days in hospital for treatment of nausea and vomiting

No evidence was identified to inform this outcome.

Women’s experience and satisfaction of care during or at end of pregnancy

No evidence was identified to inform this outcome.

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 10. Pyridoxine hydrochloride versus placebo

Critical outcomes

Symptomatic relief during pregnancy

Overall relief

Moderate quality evidence from 1 RCT (N=49) showed that there is a clinically important difference favouring pyridoxine hydrochloride over placebo on overall relief after treatment as assessed by the Rhodes Index in women who experience pregnancy-related nausea and vomiting: MD −5.50 (95% CI −7.66 to −3.34).

Nausea intensity

Low quality evidence from 1 RCT (N=49) showed that there is a clinically important difference favouring pyridoxine hydrochloride over placebo on nausea intensity after treatment as assessed by the Rhodes Index in women who experience pregnancy-related nausea and vomiting: MD −0.89 (95% CI −1.38 to −0.4).
Moderate quality evidence from 2 RCTs (N=401) showed that there is no clinically important difference between pyridoxine hydrochloride and placebo on nausea intensity after treatment as assessed by a visual analogue scale: MD −0.60 (95% CI −1.2 to −0.01).

Nausea frequency

Low quality evidence from 1 RCT (N=49) showed that there is a clinically important difference favouring pyridoxine hydrochloride over placebo on nausea frequency after treatment as assessed by the Rhodes Index in women who experience pregnancy-related nausea and vomiting: MD −0.67 (95% CI −1.08 to −0.26).

Vomiting intensity

Low quality evidence from 1 RCT (N=49) showed that there is a clinically important difference favouring pyridoxine hydrochloride over placebo on vomiting intensity after treatment as assessed by the Rhodes Index in women who experience pregnancy-related nausea and vomiting: MD −0.7 (95% CI −1.14 to −0.26).

Vomiting frequency

Low quality evidence from 1 RCT (N=49) showed that there is a clinically important difference favouring pyridoxine hydrochloride over placebo on vomiting frequency after treatment as assessed by the Rhodes Index in women who experience pregnancy-related nausea and vomiting: MD −0.97 (95% CI −1.43 to −0.51).

Change in vomiting frequency

High quality evidence from 1 RCT (N=342) showed that there no clinically important difference between pyridoxine hydrochloride and placebo on change in vomiting frequency after treatment as assessed by patient report in women who experience pregnancy-related nausea and vomiting: MD −0.1 (95% CI −0.62 to 0.42).

Number of patients vomiting on last day of treatment

Low quality evidence from 1 RCT (N=59) showed that there is a clinically important difference favouring pyridoxine hydrochloride over placebo on the number of patients vomiting on last day of treatment in women who experience pregnancy-related nausea and vomiting: RR 0.48 (95% CI 0.24 to 0.96).

Improvement on symptoms

Very low quality evidence from 1 RCT (N=372) showed that there is a clinically important difference favouring pyridoxine hydrochloride over placebo on the number of women with improvement in nausea after treatment as assessed by physician evaluation in women who experience pregnancy-related nausea and vomiting: RR 1.31 (95% CI 1.11 to 1.55).
Low quality evidence from 1 RCT (N=372) showed that there is no clinically important difference favouring pyridoxine hydrochloride over placebo on the number of women with improvement in vomiting after treatment as assessed by physician evaluation in women who experience pregnancy-related nausea and vomiting: RR 1.00 (95% CI 0.87 to 1.16).

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

No evidence was identified to inform this outcome.

Number of days in hospital for treatment of nausea and vomiting

No evidence was identified to inform this outcome.

Women’s experience and satisfaction of care during or at end of pregnancy

No evidence was identified to inform this outcome.

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 11. Pyridoxine hydrochloride versus histamine H1-receptor antagonist

Critical outcomes

Symptomatic relief during pregnancy

Improvement on symptoms

Low quality evidence from 1 RCT (N=400) showed that there is no clinically important difference between pyridoxine hydrochloride and histamine H1-receptor antagonist (doxylamine succinate) on the number of women with improvement in nausea after treatment as assessed by physician evaluation in women who experience pregnancy-related nausea and vomiting: RR 0.99 (95% CI 0.86 to 1.13).
Very low quality evidence from 1 RCT (N=400) showed that there is no clinically important difference between pyridoxine hydrochloride and histamine H1-receptor antagonist (doxylamine succinate) on the number of women with improvement in vomiting after treatment as assessed by physician evaluation in women who experience pregnancy-related nausea and vomiting: RR 0.85 (95% CI 0.75 to 0.96).

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

No evidence was identified to inform this outcome.

Number of days in hospital for treatment of nausea and vomiting

No evidence was identified to inform this outcome.

Women’s experience and satisfaction of care during or at end of pregnancy

No evidence was identified to inform this outcome.

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 12. Pyridoxine hydrochloride + dopamine D2-receptor antagonist versus histamine H1-receptor antagonist

Critical outcomes

Symptomatic relief during pregnancy

Vomiting frequency

Moderate quality evidence from 1 RCT (N=106) showed that there is no clinically important difference between pyridoxine hydrochloride + dopamine D2-receptor antagonist (metoclopramide hydrochloride) and histamine H1-receptor antagonist (promethazine hydrochloride) on vomiting frequency after treatment as assessed by patient report in women who experience pregnancy-related nausea or vomiting: MD −0.20 (95% CI −0.5 to 0.1).

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

No evidence was identified to inform this outcome.

Number of days in hospital for treatment of nausea and vomiting

No evidence was identified to inform this outcome.

Women’s experience and satisfaction of care during or at end of pregnancy

No evidence was identified to inform this outcome.

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 13. Pyridoxine hydrochloride + histamine H1-receptor antagonist versus placebo

Critical outcomes

Symptomatic relief during pregnancy

Overall relief

Moderate quality evidence from 1 RCT (N=256) showed that there is no clinically important difference between pyridoxine hydrochloride + histamine H1-receptor antagonist (doxylamine succinate) and placebo on overall relief at 15 days after treatment as assessed by change scores on the PUQE (pregnancy unique quantification of emesis and nausea) index in women who experience pregnancy-related nausea and vomiting: MD −0.90 (95% CI −1.55 to −0.25).

Relief from nausea and vomiting

Low quality evidence from 2 RCTs (N=310) showed that there is a clinically important difference favouring pyridoxine hydrochloride and histamine H1-receptor antagonist (doxylamine succinate or cyclizine hydrochloride) over placebo on relief from nausea and vomiting after treatment as assessed by patient report in women who experience pregnancy-related nausea and vomiting: RR 3.40 (1.08 to 10.70).

Improvement on symptoms

Very low quality evidence from 1 RCT (N=394) showed that there is a clinically important difference favouring pyridoxine hydrochloride + histamine H1-receptor antagonist (doxylamine succinate) over placebo on the number of women with improvements in nausea after treatment as assessed by physician evaluation in women who experience pregnancy-related nausea and vomiting: RR 1.45 (95% CI 1.23 to 1.70).
Very low quality evidence from 1 RCT (N=394) showed that there is no clinically important difference between pyridoxine hydrochloride + histamine H1-receptor antagonist (doxylamine succinate) and placebo on the number of women with improvements in vomiting after treatment as assessed by physician evaluation in women who experience pregnancy-related nausea and vomiting: RR 1.11 (95% CI 0.97 to 1.26).

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

Low quality evidence from 2 RCTs (N=368) showed that there is no clinically important difference between pyridoxine hydrochloride + histamine H1-receptor antagonist (doxylamine succinate and cyclizine hydrochloride) and placebo on adverse events requiring hospitalisation after treatment in women who experience pregnancy-related nausea and vomiting: RD 0.00 (95% CI −0.02 to 0.02).

Number of days in hospital for treatment of nausea and vomiting

No evidence was identified to inform this outcome.

Women’s experience and satisfaction of care during or at end of pregnancy

No evidence was identified to inform this outcome.

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 14. Pyridoxine hydrochloride + histamine H1-receptor antagonist versus pyridoxine hydrochloride

Critical outcomes

Symptomatic relief during pregnancy

Number of women with improvements in symptoms

Very low quality evidence from 1 RCT (N=404) showed that there is no clinically important difference between pyridoxine hydrochloride + histamine H1-receptor antagonist (doxylamine succinate) and pyridoxine hydrochloride on the number of women with improvement in nausea after treatment as assessed by physician evaluation in women who experience pregnancy-related nausea and vomiting: RR 1.10 (95% CI 0.97 to 1.25).
Very low quality evidence from 1 RCT (N=404) showed that there is no clinically important difference between pyridoxine hydrochloride + histamine H1-receptor antagonist (doxylamine succinate) and pyridoxine hydrochloride on the number of women with improvement in vomiting after treatment as assessed by physician evaluation in women who experience pregnancy-related nausea and vomiting: RR 1.10 (95% CI 0.97 to 1.26).

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

No evidence was identified to inform this outcome.

Number of days in hospital for treatment of nausea and vomiting

No evidence was identified to inform this outcome.

Women’s experience and satisfaction of care during or at end of pregnancy

No evidence was identified to inform this outcome.

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 15. Pyridoxine hydrochloride + histamine H1-receptor antagonist versus histamine H1-receptor antagonist

Critical outcomes

Symptomatic relief during pregnancy

Number of women with improvements in symptoms

Low quality evidence from 1 RCT (N=422) showed that there is no clinically important difference between pyridoxine hydrochloride + histamine H1-receptor antagonist (doxylamine succinate) and histamine H1-receptor antagonist (doxylamine succinate) on the number of women with improvement in nausea after treatment as assessed by physician evaluation in women who experience pregnancy-related nausea and vomiting: RR 1.09 (95% CI 0.97 to 1.23).
Low quality evidence from 1 RCT (N=422) showed that there is no clinically important difference between pyridoxine hydrochloride + histamine H1-receptor antagonist (doxylamine succinate) and histamine H1-receptor antagonist (doxylamine succinate) on the number of women with improvement in vomiting after treatment as assessed by physician evaluation in women who experience pregnancy-related nausea and vomiting: RR 0.93 (95% CI 0.84 to 1.04).

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

No evidence was identified to inform this outcome.

Number of days in hospital for treatment of nausea and vomiting

No evidence was identified to inform this outcome.

Women’s experience and satisfaction of care during or at end of pregnancy

No evidence was identified to inform this outcome.

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 16. Serotonin 5-HT antagonist + placebo versus pyridoxine hydrochloride + histamine H1-receptor antagonist

Critical outcomes

Symptomatic relief during pregnancy

Nausea intensity

Low quality evidence from 1 RCT (N=30) showed that there is a statistically significant favouring serotonin 5-HT antagonist (ondansetron) + placebo over pyridoxine hydrochloride + histamine H1-receptor antagonist (doxylamine succinate) on nausea intensity 7 days after treatment as assessed by change scores on a visual analogue scale in women who experience pregnancy-related nausea and vomiting: difference between medians 31, p=0.019.

Vomiting intensity

Low quality evidence from 1 RCT (N=30) showed that there is a statistically significant difference favouring serotonin 5-HT antagonist (ondansetron) + placebo over pyridoxine hydrochloride + histamine H1-receptor antagonist (doxylamine succinate) on vomiting intensity 7 days after treatment as assessed by change scores on a visual analogue scale in women who experience pregnancy-related nausea and vomiting: difference between medians 24, p=0.049.

Number of women with improvement in symptoms (score on VAS ≥25 mm, considered clinically important in study)

Moderate quality evidence from 1 RCT (N=30) showed that there is a clinically important difference favouring serotonin 5-HT antagonist (ondansetron) + placebo over pyridoxine hydrochloride + histamine H1-receptor antagonist (doxylamine succinate) on the number of women with a clinically significant improvement in nausea symptoms 7 days after treatment as assessed by a visual analogue scale in women who experience pregnancy-related nausea and vomiting: RR 2.24 (95% CI 1.24 to 4.04).
Moderate quality evidence from 1 RCT (N=30) showed that there is a clinically important difference favouring serotonin 5-HT antagonist (ondansetron) + placebo over pyridoxine hydrochloride + histamine H1-receptor antagonist (doxylamine succinate) on the number of women with a clinically significant improvement in vomiting symptoms 7 days after treatment as assessed by a visual analogue scale in women who experience pregnancy-related nausea and vomiting: RR 2.18 (95% CI 1.07 to 4.43).

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

Low quality evidence from 1 RCT (N=30) showed that there is no clinically important difference between serotonin 5-HT antagonist (ondansetron) + placebo and pyridoxine hydrochloride + histamine H1-receptor antagonist (doxylamine succinate) on adverse events requiring hospitalisation after treatment in women who experience pregnancy-related nausea and vomiting: RD 0.00 (95% CI −0.12 to 0.12).

