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RCOG GREEN-TOP GUIDELINES
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The Management of Nausea and Vomiting in Pregnancy and Hyperemesis Gravidarum (Green-top Guideline No. 69)

First published: 04 February 2024
Citations: 1

Correspondence

Royal College of Obstetricians and Gynaecologists, 10–18 Union Street, London SE1 1SZ.

Email: [email protected]

This is the second edition of this guideline which was previously published in 2016 under the same name. This guideline is for healthcare professionals who care for women, non-binary and trans people.

This guideline has been endorsed by the Royal College of Emergency Medicine (RCEM), the Association of Early Pregnancy Units (AEPU), and the General Practitioners Championing Perinatal Care (GPCPC); and it has been supported by the Royal College of General Practitioners (RCGP).

Key recommendations

  • An objective and validated index of nausea and vomiting such as the Pregnancy-Unique Quantification of Emesis (PUQE) and HyperEmesis Level Prediction (HELP) tools can be used to classify the severity of NVP and HG. [Grade C]
  • Ketonuria is not an indicator of dehydration and should not be used to assess severity. [Grade A]
  • There are safety and efficacy data for first line antiemetics such as anti (H1) histamines, phenothiazines and doxylamine/pyridoxine (Xonvea®) and they should be prescribed initially when required for NVP and HG (Appendix III). [Grade A]
  • There is evidence that ondansetron is safe and effective. Its use as a second line antiemetic should not be discouraged if first line antiemetics are ineffective. Women can be reassured regarding a very small increase in the absolute risk of orofacial clefting with ondansetron use in the first trimester, which should be balanced with the risks of poorly managed HG. [Grade B]
  • Metoclopramide is safe and effective and can be used alone or in combination with other antiemetics. [Grade B]
  • Because of the risk of extrapyramidal effects metoclopramide should be used as second-line therapy. Intravenous doses should be administered by slow bolus injection over at least 3 minutes to help minimise these. [Grade C]
  • Women should be asked about previous adverse reactions to antiemetic therapies. If adverse reactions occur, there should be prompt cessation of the medications. [GPP]
  • Normal saline (0.9% NaCl) with additional potassium chloride in each bag, with administration guided by daily monitoring of electrolytes, is the most appropriate intravenous hydration. [Grade C]
  • Combinations of different drugs should be used in women who do not respond to a single antiemetic. Suggested antiemetics for UK use are given in Appendix III. [GPP]
  • Thiamine supplementation (either oral 100 mg tds or intravenous as part of vitamin B complex (Pabrinex®)) should be given to all women admitted with vomiting, or severely reduced dietary intake, especially before administration of dextrose or parenteral nutrition. [Grade D]
  • All therapeutic measures should have been tried before considering termination of pregnancy. [Grade C]

1 PURPOSE AND SCOPE

There is variation in the care of women who have nausea and vomiting of pregnancy (NVP) or hyperemesis gravidarum (HG) with the potential for lack of understanding of its severity and options for treatment and support.

The aim of this guideline is to provide updated evidence-based or best clinical practice information regarding the diagnosis and subsequent management of NVP and HG across community, ambulatory day care and inpatient settings. A summary for general practitioners is given in Appendix Vai and Vaii. It gives advice for multidisciplinary professionals involved in the care of women with these conditions, including how to counsel and support women before, during and after their pregnancies.

Within this document we use the terms woman and women's health. However, it is important to acknowledge that it is not only women for whom it is necessary to access women's health and reproductive services in order to maintain their gynaecological health and reproductive wellbeing. Gynaecological and obstetric services and delivery of care must therefore be appropriate, inclusive and sensitive to the needs of those individuals whose gender identity does not align with the sex they were assigned at birth.

2 INTRODUCTION AND BACKGROUND EPIDEMIOLOGY

NVP affects up to 90% of pregnant women1 and is one of the most common indications for hospital admission among pregnant women, with typical stays of between three and four days. The annual cost to the National Health Service (NHS) of NVP has been estimated to be up to £62 million due to hospital admissions, general practice (GP) visits and ambulance call-outs.1-4 NVP is defined as the symptom of nausea and/or vomiting during pregnancy when onset is prior to 16 weeks of gestation and where there are no other causes. The term often used in the lay media for NVP is “morning sickness” which is not only inaccurate (as symptoms occur both before and after noon), but is felt by sufferers to trivialise the condition.5

HG is a severe form of NVP, which affects between 0.3 and 3.6% of pregnant women, interfering with quality of life and the ability to eat and drink normally. Reported HG recurrence rates vary, from 15.2% in a Norwegian hospital registry study to 89% if using self-reported diagnosis.6-9 In a population based pregnancy cohort using general practice records prevalence of clinically recorded NVP/HG was 9.1%: 2.1% had hospital admissions, 3.4% were treated with antiemetics in primary care only, and 3.6% had only recorded diagnoses.10 Therefore it is likely that use of a definition that puts more emphasis on subjective patient focussed criteria (see section 5 below) will lead to an increase in reported incidence rates.