Number of days in hospital for treatment of nausea and vomiting

No evidence was identified to inform this outcome.

Women’s experience and satisfaction of care during or at end of pregnancy

No evidence was identified to inform this outcome.

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Moderate to severe nausea and vomiting (including hyperemesis gravidarum)

Comparison 1. Acupressure vs placebo

Critical outcomes

Symptomatic relief during pregnancy

Overall relief

Moderate quality evidence from 1 RCT (N=120) showed that there is a clinically important difference favouring P6 acupressure combined with standard care over placebo on overall relief after treatment as assessed by the PUQE (pregnancy unique quantification of emesis and nausea) index in women who experience pregnancy-related nausea and vomiting: MD −2.70 (95% CI −3.28 to −2.12).

Nausea severity

Moderate quality evidence from 1 RCT (N=120) showed that there is a clinically important difference favouring P6 acupressure combined with standard care over placebo on nausea severity after treatment as assessed by the PUQE (pregnancy unique quantification of emesis and nausea) index in women who experience pregnancy-related nausea and vomiting: MD −1.01 (95% CI −1.32 to −0.70).

Vomiting severity

Moderate quality evidence from 1 RCT (N=120) showed that there is a clinically important difference favouring P6 acupressure combined with standard care over placebo on vomiting severity after treatment as assessed by the PUQE (pregnancy unique quantification of emesis and nausea) index in women who experience pregnancy-related nausea and vomiting: MD −1.10 (95% CI −1.33 to −0.87).

Retching severity

Low quality evidence from 1 RCT (N=120) showed that there is no clinically important difference between P6 acupressure combined with standard care and placebo on retching severity after treatment as assessed by the PUQE (pregnancy unique quantification of emesis and nausea) index in women who experience pregnancy-related nausea and vomiting: MD −0.58 (95% CI −0.81 to −0.35).

Number of women with disappearance of symptoms

Moderate quality evidence from 1 RCT (N=18) showed that there is a clinically important difference favouring P6 acupressure over placebo on the number of women with disappearance of symptoms 2 weeks after treatment in women who experience pregnancy-related nausea and vomiting: Peto OR 12.54 (95% CI 1.90 to 82.93).

Fetal death

Miscarriage before 20 weeks

Very low quality evidence from 1 RCT (N=57) showed that there was no statistically significant difference between P6 acupressure and placebo on fetal death after treatment in women who experience pregnancy-related nausea and vomiting: RR 0.48 (95% CI 0.05 to 5.03) p=0.54.

Termination of pregnancy

Very low quality evidence from 1 RCT (N=57) showed that there was no statistically significant difference between P6 acupressure and placebo on fetal death after treatment in women who experience pregnancy-related nausea and vomiting: RR 0.72 (95% CI 0.18 to 2.95) p=0.65.

Intra-uterine fetal death after 20 weeks

Very low quality evidence from 1 RCT (N=36) showed that there was no statistically significant difference between P6 acupressure and placebo on fetal death after treatment in women who experience pregnancy-related nausea and vomiting: RR 0.57 (95% CI 0.04 to 8.30) p=0.68.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

No evidence was identified to inform this outcome.

Number of days in hospital for treatment of nausea and vomiting

Moderate quality evidence from 1 RCT (N=120) showed that there is a clinically important difference between P6 acupressure combined with standard care and placebo on number of days in hospital after treatment in women who experience pregnancy-related nausea and vomiting: MD −1.05 (95% CI −1.32 to −0.78).
Very low quality evidence from 1 RCT (N=80) showed that there was no statistically significant difference favouring P6 acupressure over placebo on number of days in hospital after treatment in women who experience pregnancy-related nausea and vomiting: difference between medians 0, p= not stated.

Women’s experience and satisfaction of care during or at end of pregnancy

Low quality evidence from 1 RCT (N=120) showed that there was no clinically important difference between P6 acupressure combined with standard care and placebo on women’s experience and satisfaction after treatment in women who experience pregnancy-related nausea and vomiting: RR 0.84 (95% CI 0.70 to 1.02).

Preterm birth

Moderate quality evidence from 1 RCT (N=36) showed that there was no clinically important difference between P6 acupressure and placebo on preterm birth after treatment in women who experience pregnancy-related nausea and vomiting: Peto OR 0.06 (95% CI 0.00 to 1.08) p=0.06.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 2. Acupuncture vs placebo

Critical outcomes

Symptomatic relief during pregnancy

Number of women with relief from symptoms

Low quality evidence from 1 RCT (N=18) showed that there is a clinically important difference favouring P6 acupuncture over placebo on the number of women with disappearance of symptoms 2 weeks after treatment in women who experience pregnancy-related nausea and vomiting: RR 7.2 (95% CI 1.14 to 45.56).

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

No evidence was identified to inform this outcome.

Number of days in hospital for treatment of nausea and vomiting

No evidence was identified to inform this outcome.

Women’s experience and satisfaction of care during or at end of pregnancy

No evidence was identified to inform this outcome.

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 3. Pyridoxine hydrochloride vs placebo

Critical outcomes

Symptomatic relief during pregnancy

Nausea intensity

Very low quality evidence from 1 RCT (N=52) showed that there is no statistical significance between pyridoxine hydrochloride and placebo on nausea intensity 2 weeks after treatment as assessed by a visual analogue scale in women who experience pregnancy-related nausea and vomiting: difference between medians 0.5, p=0.69.

Daily mean vomiting episodes

Very low quality evidence from 1 RCT (N=52) showed that there is no clinically important difference between pyridoxine hydrochloride and placebo on daily mean vomiting episodes 2 weeks after treatment as assessed by patient report in women who experience pregnancy-related nausea and vomiting: MD 0 (95% CI −0.79 to 0.79).

Number of women vomiting in the last 24 hours

Very low quality evidence from 1 RCT (N=92) showed that there is no clinically important difference favouring pyridoxine hydrochloride over placebo on the number of women vomiting in the last 24 hours before discharge 2 weeks after treatment in women who experience pregnancy-related nausea and vomiting: RR 1.4 (95% CI 0.79 to 2.49).

Fetal death

Very low quality evidence from 1 RCT (N=68) showed that there is no statistically significant difference between pyridoxine hydrochloride and placebo on fetal death 2 weeks after treatment in women who experience pregnancy-related nausea and vomiting: Peto OR 0.15 (95% CI 0.00 to 7.67) p=0.35.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

Very low quality evidence from 1 RCT (N=52) showed that there is no clinically important difference between pyridoxine hydrochloride and placebo on adverse events requiring hospitalisation 2 weeks after treatment in women who experience pregnancy-related nausea and vomiting: RD 0.00 (95% CI −0.07 to 0.07).

Number of days in hospital for treatment of nausea and vomiting

No evidence was identified to inform this outcome.

Women’s experience and satisfaction of care during or at end of pregnancy

Overall wellbeing score

Very low quality evidence from 1 RCT (N=52) showed that there is no statistically significant difference between pyridoxine hydrochloride and placebo on overall wellbeing score 2 weeks after treatment as assessed by a visual analogue scale in women who experience pregnancy-related nausea and vomiting: difference between medians 1, p=0.73.

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 4. Dopamine D2 receptor antagonist vs Histamine H1-receptor antagonist

Critical outcomes

Symptomatic relief during pregnancy

Nausea severity

Low quality evidence from 1 RCT (N=149) showed that there is no statistically significant difference between dopamine D2 receptor antagonist (metoclopramide hydrochloride) and histamine H1-receptor antagonist (promethazine hydrochloride) on nausea severity after treatment as assessed by a visual numerical rating scale in women who experience pregnancy-related nausea and vomiting: difference between medians 0, p=0.99.

Vomiting frequency

Low quality evidence from 1 RCT (N=149) showed that there is no statistically significant difference between dopamine D2 receptor antagonist (metoclopramide hydrochloride) and histamine H1-receptor antagonist (promethazine hydrochloride) on vomiting frequency after treatment as assessed by patient report in women who experience pregnancy-related nausea and vomiting: difference between medians 1, p=0.81.

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

No evidence was identified to inform this outcome.

Number of days in hospital for treatment of nausea and vomiting

Low quality evidence from 1 RCT (N=149) showed that there is no statistically significant difference between dopamine D2 receptor antagonist (metoclopramide hydrochloride) and histamine H1-receptor antagonist (promethazine hydrochloride) on number of days in hospital after treatment in women who experience pregnancy-related nausea and vomiting: difference between medians 0.1, p=0.71.

Women’s experience and satisfaction of care during or at end of pregnancy

Patient wellbeing

Moderate quality evidence from 1 RCT (N=149) showed that there is no clinically important difference between dopamine D2 receptor antagonist (metoclopramide hydrochloride) and histamine H1-receptor antagonist (promethazine hydrochloride) on patient wellbeing after treatment as assessed by a visual numerical rating scale in women who experience pregnancy-related nausea and vomiting: MD 0.5 (95% CI −0.22 to 1.22).

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 5. Serotonin 5-HT antagonist vs Dopamine D2 receptor antagonist

Critical outcomes

Symptomatic relief during pregnancy

Nausea severity

High quality evidence from 1 RCT (N=83) showed that there is no clinically important difference between serotonin 5-HT antagonist (ondansetron) and dopamine D2 receptor antagonist (metoclopramide hydrochloride) on nausea severity 7 days after treatment as assessed by a visual analogue scale in women who experience pregnancy-related nausea and vomiting: MD −0.70 (95% CI −1.97 to 0.57).
Low quality evidence from 1 RCT (N=120) showed that there is no statistically significant difference between serotonin 5-HT antagonist (ondansetron) and dopamine D2 receptor antagonist (metoclopramide hydrochloride) on nausea severity after treatment as assessed by a visual numerical rating scale in women who experience pregnancy-related nausea and vomiting: difference between medians 1, p=0.68.

Vomiting severity

High quality evidence from 1 RCT (N=83) showed that there is no clinically important difference between serotonin 5-HT antagonist (ondansetron) and dopamine D2 receptor antagonist (metoclopramide hydrochloride) on vomiting severity 7 days after treatment as assessed by a visual analogue scale in women who experience pregnancy-related nausea and vomiting: MD 0 (95% CI −1.24 to 1.24).

Number of women vomit free during 24 hours

Moderate quality evidence from 1 RCT (N=120) showed that there is no clinically important difference between serotonin 5-HT antagonist (ondansetron) and dopamine D2 receptor antagonist (metoclopramide hydrochloride) on the number of women vomit free during 24 hours after treatment in women who experience pregnancy-related nausea and vomiting: RR 1.15 (95% CI 0.86 to 1.53).

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

No evidence was identified to inform this outcome.

Number of days in hospital for treatment of nausea and vomiting

Low quality evidence from 1 RCT (N=120) showed that there is no statistically significant difference between serotonin 5-HT antagonist (ondansetron) and dopamine D2 receptor antagonist (metoclopramide hydrochloride) after treatment in women who experience pregnancy-related nausea and vomiting: difference between medians 0.1, p=0.10.

Women’s experience and satisfaction of care during or at end of pregnancy

Patient wellbeing

Moderate quality evidence from 1 RCT (N=160) showed that there is no clinically important difference between serotonin 5-HT antagonist (ondansetron) and dopamine D2 receptor antagonist (metoclopramide hydrochloride) on patient wellbeing after treatment as assessed by a visual numerical rating scale in women who experience pregnancy-related nausea and vomiting: MD 0.4 (95% CI −0.03 to 0.83).

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 5. Serotonin 5-HT antagonist vs Histamine H1-receptor antagonist

Critical outcomes

Symptomatic relief during pregnancy

No evidence was identified to inform this outcome.

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

Sedation

Low quality evidence from 1 RCT (N=30) showed that there is a clinically important difference favouring serotonin 5-HT antagonist (ondansetron) over histamine H1-receptor antagonist (promethazine hydrochloride) on sedation after treatment in women who experience pregnancy-related nausea and vomiting: Peto OR 0.07 (95% CI 0.01 to 0.35).

Number of days in hospital for treatment of nausea and vomiting

Very low quality evidence from 1 RCT (N=30) showed that there is no clinically important difference between serotonin 5-HT antagonist (ondansetron) and histamine H1-receptor antagonist (promethazine hydrochloride) on number of days in hospital in women who experience pregnancy-related nausea and vomiting: MD 0 (95% CI −1.39 to 1.39).

Women’s experience and satisfaction of care during or at end of pregnancy

No evidence was identified to inform this outcome.

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 6. Corticosteroid vs Placebo

Critical outcomes

Symptomatic relief during pregnancy

Improvement in nausea intensity

Low quality evidence from 1 RCT (N=24) showed that there is no statistically significant difference between corticosteroids (prednisolone) and placebo on improvement in nausea intensity 7 days after treatment as assessed by a numerical scale in women who experience pregnancy-related nausea and vomiting: difference between medians 2.5, p=0.10.

Reduction in vomiting intensity

Low quality evidence from 1 RCT (N=24) showed that there is no statistically significant difference between corticosteroids (prednisolone) and placebo on reduction in vomiting intensity 7 days after treatment as assessed by a numerical scale in women who experience pregnancy-related nausea and vomiting: difference between medians 0.5, p=0.26.

Vomiting frequency

Low quality evidence from 1 RCT (N=24) showed that there is no clinically important difference between corticosteroids (prednisolone) and placebo on vomiting frequency 7 days after treatment as assessed by patient report in women who experience pregnancy-related nausea and vomiting: RR 0.4 (95% CI 0.1 to 1.67).

Fetal death

Very low quality evidence from 2 RCTs (N=134) showed that there is no statistically significant difference between corticosteroids (prednisolone and methylprednisolone + oral prednisolone) and placebo on fetal death up to 7 days after treatment in women with pregnancy-related nausea and vomiting: RR 0.65 (95% CI 0.19 to 2.19) p=0.49.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

No evidence was identified to inform this outcome.

Number of days in hospital for treatment of nausea and vomiting

Low quality evidence from 1 RCT (N=24) showed that there is no statistically significant difference between corticosteroids (prednisolone) and placebo on number of days in hospital 7 days after treatment in women who experience pregnancy-related nausea and vomiting: difference between medians 0, p=0.84
Low quality evidence from 1 RCT (N=110) showed that there is no clinically important difference between corticosteroids (methylprednisolone + oral prednisolone) and placebo on number of days in hospital after treatment in women who experience pregnancy-related nausea and vomiting: MD 3.3 (95% CI −1.55 to 8.15).

Women’s experience and satisfaction of care during or at end of pregnancy

No evidence was identified to inform this outcome.

Preterm birth

Moderate quality evidence from 2 RCTs (N=134) showed that there is no clinically important difference between corticosteroids (prednisolone and methylprednisolone + oral prednisolone) and placebo on preterm birth up to 7 days after treatment in women with pregnancy-related nausea and vomiting: RR 1.1 (95% CI 0.45 to 2.67).

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 7. Corticosteroid vs Dopamine D2 receptor antagonist

Critical outcomes

Symptomatic relief during pregnancy

Reduction in mean number of vomiting episodes

Moderate quality evidence from 1 RCT (N=40) showed that there is a clinically significant difference favouring corticosteroid (hydrocortisone) over dopamine D2 receptor antagonist (metoclopramide hydrochloride) on reduction in mean number of vomiting episodes 2 weeks after treatment as assessed by patient report in women who experience pregnancy-related nausea and vomiting: SMD −1.37 (95% CI −2.06 to −0.68).

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

No evidence was identified to inform this outcome.

Number of days in hospital for treatment of nausea and vomiting

No evidence was identified to inform this outcome.

Women’s experience and satisfaction of care during or at end of pregnancy

No evidence was identified to inform this outcome.

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 8. Corticosteroid vs Histamine H1-receptor antagonist

Critical outcomes

Symptomatic relief during pregnancy

Number of women with severe nausea

Low quality evidence from 1 RCT (N=78) showed that there is no clinically important difference between corticosteroid (prednisolone) and histamine H1-receptor antagonist (promethazine hydrochloride) on number of women with severe nausea 7 days after treatment in women who experience pregnancy-related nausea and vomiting: RR 0.81 (95% CI 0.58 to 1.15).

Vomiting frequency

Very low quality evidence from 1 RCT (N=78) showed that there is no statistically significant difference between corticosteroid (prednisolone) and histamine H1-receptor antagonist (promethazine hydrochloride) on vomiting frequency 7 days after treatment as assessed by patient report in women who experience pregnancy-related nausea and vomiting: difference between medians 0, p=1.00.

Number of patients with complete or partial relief

Low quality evidence from 1 RCT (N=80) showed that there is no clinically important difference between corticosteroid (prednisolone) and histamine H1-receptor antagonist (promethazine hydrochloride) on number of patients with complete or partial relief 7 days after treatment in women who experience pregnancy-related nausea and vomiting: RR 1.67 (95% CI 0.95 to 2.92).

Number of women with improvement of symptoms

Low quality evidence from 1 RCT (N=40) showed that there is no clinically important difference between corticosteroid (methylprednisolone) and histamine H1-receptor antagonist (promethazine hydrochloride) on number of women with improvement of symptoms 2 weeks after treatment in women who experience pregnancy-related nausea and vomiting: RR 0.94 (95% CI 0.75 to 1.19).

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

Very low quality evidence from 1 RCT (N=40) showed that there is no clinically important difference between corticosteroid (methylprednisolone) and histamine H1-receptor antagonist (promethazine hydrochloride) on adverse events requiring hospitalisation 2 weeks after treatment in women who experience pregnancy-related nausea and vomiting: RD 0.00 (95% CI −0.09 to 0.09).

Abdominal pain

Low quality evidence from 1 RCT (N=80) showed that there is a clinically important difference between corticosteroid (prednisolone) and histamine H1-receptor antagonist (promethazine hydrochloride) on abdominal pain 7 days after treatment in women who experience pregnancy-related nausea and vomiting: Peto OR 0.13 (95% CI 0.02 to 0.92).

Drowsiness

Moderate quality evidence from 1 RCT (N=80) showed that there is a clinically important difference between corticosteroid (prednisolone) and histamine H1-receptor antagonist (promethazine hydrochloride) on drowsiness 7 days after treatment in women who experience pregnancy-related nausea and vomiting: Peto OR 0.12 (95% CI 0.02 to 0.62).

Number of days in hospital for treatment of nausea and vomiting

Moderate quality evidence from 1 RCT (N=34) showed that there is a clinically important difference between corticosteroid (methylprednisolone) and histamine H1-receptor antagonist (promethazine hydrochloride) on number of days in hospital 2 weeks after treatment in women who experience pregnancy-related nausea and vomiting: Peto OR 0.10 (95% CI 0.02 to 0.67).

Women’s experience and satisfaction of care during or at end of pregnancy

No evidence was identified to inform this outcome.

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 9. Intravenous fluids vs Intravenous fluids

Critical outcomes

Symptomatic relief during pregnancy

Nausea intensity

Moderate quality evidence from 1 RCT (N=203) showed that there is no statistically significant difference between dextrose saline and normal saline on nausea intensity after treatment as assessed by a visual numerical rating scale in women who experience pregnancy-related nausea and vomiting: difference between medians 0, p=0.39.

Vomiting frequency

Moderate quality evidence from 1 RCT (N=203) showed that there is no statistically significant difference between dextrose saline and normal saline on vomiting frequency after treatment as assessed by patient report in women who experience pregnancy-related nausea and vomiting: difference between medians 0, p=0.66.

Fetal death

No evidence was identified to inform this outcome.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

No evidence was identified to inform this outcome.

Number of days in hospital for treatment of nausea and vomiting

No evidence was identified to inform this outcome.

Women’s experience and satisfaction of care during or at end of pregnancy

High quality evidence from 1 RCT (N=203) showed that there is no clinically important difference between dextrose saline and normal saline on women’s experience and satisfaction after treatment as assessed by a visual numerical rating scale in women who experience pregnancy-related nausea and vomiting: MD 0.1 (95% CI −0.33 to 0.53).

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

No evidence was identified to inform this outcome.

Comparison 10. Intravenous fluids in one setting vs Intravenous fluids in another setting

Critical outcomes

Symptomatic relief during pregnancy

Overall relief

Very low quality of evidence from 1 RCT (N=31) showed that there is no clinically important difference between IV fluids in the maternity assessment unit and IV fluids in the antenatal ward on overall relief after treatment as assessed by the PUQE (pregnancy unique quantification of emesis and nausea) index in women who experience pregnancy-related nausea and vomiting: MD 0.7 (95% CI −1.77 to 3.17).

Fetal death

Spontaneous abortions

Very low quality evidence from 1 RCT (N=53) showed that there is no statistically significant difference between IV fluids in the maternity assessment unit and IV fluids in the antenatal ward on spontaneous abortions after treatment in women who experience pregnancy-related nausea and vomiting: RR 0.96 (95% CI 0.15 to 6.34) p=0.97).

Termination of pregnancy

Very low quality evidence from 1 RCT (N=53) showed that there is no statistically significant difference between IV fluids in the maternity assessment unit and IV fluids in the antenatal ward on termination of pregnancy after treatment in women who experience pregnancy-related nausea and vomiting: Peto OR 7.12 (95% CI 0.14 to 359.1) p=0.33.

Infant death up to 4 weeks chronological age

No evidence was identified to inform this outcome.

Important outcomes

Adverse event that is not immediately due to nausea and vomiting and which requires hospitalisation during treatment

No evidence was identified to inform this outcome.

Number of days in hospital for treatment of nausea and vomiting

Low quality evidence from 1 RCT (N=98) showed that there is a statistically significant difference favouring IV fluids in day care over IV fluids in inpatient care on number of days in hospital after treatment in women who experience pregnancy-related nausea and vomiting: difference between medians 2, p=0.001.

Women’s experience and satisfaction of care during or at end of pregnancy

Low quality evidence from 1 RCT (N=98) showed that there is no statistically significant difference between IV fluids in inpatient care and IV fluids in day care on women’s experience and satisfaction after treatment as assessed by the client satisfaction questionnaire in women who experience pregnancy-related nausea and vomiting: difference between medians 67, p=0.70.
Low quality evidence from 1 RCT (N=29) showed that there is no clinically important difference between IV fluids in the maternity assessment unit and IV fluids in the antenatal ward on women’s experience and satisfaction after treatment as assessed by the short satisfaction survey in women who experience pregnancy-related nausea and vomiting: MD −0.60 (95% CI −3.51 to 2.31).

Preterm birth

No evidence was identified to inform this outcome.

Small for gestational age

Very low quality of evidence from 1 RCT (N=53) showed that there is no clinically important difference favouring IV fluids in the maternity assessment unit over IV fluids in the antenatal ward on small for gestational age after treatment for women who experience pregnancy-related nausea and vomiting: RR 0.96 (95% CI 0.21 to 4.35).

The committee’s discussion of the evidence

Interpreting the evidence

The outcomes that matter most

The committee agreed that symptomatic relief during pregnancy was a critical outcome for the woman, and fetal death and infant death up to 4 weeks chronological age were critical outcomes for the baby. Important outcomes were adverse events requiring hospitalisation; number of days in hospital; and women’s experience and satisfaction of care; preterm birth and small for gestational age.

The quality of the evidence

The quality of evidence for outcomes in this review ranged from high to very low quality and was generally moderate to low quality.

Outcomes were typically downgraded due to imprecision around the effect estimate in a few outcomes; the presence of serious heterogeneity in some outcomes, which was unresolved by subgroup analysis; and risk of bias, most often arising due to selection and attrition bias.

The evidence for pyridoxine hydrochloride as a treatment for mild to moderate NVP was of a mixed quality and showed variation in clinical effectiveness. Larger studies showed no effect whilst smaller studies showed clinically important benefits over placebo. Although publication bias was not formally detected through the GRADE process, the committee suspected some bias was present.

One RCT conducted an 8-arm trial in the US in the 1970s, which was published in 2017 under the ‘restoring invisible and abandoned trials’ (RIAT) initiative. This study, known as the “‘8-way’ Bendectin Study”, examined the efficacy of doxylamine, pyridoxine hydrochloride, and dicyclomine in tablet form, separately and in combination, compared to each other and placebo. The study reported high risk of bias in the results given the high attrition rate in the 7 day trial, the absence of prespecified outcomes or analyses, and the exclusion of some data because of questionable data integrity. The committee agreed that this evidence should be included on the basis that it was downgraded to very low evidence. The committee agreed they would not consider this evidence when making recommendations due to data integrity concerns.

Evidence was found for all interventions noted in the protocol. Studies mostly reported on symptoms relating to nausea & vomiting, including relief and vomiting intensity. There was very little evidence for the critical outcomes on maternal or fetal deaths. There was no evidence identified for the outcome of infant death up to 4 weeks chronological age.

Benefits and harms

The committee discussed that mild to moderate nausea and vomiting are common in early pregnancy and can significantly affect the day-to-day life and quality of life for some pregnant women. The committee discussed that it is important to reassure women that in most cases it is likely to resolve before 16 to 20 weeks and so a recommendation was made to reflect this.

The committee discussed that many women may consider nausea and vomiting to be a normal part of pregnancy and endure even guite significant nausea and vomiting before seeking help. Some women may also try self-help interventions at home to alleviate their nausea and vomiting before consulting a healthcare professional. The committee discussed that in this case it is important for healthcare professionals to recognise that these pregnant women consider their symptoms severe enough to seek medical help. The committee agreed that it was important for healthcare providers to acknowledge this and give advice about interventions accordingly.

Non-pharmacological treatments for women with mild to moderate nausea and vomiting in pregnancy

Evidence from 5 RCTs showed that ginger had a clinically important benefit compared to placebo or acupressure in terms of a variety of nausea and vomiting symptom related outcomes (for example overall symptomatic relief and nausea relief). Ginger tablets were the most common form of ginger product used in the evidence, although the committee were aware from their own experience that ginger biscuits are often suggested to women. Although there were some outcomes for which no clinically important difference was observed (for example vomiting intensity) the committee agreed that those were generally less impactful outcomes as far as the woman’s own experience. There was no evidence of harms from the use of ginger. The committee also noted that ginger is generally readily accessible to women with NVP and does not need to be prescribed.

The committee recognised that some women prefer a non-pharmacological treatment. Based on the evidence, the committee recommended that ginger could be used as a non-pharmacological treatment for mild to moderate nausea and vomiting in pregnancy (NVP) because there was evidence that ginger is effective in providing symptomatic relief during pregnancy - overall and for nausea, vomiting and retching - and that there are no substantial harms associated with its use compared to either placebo or acupressure.

There was no evidence showing a clinically important benefit of acupuncture in this population and very little evidence of benefit from acupressure. Acupressure was shown to be less effective than ginger in this group in terms of symptomatic relief and for most outcomes it had no benefit compared to placebo (for example overall relief) and any benefits were generally in comparisons likely to be less impactful for women (for example vomiting intensity).

Pharmacological treatments for women with mild to moderate nausea and vomiting in pregnancy

There was high quality evidence supporting metoclopramide hydrochloride, a dopamine D2-receptor antagonist, as a treatment for mild to moderate NVP when compared to placebo. One RCT of 68 women with mild to moderate NVP showed that there is a clinically important benefit favouring 10mg of metoclopramide three times a day for 5 days on providing overall symptomatic relief, and alleviating nausea intensity and vomiting intensity, compared to placebo. This trial did not report any adverse effects or other harms.

There was moderate quality evidence supporting ondansetron, a serotonin 5-HT antagonist as treatment for mild to moderate NVP. The evidence showed that women who received ondansetron combined with a placebo tablet are more likely to show an improvement on nausea symptoms and on vomiting symptoms, respectively, compared to those who received a combination of pyridoxine hydrochloride and doxylamine succinate. This study also found a statistically significant difference favouring ondansetron on reducing nausea intensity and reducing vomiting intensity, compared to pyridoxine hydrochloride and doxylamine succinate. Finally, the trial reported that there were no adverse events in any of the participants.

The committee agreed that the evidence for metoclopramide hydrochloride and ondansetron was consistent with their clinical experience. The committee discussed that it was important to highlight and discuss the advantages and disadvantages of pharmacological treatments with the woman.

The evidence for histamine H1 receptor antagonists as a treatment for mild to moderate NVP was of very low quality and the one identified study was at high risk of bias. Evidence for the use of doxylamine succinate, a histamine H1 receptor antagonist, for the treatment of mild to moderate NVP was gleaned from one RCT conducted in the US in the 1970s but not published until 2017 under the ‘restoring invisible and abandoned trials’ (RIAT) initiative. This 8-arm study, known as the “‘8-way’ Bendectin Study”, examined the efficacy of doxylamine, pyridoxine hydrochloride, and dicyclomine in tablet form, separately and in combination, compared to each other and placebo. Women randomised to each arm were instructed to take 2 tablets before going to sleep for 7 nights and could take an additional 2 tablets (one in the morning and one in the mid-afternoon) as needed. The authors of the article (who were not involved in the original trial itself) raise several serious issues with the quality of the data and provenance of the trial.

The evidence for pyridoxine hydrochloride as a treatment for mild to moderate NVP showed mixed results, where larger studies showed no effect whilst smaller studies did show clinically important benefits of the drug over placebo in terms of symptom related outcomes. Although publication bias was not formally detected through the GRADE process, this is challenging when few published studies are available and the committee suspected some bias was present. The committee discussed that pyridoxine hydrochloride was commonly used as first line treatment in current practice.

The committee discussed that pyridoxine hydrochloride was commonly used as a combination treatment with a histamine H1 receptor antagonist like doxylamine succinate. Some evidence of low quality was identified that suggested a clinically important benefit of pyridoxine hydrochloride combined with doxylamine succinate vs placebo on the outcome of relief from nausea and vomiting. However, the committee noted that this evidence was published in the 1950s and as such might not be relevant to the population today and a more recent trial found no important benefit of the combination for overall relief. One RCT from the US, conducted in 1975 and reported in 2017 under the RIAT initiative, compared combined pyridoxine hydrochloride and doxylamine succinate against a placebo, pyridoxine hydrochloride alone, and doxylamine succinate alone. The evidence was of a very low quality and showed no clinically important benefit on any symptomatic outcomes. The committee also noted that this combination treatment is more expensive compared to other treatments. Overall, despite the fact that doxylamine succinate/pyridoxine hydrochloride is the only drug licensed for use in pregnancy for nausea & vomiting, the committee agreed the evidence did not justify specifically recommending its use.

There was no evidence assessing the efficacy of cyclizine as a monotherapy for treatment of mild to moderate NVP. The committee noted that this is commonly used in the UK as a first line pharmacological treatment, however the only evidence identified on cyclizine was in combination with pyridoxine hydrochloride, a combination that is not available in the UK.

The committee agreed that there are various pharmacological treatments used in current practice, all with different levels of evidence and varying advantages and disadvantages in terms of effectiveness, safety and practical aspects. The drugs may have side effects and safety profiles (not covered by this review). The committee used information available from the British National Formulary (BNF), the UK teratology information service monographs and patient information leaflets, and the manufacturers’ summaries of product characteristics to inform about the potential side effects and potential effects on the baby. The committee recognised that women are concerned about the effects of medicines on the baby and how, in the unfortunate event of an adverse pregnancy outcome, women might associate it with medicine use, even when there is no evidence of harm. The committee discussed how it is important to discuss with women that there is always a background risk of congenital malformations, miscarriage and stillbirths irrespective of whether any medicines are taken during pregnancy. In order to support shared decision making about what pharmacological treatment to choose, a table listing the different pharmacological treatment option and their advantages and disadvantages were listed (see Table 1 in the guideline). The committee agreed that the shared decision making should take into consideration the woman’s preferences, her experience with medicines in previous pregnancies, any co-morbidities, and any current medications.

Moderate to severe nausea and vomiting

The committee discussed that nausea and vomiting in pregnancy is a continuum with most cases presenting as mild to moderate and some as more severe. At the extreme severe end of the spectrum is hyperemesis gravidarum which is a rare and significant condition with potentially serious consequences, including decision to terminate the pregnancy. The committee agreed that the management of hyperemesis gravidarum does not only require consideration about the treatment of the nausea and vomiting itself but also the consequences of it, for example nutritional interventions and psychological management. The focus of this review was on interventions to treat nausea and vomiting in pregnancy and the committee considered the comprehensive management of hyperemesis gravidarum to be outside the scope of this guideline which covers routine antenatal care.

Generally, the committee concluded that for pregnant women with more severe nausea and vomiting, the same antiemetics should be offered as to those women with nausea and vomiting in the mild to moderate end of the continuum. The committee discussed that there is no clearly defined point at which severe nausea and vomiting becomes hyperemesis gravidarum and so the way the population is defined in studies can be unclear. For example, some studies investigating treatments for hyperemesis gravidarum clearly focus on hyperemesis gravidarum while others include a population with moderate to severe nausea and vomiting of pregnancy.

Outpatient care

The committee recommended that intravenous (IV) fluids should be considered as part of treatment for women with moderate to severe nausea and vomiting, ideally in outpatient care. One RCT from Ireland (2014) reported that pregnant women with severe nausea and vomiting who had received IV fluids in day care, spent fewer days in hospital for the treatment of nausea and vomiting than those women who had received IV fluids in inpatient care and that there were no clinically important differences for overall relief of symptoms or experience and satisfaction of care.

The committee decided to recommend offering IV fluids as outpatient care because there was no evidence showing inpatient care was superior for any outcomes and the economic data suggested no difference between the two outcomes in terms of QALYs.

The committee agreed that for this comparison, a woman’s preferences in terms of setting of treatment was particularly important and that the decision should be made taking into account the woman’s preferences. The committee discussed that if vomiting is severe and cannot be managed without inpatient care, this should be considered.

Acupressure

The committee recommended that acupressure should be considered as an adjunct treatment of moderate to severe nausea and vomiting in pregnant women because there was evidence that acupressure in addition to standard care is effective in aiding symptomatic relief during pregnancy, compared to placebo.

One RCT from Malaysia (2017) reported that pregnant women with severe nausea and vomiting, who had received P6 acupressure in addition to standard care (IV fluids, IV metoclopramide and thiamine supplements) showed a clinically important difference on overall relief, nausea severity, and vomiting severity than those who had taken the placebo.

Two RCTs, one from Malaysia (2017) and one from the UK (2006) found that there was a clinically important and statistically significant difference, respectively, on number of days in hospital for women treated with P6 acupressure than those who had taken a placebo. The results show that women spend fewer days in hospital when given acupressure in addition to standard treatment than a placebo and standard treatment.

There was no evidence of a difference between the interventions on the outcomes of retching severity (PUQE score); number of women with disappearance of symptoms; women’s experience and satisfaction of care; fetal death; and preterm birth.

Other interventions

Acupuncture

One RCT from Croatia (2004) reported a clinically important difference favouring P6 acupuncture over placebo for pregnant women on the number of women with relief from symptoms. However, since this was the only evidence found for this intervention and it was of a low quality, the committee did not recommend acupuncture for severe nausea and vomiting in pregnancy.

Pyridoxine hydrochloride

One RCT from Malaysia (2009) was found for this intervention, but no evidence of a difference between the interventions was found on overall wellbeing score; nausea intensity; daily mean vomiting episodes; number of women vomiting in the last 24 hours; adverse events; and fetal death. Since the evidence showed no benefits or no harms, the committee could not make a recommendation.

Dopamine D2 receptor antagonist

One RCT from Malaysia (2010) was found for this intervention, but no evidence of a difference between the interventions was found on nausea severity; vomiting frequency; number of days in hospital; and women’s experience and satisfaction of care. Since the evidence showed no benefits or no harms, the committee could not make a recommendation.

Histamine H1 receptor antagonist

One RCT from US (1996) reported a clinically important difference on the adverse event sedation for women in the serotonin 5-HT antagonist arm over the women in the promethazine hydrochloride arm. The committee discussed that this was not an unusual adverse event of this pharmacological agent. Since there was no evidence of a difference between the interventions on the outcome of number of days in hospital, the committee concluded that there was no difference between promethazine hydrochloride and ondansetron and did not make a recommendation. No recommendation was made on the use of promethazine hydrochloride as a treatment for severe nausea and vomiting in pregnant women.

Serotonin 5-HT receptor antagonist

Although two RCTs were found for this intervention among women with hyperemesis gravidarum from Iran (2013) and Malaysia (2014), there was no evidence of a difference between the interventions on the outcomes of number of women vomit free during 24 hours; vomiting severity; nausea severity; number of days in hospital; and women’s experience and satisfaction of care.

Corticosteroids

Two RCTs comparing corticosteroids to a placebo were found for this intervention from the UK (2001) and US (2003). However, there was no evidence of a difference between the interventions on the outcomes of improvement in nausea intensity; vomiting frequency; reduction in vomiting intensity; number of days in hospital; fetal death; and preterm birth.

One RCT from Egypt (2006) comparing corticosteroids to a dopamine D2 receptor antagonist (metoclopramide hydrochloride) reported a clinically important difference favouring hydrocortisone over metoclopramide hydrochloride on the reduction in mean number of vomiting episodes. Though the evidence shows that hydrocortisone reduced the frequency of vomiting, these results come from a small study that is of low quality. Therefore, the committee could not make a recommendation based on this evidence.

One RCT from Iran (2004) comparing prednisolone to a histamine H1 receptor antagonist (promethazine hydrochloride) found that there was no clinically important difference between the number of patients with complete and partial relief although the result bordered on statistical significance. There was an important difference favouring corticosteroids in terms of abdominal pain, drowsiness and number of days in hospital however this evidence was of low to moderate quality principally due to the very low event rates. Within this comparison, there was no evidence of a difference between the interventions on the outcomes of number of women with severe nausea; vomiting frequency; number of women with improvement of symptoms.

Overall, there was not enough evidence of benefit of steroids when compared to a placebo, a histamine H1 receptor antagonist, or a dopamine D2 receptor antagonist for the committee to make a recommendation. The committee suggested a research recommendation was appropriate in this case. Although not found in the evidence, the committee discussed that steroids have well known harms and side effects that should be highlighted when used in the treatment of severe nausea and vomiting in pregnancy. The committee also pointed out that corticosteroids are commonly prescribed to women in cases of very severe nausea and vomiting in pregnancy.

Type of intravenous fluid

No recommendation was made on the type of intravenous fluid used for pregnant women with severe nausea and vomiting needing IV fluids.

Although one RCT was found for this intervention from Malaysia (2013), there was no evidence of a difference between the interventions on the outcomes of vomiting frequency; nausea intensity; and women’s experience and satisfaction of care. Since the evidence showed no benefits or no harms, the committee could not make a recommendation.

Cost effectiveness and resource use

The recommendation made by the committee to recommend ginger as a non-pharmacological treatment reflects current practice. The committee refrained from specifying a dose or form of ginger, but indicated from their professional experience that it would usually be suggested as a dietary supplement. Therefore, this would not lead to any additional costs to the NHS and, due to evidence of a lack of adverse effects, would be unlikely to have associated downstream treatment costs.

The committee considered evidence presented in the accompanying clinical review and recommended metoclopramide hydrochloride as a potential option following discussion as a pharmacological treatment for women. Current practice, according to the Management of Nausea and Vomiting of Pregnancy and Hyperemesis Gravidarum Green-top guideline (Royal College of Obstetricians and Gynaecologists, 2016) is that cyclizine is usually administered as a treatment in tablet form. This was also current practice from the committee’s own experience. There may be some additional costs owing to the increase in staff time where metoclopramide is administered as an injection. However, these additional costs are minimal and, owing to the increase in effectiveness, as presented in the clinical review, may be a cost effective use of resources. The committee recommended Ondansetron as a treatment, noting the one included study demonstrating its effectiveness. The committee were also mindful that administering Ondansetron can be costlier than other pharmacological interventions, though this would be dependent on the mode of birth. According to the BNF (2019), Ondansetron is only costlier when it is administered in the form of a solution for injection. Owing to the short duration of nausea and vomiting and that the majority of women would choose alternative recommended pharmacological treatments following discussion, it is unlikely that this recommendation would lead to a great increase in costs.

The recommendation to consider acupressure as a complementary therapy represents current practice and is usually administered as a self-administered therapy.

The committee also considered evidence presented in the clinical review of an Irish study that compared day care over inpatient management of nausea and vomiting during pregnancy (Murphy 2015). It was acknowledged that day care management was a cost effective option as it resulted in lower costs and a slight increase in QALYs. The committee acknowledged that the driver of cost effectiveness was the lower costs associated with day care management. Day care was associated a higher QALY gain although with uncertainty between the two interventions. At a cost per additional QALY threshold of €45,000 day care was 73% likely to be cost effective. Day care had a higher probability of cost effectiveness as the threshold decreased, thus furthering its relevance to the NICE decision making context.

Other factors the committee took into account

The long term effects of treatments for nausea and vomiting in pregnancy and hyperemesis gravidarum on the child was an outcome the committee considered to be important, however, this outcome was outside the scope of the guideline and for information on the safety of any pharmacological interventions BNF/MHRA should be consulted.

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Appendices

Appendix G. Economic evidence study selection

Economic evidence study selection for review question: What interventions are effective in treating nausea and vomiting during pregnancy?

A single economic search was undertaken for all topics included in the scope of this guideline. One economic study was identified which was applicable to this review question. See supplementary material 2 for details.

Appendix H. Economic evidence tables

Economic evidence tables for review question: What interventions are effective in treating nausea and vomiting during pregnancy? (PDF, 175K)

Appendix I. Health economic evidence profiles

Economic evidence profiles for review question: What interventions are effective in treating nausea and vomiting during pregnancy? (PDF, 159K)

Appendix J. Health economic analysis

Economic analysis for review question: What interventions are effective in treating nausea and vomiting during pregnancy?

No economic analysis was conducted for this review question.

Appendix K. Excluded studies

Excluded studies for review question: What interventions are effective in treating nausea and vomiting during pregnancy?

Table 36Clinical studies

Study	Reason for exclusion
Adibah, I; Khursiah, D; A Amir, I; NM, Zaki;, Fluid therapy in the treatment of hyperemesis gravidarum: normal saline or ringer’s lactate, does it really matter? , The Malaysian Journal of Medical Sciences, 15, 201, 2008	Study design does not meet protocol eligibility criteria - conference abstract.
Aga-Miri, Z, Hosseini, N, Ramazanadeh, F, Hagollah, F, Vijeh, M, Effect of acupressure on the frequency and severity of nausea in pregnancy, J Payesh, 7, 370–4, 2008	Non-English language article.
Aghadam, S. K. Z., Mahfoozi, B., Evaluation of the effects of acupressure by sea band on nausea and vomiting of pregnancy, Iranian journal of obstetrics, gynecology and infertility, 13, 3944, 2010	Non-English language publication.
Aleyasin, A., Saffarieh, E., Torkamandi, H., Hanafi, S., Sadeghi, F., Mahdavi, A., Bahmaei, F., Javadi, M., Comparison of Efficacy of Granisetron and Promethazine in Control of Hyperemesis Gravidarum, Journal of Obstetrics and Gynecology of India, 66, 409–414, 2016 [PMC free article: PMC5080214] [PubMed: 27821979]	Study comparisons do not meet protocol eligibility criteria - 5-HT3 receptor antagonis (Granisetron) versus H1 receptor-blocking agent (promethazine).
Alhajri, L., AlFalasi, M., Abdelrahim, M., AlKaabi, R., The efficacy of ginger for pregnancy-induced nausea and vomiting: A systematic review, Journal of Natural Remedies, 17, 48–56, 2017	Systematic review including eligible and non-eligible comparisons - references checked, no additional evidence identified.
Babaei, A. H., Foghaha, M. H., A randomized comparison of vitamin B6 and dimenhydrinate in the treatment of nausea and vomiting in early pregnancy, Iranian Journal of Nursing and Midwifery ResearchIran J Nurs Midwifery Res, 19, 199–202, 2014 [PMC free article: PMC4020031] [PubMed: 24834091]	Study comparison does not meet protocol eligibility criteria - antihistamine/anticholinergic (dimenhydrinate) versus pyridoxine (vitamin B6).
Basirat, Z., Barat, S., Moghadamnia, A. A., Comparing the effects of prednisolone and promethazine in the treatment of hyperemesis gravidarum: a double-blind, randomized clinical trial, Feyz journal of kashan university of medical sciences, 16, 414419, 2012	Full text article is not available in English.
Bergamo, T. R., Latorraca, C. O. C., Pachito, D. V., Martimbianco, A. L. C., Riera, R., Findings and methodological quality of systematic reviews focusing on acupuncture for pregnancy-related acute conditions, Acupuncture in MedicineAcupunct Med, 36, 146–152, 2018 [PubMed: 29559431]	Systematic review of systematic reviews - references checked, no additional evidence identified.
Biswas, S. C., Dey, R., Kamliya, G. S., Bal, R., Hazra, A., Tripathi, S. K., A single-masked, randomized, controlled trial of ginger extract in the treatment of nausea and vomiting of pregnancy, Journal international medical sciences academy, 24, 167–169, 2011	Study comparison does not meet the protocol eligibility criteria - dietary supplement vs pharmacological intervention.
Boelig, R. C., Barton, S. J., Saccone, G., Kelly, A. J., Edwards, S. J., Berghella, V., Interventions for treating hyperemesis gravidarum, Cochrane Database of Systematic Reviews, 2016, CD010607, 2016 [PMC free article: PMC10421833] [PubMed: 27168518]	Cochrane review - 3 additional relevant studies were identified and included in our review.
Boelig, R. C., Barton, S. J., Saccone, G., Kelly, A. J., Edwards, S. J., Berghella, V., Interventions for treating hyperemesis gravidarum: A cochrane systematic review and meta-analysis, Journal of Maternal-Fetal and Neonatal Medicine, 31, 2492–2505, 2017 [PubMed: 28614956]	Journal article to Boelig (2016) Cochrane review - no additional evidence.
Bryer, E., A literature review of the effectiveness of ginger in alleviating mild-to-moderate nausea and vomiting of pregnancy, Journal of midwifery & women’s health, 50, e1e3, 2005 [PubMed: 15637501]	A review paper of 4 RCTs. All references checked and added to this review if relevant.
Buchberger, B., Krabbe, L., Evaluation of outpatient acupuncture for relief of pregnancy-related conditions, International Journal of Gynecology and Obstetrics, 141, 151–158, 2018 [PubMed: 29355951]	Systematic review of systematic reviews and RCTs for different pregnancy conditions - references checked, no additional evidence identified.
Campbell, K., Rowe, H., Azzam, H., Lane, C. A., The Management of Nausea and Vomiting of Pregnancy, Journal of Obstetrics and Gynaecology Canada, 38, 1127–1137, 2016 [PubMed: 27986189]	Clinical practice guideline - references checked, no additional relevant evidence.
Can Gurkan, O., Arslan, H., Effect of acupressure on nausea and vomiting during pregnancy, Complementary therapies in clinical practice, 14, 46–52, 2008 [PubMed: 18243942]	Insufficient data available for analysis.
Carstairs, S. D., Ondansetron Use in Pregnancy and Birth Defects: A Systematic Review, Obstetrics & GynecologyObstet Gynecol, 127, 878–83, 2016 [PubMed: 27054939]	Systematic review of registry data, case-controls and cohort studies (RCT data available for ondansetron). References checked, no additional evidence identified.
Chin, J. W. S., Gregor, S., Persaud, N., Re-analysis of safety data supporting doxylamine use for nausea and vomiting of pregnancy, American journal of perinatology, 31, 701–710, 2014 [PubMed: 24323370]	Study design does not meet protocol eligibility criteria - re-analysis of meta-analysis including case-control and cohort studies of different antihistamines for congenital malformations.
Chittumma,P., Kaewkiattikun,K., Wiriyasiriwach,B., Comparison of the effectiveness of ginger and vitamin B6 for treatment of nausea and vomiting in early pregnancy: A randomized double-blind controlled trial, Journal of the Medical Association of Thailand, 90, 15–20, 2007 [PubMed: 17621727]	Duplicate
Chittumma,P., Kaewkiattikun,K., Wiriyasiriwach,B., Comparison of the effectiveness of ginger and vitamin B6 for treatment of nausea and vomiting in early pregnancy: A randomized double-blind controlled trial, Journal of the Medical Association of Thailand, 90, 15–20, 2007 [PubMed: 17621727]	Study comparison does not meet protocol eligibility criteria - dietary supplement versus pharmacological intervention.
Collins, K. L., Wilson, M., Vincent, E. C., Safranek, S., How safe and effective is ondansetron for nausea and vomiting in pregnancy?, Journal of Family Practice, 68, E12–E14, 2019 [PubMed: 31532822]	A review paper of 3 RCTs. All references checked and added to this review if relevant.
Crawford-Faucher, A., Which drug is more effective for treating hyperemesis gravidarum?, American family physician, 83, 842, 2011	Study design does not meet protocol eligibility criteria - commentary.
Cunningham, K., Odansetron compared with doxylamine and pyridoxine for treatment of nausea in pregnancy: A randomized controlled trial, Obstetrics and gynecology, 125, 490–491, 2015 [PubMed: 25611627]	Study design does not meet protocol eligibility criteria - letter to the Editor.
Dante, G., Bellei, G., Neri, I., Facchinetti, F., Herbal therapies in pregnancy: what works?, Current Opinion in Obstetrics & GynecologyCurr Opin Obstet Gynecol, 26, 83–91, 2014 [PubMed: 24535321]	Systematic review on various herbal treatments - references checked for relevant studies; no additional evidence identified.
Dante, G., Pedrielli, G., Annessi, E., Facchinetti, F., Herb remedies during pregnancy: A systematic review of controlled clinical trials, Journal of Maternal-Fetal and Neonatal Medicine, 26, 306–312, 2013 [PubMed: 22928540]	Systematic review of eligible and non-eligible study comparisons - references checked, no additional evidence identified. updated by Dante 2014.
de Aloysio, D., Penacchioni, P., Morning sickness control in early pregnancy by Neiguan point acupressure, Obstet GynecolObstetrics and gynecology, 80, 852–4, 1992 [PubMed: 1407927]	Study design does not meet protocol eligibility criteria - cross-over design.
Dennehy,C., Omega-3 fatty acids and ginger in maternal health: pharmacology, efficacy, and safety, Journal of Midwifery and Women’s Health, 56, 584–590, 2011 [PubMed: 22060218]	Study design does not meet protocol eligibility criteria - narrative review.
Ding, M., Leach, M., Bradley, H., The effectiveness and safety of ginger for pregnancy-induced nausea and vomiting: A systematic review, Women and Birth, 26, e26–e30, 2013 [PubMed: 22951628]	Systematic review of eligible and non-eligible comparisons - references checked, no additional evidence identified.
Dror, D. K., Allen, L. H., Interventions with vitamins B6, B12 and C in pregnancy, Paediatric and Perinatal Epidemiology, 26 Suppl 1, 55–74, 2012 [PubMed: 22742602]	Systematic review - not specifically on nausea and vomiting during pregnancy. References checked, no additional evidence identified.
Duggar, CR, Carlan, SJ, The efficacy of methylprednisolone in the treatment of hyperemesis gravidarum: a randomized double-blind controlled study [abstract]. , Obstetrics & Gynecology, 97, 45S, 2001	Study design does not meet protocol eligibility criteria - conference abstract.
Dundee, J. W., Sourial, F. B., Ghaly, R. G., Bell, P. F., P6 acupressure reduces morning sickness, J R Soc MedJournal of the Royal Society of Medicine, 81, 456–7, 1988 [PMC free article: PMC1291716] [PubMed: 3418660]	Study outcomes not presented in a useable format.
El-Deeb, A. M., Ahmady, M. S., Effect of acupuncture on nausea and/or vomiting during and after cesarean section in comparison with ondansetron, Journal of anesthesia, 25, 698–703, 2011 [PubMed: 21761206]	Study does not meet protocol eligibility criteria - interventions for post-operative nausea and vomiting.
Enblom, A., Johnsson, A., Type and frequency of side effects during PC6 acupuncture: observations from therapists and patients participating in clinical efficacy trials of acupuncture, Acupuncture in medicine : journal of the British Medical Acupuncture Society, 35, 421–429, 2017 [PubMed: 29222203]	Study population does not meet protocol eligibility criteria - patients with radiotherapy-induced nausea versus healthy participants.
Ensiyeh, J., Sakineh, M. A. C., Comparing ginger and vitamin B6 for the treatment of nausea and vomiting in pregnancy: a randomised controlled trial, Midwifery, 25, 649–653, 2009 [PubMed: 18272271]	Study comparison does not meet protocol eligibility criteria - dietary supplement versus pharmacological intervention.
Ensiyeh, J., Sakineh, M. A., Zingiber officinale (ginger) might be better than vitamin B<inf>6</inf> for treating nausea in pregnancy, Focus on Alternative and Complementary Therapies, 15, 121, 2010	Study comparison does not meet protocol eligibility criteria - dietary supplement versus pharmacological intervention.
Ernst, E., Lee, M. S., Choi, T. Y., Acupuncture in obstetrics and gynecology: An overview of systematic reviews, American Journal of Chinese Medicine, 39, 423–431, 2011 [PubMed: 21598411]	Study design does not meet protocol eligibility criteria - review of reviews. References checked, no additional evidence identified.
Ernst, E., Matthews, A., What works for morning sickness?, Focus on Alternative & Complementary Therapies, 16, 51–52, 2011	Study design does not meet protocol eligibility criteria - commentary on Cochrane Review (Matthews 2010).
Etwel, F., Faught, L. H., Rieder, M. J., Koren, G., The Risk of Adverse Pregnancy Outcome After First Trimester Exposure to H1 Antihistamines: A Systematic Review and Meta-Analysis, Drug SafetyDrug Saf, 40, 121–132, 2017 [PubMed: 27878468]	Systematic review of cohort and case-control studies. References checked, no additional evidence identified.
Ezzo, J., Streitberger, K., Schneider, A., Cochrane systematic reviews examine P6 acupuncture-point stimulation for nausea and vomiting, Journal of Alternative and Complementary Medicine, 12, 489–495, 2006 [PubMed: 16813514]	Narrative review.
Farazmand, T., Khadem, N., Comparison of the effect of methylprednisolone and promethazine in the treatment of hyperemesis gravidarum (2001-2002), International Journal of Gynecology and Obstetrics, 2), S523, 2009	Study design does not meet protocol eligibility criteria - conference abstract.
Festin, M., Nausea and Vomiting in Early Pregnancy, American Family Physician, 92, 516–7, 2015 [PubMed: 26371736]	Study design does not meet protocol eligibility criteria - chapter from handbook.
Festin, M., Nausea and vomiting in early pregnancy, Clinical EvidenceClin Evid (Online), 19, 19, 2014 [PMC free article: PMC3959188] [PubMed: 24646807]	Systematic review - references checked, one additional relevant study was identified and included in our review.
Firouzbakht, M., Nikpour, M., Jamali, B., Omidvar, S., Comparison of ginger with vitamin B6 in relieving nausea and vomiting during pregnancy, AyuAyu, 35, 289–93, 2014 [PMC free article: PMC4649576] [PubMed: 26664238]	Serious risk surrounding quality of data.
Fischer-Rasmussen, W, Kjaer, SK, Dahl, C, Asping, U, Ginger treatment of hyperemesis gravidarum., Eur J Obstet Gynecol Reprod Biol, 38, 19–24, 1991 [PubMed: 1988321]	Study design does not meet protocol eligibility criteria - cross-over trial.
Fletcher, S. J., Waterman, H., Nelson, L., Carter, L. A., Dwyer, L., Roberts, C., Torgerson, D., Kitchener, H., Holistic assessment of women with hyperemesis gravidarum: A randomised controlled trial, International Journal of Nursing Studies, 52, 1669–1677, 2015 [PubMed: 26212603]	Study comparison does not meet protocol eligibility criteria - all women received IV rehydration and antiemetic therapy (not specified).
Forouhari, S, Ghaemi, SZ, Roshandel, A, Moshfegh, Z, Rostambeigy, P, Mohaghegh, Z, The effect of acupressure on nausea and vomiting during pregnancy. , Researcher, 6, 27–34, 2014	Study does not specify how many women in each treatment group.
Gawande, S., Vaidya, M., Tadke, R., Kirpekar, V., Bhave, S., Progressive muscle relaxation in hyperemesis gravidarum, Journal of SAFOG, 3, 28–32, 2011	Study comparison does not meet protocol eligibility criteria - pharmacological intervention muscle relaxation versus pharmacological intervention alone.
Ghahiri, A. A., Abdi, F., Mastoo, R., Ghasemi, M., The effect of Ondansetron and Metoclopramide in nausea and vomiting of pregnancy, Journal of isfahan medical school, 29, 2011	Non-English language publication.
Giacosa, A., Morazzoni, P., Bombardelli, E., Riva, A., Bianchi Porro, G., Rondanelli, M., Can nausea and vomiting be treated with ginger extract?, European Review for Medical & Pharmacological SciencesEur Rev Med Pharmacol Sci, 19, 1291–6, 2015 [PubMed: 25912592]	Narrative review
Gilbey, A., Ernst, E., Tani, K., A systematic review of reviews of systematic reviews of acupuncture, Focus on Alternative and Complementary Therapies, 18, 8–18, 2013	Systematic review of reviews of reviews (not specifically nausea and vomiting during pregnancy). References checked, no additional studies were identified
Gilboa, S. M., Ailes, E. C., Rai, R. P., Anderson, J. A., Honein, M. A., Antihistamines and birth defects: A systematic review of the literature, Expert Opinion on Drug Safety, 13, 1667–1698, 2014 [PMC free article: PMC4474179] [PubMed: 25307228]	Systematic review of cohort and case-control studies, not specifically for nausea and vomiting. References checked, no additional studies were identified.
Gill, S. K., Einarson, A., The safety of drugs for the treatment of nausea and vomiting of pregnancy, Expert Opinion on Drug Safety, 6, 685–94, 2007 [PubMed: 17967157]	Narrative review
Gill,S.K., O’Brien,L., Koren,G., The safety of histamine 2 (H2) blockers in pregnancy: a meta-analysis, Digestive diseases and sciences, 54, 1835–1838, 2009 [PubMed: 19051023]	Study does not meet protocol eligibility criteria - H2 blockers.
Haji Seid Javadi, E., Salehi, F., Mashrabi, O., Comparing the effectiveness of vitamin b6 and ginger in treatment of pregnancy-induced nausea and vomiting, Obstetrics & Gynecology InternationalObstet Gynecol Int, 2013, 927834, 2013 [PMC free article: PMC3819920] [PubMed: 24250336]	Study comparison does not meet protocol eligibility criteria - dietary supplement versus pharmacological intervention.
Hall, Helen G., McKenna, Lisa G., Griffiths, Debra L., Complementary medicine for nausea and vomiting in pregnancy: a review of the evidence, Evidence Based Midwifery, 9, 84–88, 2011	Review - references checked; no additional evidence identified.
Hansen, L. B., Saseen, J. J., Teal, S. B., Levonorgestrel-only dosing strategies for emergency contraception, Pharmacotherapy:The Journal of Human Pharmacology & Drug Therapy, 27, 278–84, 2007 [PubMed: 17253917]	Duplicate
He, X. L., Zhong, G., He, Y., Clinical observation on treatment of hyperemesis gravidarum by integrative Chinese and Western medicine and its influence on serum motilin, Zhongguo zhong xi yi jie he za zhi zhongguo zhongxiyi jiehe zazhi = chinese journal of integrated traditional and western medicine, 29, 872874, 2009 [PubMed: 20073213]	Non-English language publication.
Helmreich, R. J., Shiao, S. Y. P. K., Dune, L. S., Meta-analysis of Acustimulation Effects on Nausea and Vomiting in Pregnant Women, Explore: The Journal of Science and Healing, 2, 412–421, 2006 [PubMed: 16979105]	Systematic review including RCTs and crossover studies. References checked, no additional studies were identified
Holmgren, C., Aagaard-Tillery, K. M., Silver, R. M., Porter, T. F., Varner, M., Hyperemesis in pregnancy: An evaluation of treatment strategies with maternal and neonatal outcomes, American Journal of Obstetrics and Gynecology, 198, 56, 2008 [PubMed: 18166306]	Study does not meet protocol eligibility criteria - unclear which medications administered.
Hosseinkhani, N, Sadeghi, T, The effect of ginger on pregnancy induced nausea during first trimester. , Iran J Nurs, 22, 75–83, 2009	Non-English language article.
Hsu, E, Pei, V, Shofer, FS, A prospective randomized controlled trial of acupressure vs shamfor pregnancy-related nausea and vomiting in the emergency department. , Acad Emerg Med, 10, 437, 2003	Study design does not meet protocol eligibility criteria - conference abstract.
Hsu, Y. Y., Hung, H. Y., Chang, S. C., Chang, Y. J., O’Donnell, A., McParlin, C., Robson, S. C., Beyer, F., Moloney, E., Bryant, A., Bradley, J., Muirhead, C., Nelson-Piercy, C., Newbury-Birch, D., Norman, J., Simpson, E., Swallow, B., Yates, L., Vale, L., Early oral intake and gastrointestinal function after cesarean delivery: a systematic review and meta-analysis Treatments for hyperemesis gravidarum and nausea and vomiting in pregnancy: a systematic review and economic assessment, Obstetrics and Gynecology, 121, 1327–1334, 2013 [PubMed: 23812470]	Study does not answer the review question.
Hu, Y., Amoah, A. N., Zhang, H., Fu, R., Qiu, Y., Cao, Y., Sun, Y., Chen, H., Liu, Y., Lyu, Q., Effect of ginger in the treatment of nausea and vomiting compared with vitamin B6 and placebo during pregnancy: a meta-analysis, Journal of Maternal-Fetal & Neonatal MedicineJ Matern Fetal Neonatal Med, 1–10, 2020 [PubMed: 31937153]	A review paper of 13 RCTs. All references checked and added to this review if relevant.
Hyde, E., Acupressure therapy for morning sickness. A controlled clinical trial, J Nurse MidwiferyJournal of nurse-midwifery, 34, 171–8, 1989 [PubMed: 2769441]	Study design does not meet protocol eligibility criteria - cross-over design.
Hyde, E., Acupressure therpy for morning sickness: A controlled clinical trial. , J Nurse MidwiferyJournal of nurse-midwifery, 34, 171–8, 1989 [PubMed: 2769441]	Duplicate
Jackson, E. A., Is ginger root effective for decreasing the severity of nausea and vomiting in early pregnancy?, Journal of Family Practice, 50, 720 , 2001 [PubMed: 11509171]	Recommendations for clinical practice based on Vutyavanich 2001.
Jamigorn, M., Phupong, V., Acupressure and vitamin B6 to relieve nausea and vomiting in pregnancy: A randomized study, Archives of gynecology and obstetrics, 276, 245–249, 2007 [PubMed: 17318558]	Study comparison does not meet protocol eligibility criteria - complementary therapy versus pharmacological intervention.
Jenett-Siems, K., With ginger against nausea and vomiting: Asian root helps pregnant women better than placebo, Deutsche Apotheker Zeitung, 155, 2015	Non-English language publication.
Jiang, N. Q., The application of Sanyinjiao (SP 6) for acupuncture treatment of gynecological and obstetrical disorders, Journal of Traditional Chinese MedicineJ Tradit Chin Med, 30, 51–2, 2010 [PubMed: 20397464]	Study design does not meet protocol eligibility criteria - case report.
Jo, J., Lee, S. H., Lee, J. M., Lee, H., Kwack, S. J., Kim, D. I., Use and safety of Korean herbal medicine during pregnancy: A Korean medicine literature review, European Journal of Integrative Medicine, 8, 4–11, 2016	Systematic review of different herbal medicines for various conditions in pregnancy. References checked, no additional studies were identified
Kang,H.S., Jeong,D., Kim,D.I., Lee,M.S., The use of acupuncture for managing gynaecologic conditions: An overview of systematic reviews, Maturitas, 68, 346–354, 2011 [PubMed: 21376483]	Systematic review - not specifically pregnant women with nausea and vomiting. References checked, no additional studies were identified
Khavandizadeh, AS, Mahfouzi, B, Evaluation of the effects of acupressure by sea band on nausea and vomiting in pregnancy. , Iranian Journal of Obstetrics, Gynecology and Infertility., 13, 39–44, 2010	Not written in English
Khorasani, F., Aryan, H., Sobhi, A., Aryan, R., Abavi-Sani, A., Ghazanfarpour, M., Saeidi, M., Rajab Dizavandi, F., A systematic review of the efficacy of alternative medicine in the treatment of nausea and vomiting of pregnancy, Journal of Obstetrics and Gynaecology, 40, 10–19, 2020 [PubMed: 31215276]	A review paper of 11 RCTs. All references checked and added to this review if relevant.
Khresheh, R., How women manage nausea and vomiting during pregnancy: A Jordanian study, Midwifery, 27, 42–45, 2011 [PubMed: 20096489]	Study design does not meet protocol eligibility criteria - Cross-sectional study.
Klauser, C. K., Fox, N. S., Istwan, N., Rhea, D., Rebarber, A., Desch, C., Palmer, B., Saltzman, D., Treatment of severe nausea and vomiting of pregnancy with subcutaneous medications, American journal of perinatology, 28, 715–721, 2011 [PubMed: 21667429]	Study design does not meet protocol eligibility criteria - RCT data available for metoclopramide and ondansetron.
Koot, M. H., Boelig, R. C., van’t Hooft, J., Limpens, J., Roseboom, T. J., Painter, R. C., Grooten, I. J., Variation in hyperemesis gravidarum definition and outcome reporting in randomised clinical trials: a systematic review, BJOG: An International Journal of Obstetrics and Gynaecology, 125, 1514–1521, 2018 [PubMed: 29727913]	Study outcomes do not meet protocol eligibility criteria - overview of definitions and outcomes, but results not reported. References checked.
Koren, G., Clark, S., Hankins, G. D., Caritis, S. N., Umans, J. G., Miodovnik, M., Mattison, D. R., Matok, I., Demonstration of early efficacy results of the delayed-release combination of doxylamine-pyridoxine for the treatment of nausea and vomiting of pregnancy, BMC Pregnancy & ChildbirthBMC Pregnancy Childbirth, 16, 371, 2016 [PMC free article: PMC5122025] [PubMed: 27881103]	Secondary analysis to Koren (2010); comparisons between different timepoints; no additional evidence.
Koren, G., Hankins, G. D., Clark, S., Caritis, S. N., Miodovnik, M., Umans, J. G., Mattison, D. R., Effectiveness of doxylamine-pyridoxine for morning sickness, American Journal of Obstetrics & GynecologyAm J Obstet Gynecol, 214, 664–6, 2016 [PubMed: 26844757]	Study design does not meet protocol eligibility criteria - research letter.
Lamondy, A. M., I.V. rounds. Managing hyperemesis gravidarum, Nursing, 37, 66–68, 2007	Narrative review.
Lavecchia, M., Chari, R., Campbell, S., Ross, S., Ondansetron in Pregnancy and the Risk of Congenital Malformations: A Systematic Review, Journal of Obstetrics and Gynaecology Canada, 40, 910–918, 2018 [PubMed: 29754832]	Systematic review - case-control, cohort and case series studies included. References checked, no additional studies were identified
Lee, E. J., Frazier, S. K., The efficacy of acupressure for symptom management: A systematic review, Journal of pain and symptom management, 42, 589–603, 2011 [PMC free article: PMC3154967] [PubMed: 21531533]	Systematic review - References checked, no additional studies were identified
London, V., Grube, S., Sherer, D. M., Abulafia, O., Hyperemesis gravidarum: A review of recent literature, Pharmacology, 100, 161–171, 2017 [PubMed: 28641304]	Narrative review.
Maltepe, C., Koren, G., Preemptive treatment of nausea and vomiting of pregnancy: results of a randomized controlled trial, Obstetrics & Gynecology InternationalObstet Gynecol Int, 2013, 809787, 2013 [PMC free article: PMC3588181] [PubMed: 23476657]	Study does not meet protocol eligibility criteria - compares pre-emptive Diclectin versus treatment with Diclectin.
Mansour, G. M., Nashaat, E. H., Helicobacter pylori and hyperemesis gravidarum.[Erratum appears in Int J Gynaecol Obstet. 2009 Nov;107(2):177], International Journal of Gynaecology & ObstetricsInt J Gynaecol Obstet, 106, 63–4, 2009 [PubMed: 19375705]	Study does not meet protocol eligibility criteria - brief communication; women with versus women without hyperemesis gravidarum.
Mao, Z. N., Liang, C. E., Observation on therapeutic effect of acupuncture on hyperemesis gravidarum, Zhongguo zhen jiu [Chinese acupuncture & moxibustion], 29, 973976, 2009 [PubMed: 20088416]	Non-English language publication.
Matok, I., Clark, S., Caritis, S., Miodovnik, M., Umans, J. G., Hankins, G., Mattison, D. R., Koren, G., Studying the antiemetic effect of vitamin B6 for morning sickness: pyridoxine and pyridoxal are prodrugs, Journal of clinical pharmacology, 54, 1429–1433, 2014 [PubMed: 25052410]	Study outcomes do not meet protocol eligibility criteria - plasma concentrations.
Matthews, A., Haas, D. M., O’Mathúna, D. P., Dowswell, T., Interventions for nausea and vomiting in early pregnancy, Cochrane Database of Systematic Reviews, 2015 [PMC free article: PMC7196889] [PubMed: 26348534]	Cochrane review - References checked, no additional studies were identified
Matthews,A., Dowswell,T., Haas,D.M., Doyle,M., O’Mathuna,D.P., Interventions for nausea and vomiting in early pregnancy, Sao Paulo Medical Journal, 129, 55-, 2011	Cochrane review - replaced by 2015 update.
McGuiness, BW, Taylor Binns, D, Debendox in pregnancy sickness. , Journal of the Royal College of General Practitioners, 21, 500–3, 1971 [PMC free article: PMC2156454] [PubMed: 4937061]	Study examines combination of pyridoxine hydrochloride, doxylamine succinate, and dicyclomine (anti-cholinergic). However, anti-cholinergics are not an intervention of interest.
McParlin, C., O’Donnell, A., Robson, S. C., Beyer, F., Moloney, E., Bryant, A., Bradley, J., Muirhead, C. R., Nelson-Piercy, C., Newbury-Birch, D., Norman, J., Shaw, C., Simpson, E., Swallow, B., Yates, L., Vale, L., Treatments for Hyperemesis Gravidarum and Nausea and Vomiting in Pregnancy: A Systematic Review, JAMAJama, 316, 1392–1401, 2016 [PubMed: 27701665]	Systematic review - References checked, no additional studies were identified
Moghadam, Z. K., Najfabady, M. T., Abedi, P., Haghighizadeh, M. H., Investigating the effect of gingerpill on the treatment of nausea and vomiting of pregnancy (NVP) in pregnancy women, International Journal of Pharmaceutical and Phytopharmacological Research, 9, 9–15, 2019	The trial is not randomised and there is only one intervention arm studied.
Moreau, C., Trussell, J., Results from pooled Phase III studies of ulipristal acetate for emergency contraception, Contraception, 86, 673–80, 2012 [PMC free article: PMC3766836] [PubMed: 22770793]	Duplicate
Naeimi Rad, M., Lamyian, M., Heshmat, R., Asghari Jaafarabadi, M., Yazdani , S., A Randomized Clinical Trial of the Efficacy of KID21 Point (Youmen) Acupressure on Nausea and Vomiting of Pregnancy, Iran Red Crescent Med J, 14, 697–701, 2012 [PMC free article: PMC3560537] [PubMed: 23397064]	Duplicate
Naeimi Rad, M., Lamyian, M., Heshmat, R., Jaafarabadi, MA., Yazdani, S., A randomized clinical trial of the efficacy of KID21 point (youmen) acupressure on nausea and vomiting of pregnancy. , Iran Red Crescent Med J, 14, 697–701, 2012 [PMC free article: PMC3560537] [PubMed: 23397064]	Duplicate
Narenji, F., Delavar, M., Rafiei, M., Comparison the effects of the ginger fresh root and vitamin B6 on the nausea and vomiting in pregnancy , Iranian journal of obstetrics, gynecology and infertility, 15, 39 43, 2012	Article is unavailable
Nazari, S., Nazari, S., Shayan, A., Shobeiri, F., Tabesh, R. A. N., Comparison of the effects of ondansetron, Vitamin b6 and ginger rhizome in nausea and vomiting of pregnancy: a randomized clinical trial, Iranian journal of obstetrics, gynecology and infertility, 21, 29–35, 2018	Article in Farsi
Nihr, Hsric, Diclectin (doxylamine succinate and pyridoxine hydrochloride) for the treatment of nausea and vomiting in pregnancy, 2016	NIHR evidence summary on diclectin (xonvea).
Norheim, A. J., Pedersen, E. J., Fonnebo, V., Berge, L., Acupressure treatment of morning sickness in pregnancy. A randomised, double-blind, placebo-controlled study, Scand J Prim Health CareScandinavian journal of primary health care, 19, 43–7, 2001 [PubMed: 11303547]	Number of participants in each arm is unclear and not mentioned in the article.
O’Brien, B., Relyea, M. J., Taerum, T., Efficacy of P6 acupressure in the treatment of nausea and vomiting during pregnancy, Am J Obstet GynecolAmerican journal of obstetrics and gynecology, 174, 708–15, 1996 [PubMed: 8623811]	Study outcomes not presented in a useable format.
O’Donnell, A., McParlin, C., Robson, S. C., Beyer, F., Moloney, E., Bryant, A., Bradley, J., Muirhead, C., Nelson-Piercy, C., Newbury-Birch, D., Norman, J., Simpson, E., Swallow, B., Yates, L., Vale, L., Treatments for hyperemesis gravidarum and nausea and vomiting in pregnancy: A systematic review and economic assessment, Health Technology Assessment, 20, 2016 [PMC free article: PMC5075747] [PubMed: 27731292]	HTA - References checked, no additional studies were identified
Ostenfeld, A., Petersen, T. S., Futtrup, T. B., Andersen, J. T., Jensen, A. K., Westergaard, H. B., Pedersen, L. H., Lokkegaard, E. C. L., Validating the effect of Ondansetron and Mirtazapine In Treating hyperemesis gravidarum (VOMIT): protocol for a randomised placebo-controlled trial, BMJ Open, 10, e034712, 2020 [PMC free article: PMC7202694] [PubMed: 32209630]	RCT protocol. The trial will compare ondansetron, mirtazapine, and placebo.
Ozgoli, G., Saei Ghare Naz, M., Effects of Complementary Medicine on Nausea and Vomiting in Pregnancy: A Systematic Review, International journal of preventive medicine, 9, 75, 2018 [PMC free article: PMC6177529] [PubMed: 30319738]	Systematic review of eligible and non-eligible studies - References checked, no additional studies were identified
Pakniat, H., Memarzadeh, M. R., Azh, N., Mafi, M., Ranjkesh, F., Comparison of the effect of chamomile, Ginger and vitamin B6 on treatment of nausea and vomiting in pregnancy: a randomized clinical trial, Iranian journal of obstetrics, gynecology and infertility, 21, 4754, 2018	Article in Farsi
Park, J., Sohn, Y., White, A. R., Lee, H., The safety of acupuncture during pregnancy: a systematic review, Acupuncture in MedicineAcupunct Med, 32, 257–66, 2014 [PMC free article: PMC4112450] [PubMed: 24554789]	A review paper focusing on benefits/harms of acupuncture during pregnancy. No specific focus on use for NVP/HG.
Parker, S. E., Van Bennekom, C., Anderka, M., Mitchell, A. A., National Birth Defects Prevention, Study, Ondansetron for Treatment of Nausea and Vomiting of Pregnancy and the Risk of Specific Birth Defects, Obstetrics & GynecologyObstet Gynecol, 132, 385–394, 2018 [PubMed: 29995744]	Study design does not meet protocol eligibility criteria - two case-control studies.
Pei, K., Xiao, B., Jing, X., Lu, S., Wei, L., Zhao, H., Weekly contraception with mifepristone, Contraception, 75, 40–44, 2007 [PubMed: 17161123]	Duplicate
Persaud, N., Meaney, C., El-Emam, K., Moineddin, R., Thorpe, K., Doxylamine-pyridoxine for nausea and vomiting of pregnancy randomized placebo controlled trial: Prespecified analyses and reanalysis, Plos one, 13 (1) (no pagination), 2018 [PMC free article: PMC5771578] [PubMed: 29342163]	Re-analysis of Koren (2010) and comparison of outcomes with other publications.
Pope, E., Maltepe, C., Koren, G., Comparing pyridoxine and doxylamine succinate-pyridoxine HCl for nausea and vomiting of pregnancy: a matched, controlled cohort study, Journal of clinical pharmacology, 55, 809814, 2015 [PubMed: 25663469]	Study design does not meet protocol eligibility criteria - cohort study (RCT data available for this comparison).
Richardson, A. R., Maltz, F. N., Ulipristal Acetate: Review of the Efficacy and Safety of a Newly Approved Agent for Emergency Contraception, Clinical therapeutics, 34, 24–36, 2012 [PubMed: 22154199]	Duplicate
Roddison, Ruth, Charlesworth, Karen, Using acupuncture for the treatment of nausea and vomiting in pregnancy and hyperemesis gravidarum, MIDIRS Midwifery Digest, 28, 173–176, 2018	Study design does not meet protocol eligibility criteria - single treatment arm; no comparison.
Rukh, L., Nazar, H., Usmanghani, K., Efficacy of Gingocap as compared to pyridoxine in the treatment of nausea and vomiting during pregnancy, Pakistan Journal of Pharmaceutical Sciences, 29, 1937–1943, 2016 [PubMed: 28375108]	Study comparison does not meet protocol eligibility criteria - compares dietary supplements (ginger extract) versus pharmacological intervention (pyridoxine).
Salam, R. A., Zuberi, N. F., Bhutta, Z. A., Pyridoxine (vitamin B6) supplementation during pregnancy or labour for maternal and neonatal outcomes, Cochrane Database of Systematic Reviews, 2016 (3) (no pagination), 2015 [PMC free article: PMC10082995] [PubMed: 26039815]	Cochrane review - outcomes do not meet protocol eligibility criteria (mean birthweight; pre-eclampsia; apgar scores; breast milk production; dental decay; non-significant adverse events). References checked, no additional studies were identified
Sanu, O., Lamont, R. F., Hyperemesis gravidarum: pathogenesis and the use of antiemetic agents, Expert Opinion on Pharmacotherapy, 12, 737–48, 2011 [PubMed: 21361848]	Narrative/general review.
Sarkar, N. N., Emergency contraception spearheading despite hurdles and hindrance, International Medical Journal, 16, 211–216, 2009	Duplicate
Sarkar, N. N., Emergency contraception: A contraceptive intervention approaching target despite controversy and opposition, Journal of Public Health, 14, 164–173, 2006	Duplicate
Schuster, K., Bailey, L. B., Dimperio, D., Mahan, C. S., Morning sickness and vitamin B6 status of pregnant women, Hum Nutr Clin NutrHuman nutrition. Clinical nutrition, 39, 75–9, 1985 [PubMed: 3997551]	Article is unavailable
Shahraki, Z., Bonjar, Z. S. H., Forghani, F., Nakhai, R., Comparing neonatal outcome following the use of ondansetron versus vitamin B6 in pregnant females with morning sickness: A randomized clinical trial, Journal of comprehensive pediatrics, 7 (4) (no pagination), 2016	Study outcomes do not meet protocol eligibility criteria - mean gestational age, mean birth weight, mean height, mean head circumference; congential abnormalities).
Shen, J., Che, Y., Showell, E., Chen, K., Cheng, L., Interventions for emergency contraception, Cochrane Database of Systematic Reviews, 2017 [PMC free article: PMC6483633] [PubMed: 28766313]	Duplicate
Shin, H. S., Song, Y. A., Seo, S., Effect of Nei-Guan point (P6) acupressure on ketonuria levels, nausea and vomiting in women with hyperemesis gravidarum, Journal of advanced nursing, 59, 510–519, 2007 [PubMed: 17645494]	Study outcomes not reported in useable format - means reported but not standard deviations.
Shrim,A., Boskovic,R., Maltepe,C., Navios,Y., Garcia-Bournissen,F., Koren,G., Pregnancy outcome following use of large doses of vitamin B6 in the first trimester, Journal of Obstetrics and Gynaecology, 26, 749–751, 2006 [PubMed: 17130022]	Study design does not meet protocol eligibility criteria - observational study assessing B6 (RCT evidence available).
Smith, C. A., Cochrane, S., Does acupuncture have a place as an adjunct treatment during pregnancy? A review of randomized controlled trials and systematic reviews, Birth, 36, 246–253, 2009 [PubMed: 19747272]	Systematic review of acupuncture for various conditions in pregnancy - References checked, no additional studies were identified
Smith, C., Crowther, C., Willson, K., Hotham, N., McMillian, V., A randomized controlled trial of ginger to treat nausea and vomiting in pregnancy, Obstet GynecolObstetrics and gynecology, 103, 639–45, 2004 [PubMed: 15051552]	No comparator of interest- Dietary supplement (ginger) vs. Vitamin B6
Solt Kirca, A., Kanza Gul, D., Effects of Acupressure Applied to P6 Point on Nausea Vomiting in Pregnancy: A Double-Blind Randomized Controlled, Alternative Therapies in Health & MedicineAltern Ther Health Med, 28, 28, 2020 [PubMed: 32857730]	Full text unavailable
Sonkusare, S., Hyperemesis gravidarum: a review, Medical Journal of MalaysiaMed J Malaysia, 63, 272–6; quiz 277, 2008 [PubMed: 19248711]	Narrative review.
Sridharan, K., Sivaramakrishnan, G., Interventions for treating hyperemesis gravidarum: a network meta-analysis of randomized clinical trials, Journal of maternal-fetal & neonatal medicine, 1–7, 2018 [PubMed: 30173590]	Systematic review - References checked, no additional studies were identified
Sridharan, K., Sivaramakrishnan, G., Interventions for treating hyperemesis gravidarum: a network meta-analysis of randomized clinical trials, Journal of Maternal-Fetal and Neonatal Medicine, 33, 1405–1411, 2020 [PubMed: 30173590]	A review paper of 20 RCTs. All references checked and added to this review if relevant.
Sridharan, K., Sivaramakrishnan, G., Interventions for treating nausea and vomiting in pregnancy: a network meta-analysis and trial sequential analysis of randomized clinical trials, Expert Review of Clinical Pharmacology, 1–8, 2018 [PubMed: 30261764]	Systematic review - References checked, no additional studies were identified
Stanisiere, J., Mousset, P. Y., Lafay, S., How Safe Is Ginger Rhizome for Decreasing Nausea and Vomiting in Women during Early Pregnancy?, FoodsFoods, 7, 01, 2018 [PMC free article: PMC5920415] [PubMed: 29614764]	Narrative review
Steele, N. M., French, J., Gatherer-Boyles, J., Newman, S., Leclaire, S., Effect of acupressure by Sea-Bands on nausea and vomiting of pregnancy, JOGNN - Journal of Obstetric, Gynecologic, & Neonatal Nursing, 30, 61–70, 2001 [PubMed: 11277163]	Study outcomes not presented in a useable format.
Stone, C. L., Acupressure wristbands for the nausea of pregnancy, Nurse PractThe Nurse practitioner, 18, 15, 18, 23, 1993 [PubMed: 8278088]	Study design does not meet protocol eligibility criteria - letter to the editor.
Streitberger, K., Ezzo, J., Schneider, A., Acupuncture for nausea and vomiting: An update of clinical and experimental studies, Autonomic Neuroscience: Basic and Clinical, 129, 107–117, 2006 [PubMed: 16950659]	General review, not specific to pregnant women with nausea and vomiting.
Sulak, P. J., Continuous oral contraception: changing times, Best Practice and Research: Clinical Obstetrics and Gynaecology, 22, 355–374, 2008 [PubMed: 17892973]	Duplicate
Tabatabaii, A., Sekhavat, L., Mojibian, M., A randomized, placebo-controlled trial of corticosteroids for hyperemesis gravidarum., Journal of Maternal-Fetal and Neonatal Medicine, 21, 225–226, 2008	Conference abstract
Tamay, A. G., Kuscu, N. K., Hyperemesis gravidarum: current aspect, Journal of Obstetrics & Gynaecology, 31, 708–12, 2011 [PubMed: 22085059]	Narrative review.
Tara, F, Azizi, H, Bahrami, H, Effects of pressure stimulation of the nei guan (PC6) point on the nausea and vomiting in pregnant women. , Avicenna J Phytomed, 5, 17–18, 2015	Study design does not meet protocol eligibility criteria - conference abstract.
Tara, F., Bahrami-Taghanaki, H., Amini Ghalandarabad, M., Zand-Kargar, Z., Azizi, H., Esmaily, H., Azizi, H., The Effect of Acupressure on the Severity of Nausea, Vomiting, and Retching in Pregnant Women: A Randomized Controlled Trial, Complementary Medical ResearchComplementary Med, 1–8, 2020 [PubMed: 32018274]	Article is unavailable
Tara, F., Bahrami-Taghanaki, H., Amini Ghalandarabad, M., Zand-Kargar, Z., Esmaily, H., Azizi, H., Wirkung der Akupressur auf den Schweregrad von Ubelkeit, Erbrechen und Wurgereiz bei Schwangeren: eine randomisierte kontrollierte Studie, The Effect of Acupressure on the Severity of Nausea, Vomiting, and Retching in Pregnant Women: A Randomized Controlled Trial, Complementary medicine research, 1–8, 2020 [PubMed: 32018274]	Duplicate.
Thomson, M., Corbin, R., Leung, L., Effects of ginger for nausea and vomiting in early pregnancy: a meta-analysis, Journal of the American Board of Family Medicine: JABFMJ Am Board Fam Med, 27, 115–22, 2014 [PubMed: 24390893]	Systematic review - references checked; no additional relevant evidence identified.
Van den Heuvel, E., Goossens, M., Vanderhaegen, H., Sun, H. X., Buntinx, F., Effect of acustimulation on nausea and vomiting and on hyperemesis in pregnancy: a systematic review of Western and Chinese literature, BMC Complementary & Alternative MedicineBMC Altern Med, 16, 13, 2016 [PMC free article: PMC4711053] [PubMed: 26758211]	Systematic review - References checked, no additional studies were identified
Viljoen, E., Visser, J., Koen, N., Musekiwa, A., A systematic review and meta-analysis of the effect and safety of ginger in the treatment of pregnancy-associated nausea and vomiting, Nutrition JournalNutr J, 13, 20, 2014 [PMC free article: PMC3995184] [PubMed: 24642205]	Systematic review - references checked; no additional evidence identified.
Wibowo, N., Purwosunu, Y., Sekizawa, A., Farina, A., Tambunan, V., Bardosono, S., Vitamin B6 supplementation in pregnant women with nausea and vomiting, International Journal of Gynaecology & ObstetricsInt J Gynaecol Obstet, 116, 206–10, 2012 [PubMed: 22189065]	Study comparison does not meet protocol eligibility criteria - compares high versus low dose pyridoxine hydrochloride.
Xu, J., MacKenzie, I. Z., The current use of acupuncture during pregnancy and childbirth, Current Opinion in Obstetrics & GynecologyCurr Opin Obstet Gynecol, 24, 65–71, 2012 [PubMed: 22249144]	Narrative review.

Economic studies

A single economic search was undertaken for all topics included in the scope of this guideline. No economic studies were identified which were applicable to this review question. See supplementary material 2 for details.

Appendix L. Research recommendations

Research recommendations for review question: What interventions are effective in treating nausea and vomiting during pregnancy? (PDF, 153K)

Final

Evidence reviews underpinning recommendations 1.4.1 to 1.4.7

These evidence reviews were developed by the National Guideline Alliance, which is a part of the Royal College of Obstetricians and Gynaecologists

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK573942PMID: 34524763

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National Guideline Alliance (UK). Management of nausea and vomiting in pregnancy: Antenatal care: Evidence review R. London: National Institute for Health and Care Excellence (NICE); 2021 Aug. (NICE Guideline, No. 201.)
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