The major mechanism of NVP and HG has recently been elucidated to be related to hypersensitivity to the vomiting hormone growth differentiation factor-15 (GDF15). GDF15 caused loss of appetite, taste aversion, nausea, vomiting and weight loss. Variation in the GDF15 gene both in families and in unrelated individuals is associated with HG. Both hCG and GDF15 are made when genes in the placenta are activated and circulating levels have a peak in the first half of pregnancy, but no genetic variants in hCG have been identified (even in very large studies) to be associated with HG. Higher circulating levels of GDF15 and not hCG were found in hospitalised HG patients, patients taking medication for NVP, and patients with 2nd trimester vomiting.11 hCG is therefore unlikely to be causative.11 Genetic variants associated with expression of GDF15 in families with HG have been identified as the greatest genetic risk factor for HG12 and are associated with recurrence in subsequent pregnancies.13

3 IDENTIFICATION AND ASSESSMENT OF EVIDENCE

The Cochrane Library and electronic databases (DARE, EMBASE, Trip, MEDLINE and PubMed) were searched using the relevant Medical Subject Headings (MeSH) terms, including all subheadings and synonyms, and this was combined with a keyword search and was limited to humans and English language; search terms included ‘hyperemesis’, ‘nausea and vomiting’ ‘pregnan*’, ‘morning sickness’ and ‘hyperemesis gravidarum’. The search was restricted to articles published between 2015 and July 2023. The full search strategy is available to view online as supporting information (Appendix S1 and S2).

This guideline was developed using the standard methodology for Green-top Guidelines.14 Where possible, recommendations are based on available evidence. In the absence of published evidence, these have been annotated as ‘good practice points’. Further information about the assessment of evidence and the grading of recommendations may be found in Appendix I.

4 HOW ARE NVP AND HG DEFINED AND DIAGNOSED?

Recommendation Evidence quality Strength Rationale for the recommendation
NVP is diagnosed when onset is prior to 16 weeks of gestation and other causes of nausea and vomiting have been excluded.

2–

D

Onset of NVP is in the first trimester and if the initial onset is after 16 weeks this should be investigated for other causes.
HG can be diagnosed when symptoms start in early pregnancy, nausea and/or vomiting are severe enough to cause an inability to eat and drink normally and strongly limits daily activities of living. Signs of dehydration are contributory to diagnosis. 2– D Definition of HG has been agreed by international consensus in published literature.
An objective and validated index of nausea and vomiting such as the Pregnancy-Unique Quantification of Emesis (PUQE) and HyperEmesis Level Prediction (HELP) tools can be used to classify the severity of NVP and HG. 2+ C The PUQE score is a validated score to objectively assess severity of NVP and treatment response for mild to moderate NVP. The HELP score is another validated score to determine treatment response in severe NVP and HG in addition to assessing severity.
Clinicians should be aware of the features in history, examination and investigation that allow NVP and HG to be assessed and for their severity to be monitored. 4 D Thorough history, examination and investigation ensure accurate assessment of severity and exclusion of other causes.
Ketonuria is not an indicator of dehydration in pregnancy and should not be used to assess severity. 1++ A Ketonuria is not associated with HG or its severity.

NVP typically starts between the fourth and seventh weeks of gestation, peaks in approximately the ninth week and resolves by the 20th week in 90% of women.15 [Evidence level 2–]

A multi-stakeholder international consensus process developed a definition for HG to aid clinical diagnosis. The Windsor definition17 describes HG as nausea and vomiting of which one is severe, beginning in early pregnancy (before 16 weeks of gestation), inability to eat and drink normally, and strongly limiting daily living activities. Signs of dehydration are considered contributory to diagnosis. This definition represents a shift from a historic reliance on objective measures such as weight loss and electrolyte imbalance, and towards subjective patient focused criteria which may lead to improved recognition and diagnosis of HG.16 [Evidence level 2–]

The Rhodes Index17, 18 was originally validated to measure nausea and vomiting in chemotherapy patients, including assessment of physical symptoms and the resulting stress, but has subsequently been used for NVP. A shorter disease-specific questionnaire (PUQE) was developed by the Motherisk Program,19 an NVP helpline in Canada, which highly correlated with the Rhodes Index and assessed symptoms over the previous 12 hours.20 The PUQE was modified to include symptom profile over the previous 24 hours including a wellbeing score that correlated with hydration status and, more recently, over the duration of the first trimester.21, 22 The PUQE score can be used to determine whether the NVP is mild, moderate or severe (Appendix II). [Evidence level 2+] The PUQE score can also be used to assess the response to treatment for mild to moderate NVP but is not valid for severe NVP and HG.

The HELP score was developed and validated by the Hyperemesis Education and Research Foundation in the USA23 to quantify HG symptoms into a score that can be trended over time to monitor progress and response to treatment. It is available as an online calculator (https://www.hyperemesis.org/tools/help-score/) and in app form. The HELP score (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815331/figure/FI13091997-1/?report=objectonly) can be used to track progress with treatment in women with severe NVP and HG. [Evidence level 2+]

NVP and HG are associated with hyponatraemia, hypokalaemia, low serum urea, raised haematocrit and ketonuria with a metabolic hypochloraemic alkalosis. If severe, a metabolic acidosis may develop. In two-thirds of women with HG, there may be abnormal thyroid function tests (based on a structural similarity between thyroid-stimulating hormone [TSH] and hCG with a biochemical thyrotoxicosis, and raised free thyroxine levels with or without a suppressed thyroid stimulating hormone level. These patients rarely have thyroid antibodies and are euthyroid clinically. The biochemical thyrotoxicosis resolves as the HG improves and treatment with antithyroid drugs is unnecessary.24 A raised T4 and low TSH therefore do not need treatment in straightforward NVP/HG where the cause is clear and the patient is responding to treatment. [Evidence level 2–]

Liver function tests are abnormal in up to 40% of women with HG,25 with the most likely abnormality being a rise in transaminases. Levels of both bilirubin and amylase may be mildly elevated. These abnormalities improve as the HG resolves. [Evidence level 3]

Ketonuria is not an indicator of dehydration and is not associated with severity of NVP or HG.26, 27 [Evidence level 1++]

Clinical assessment as outlined in table 1 or with the HELP or PUQE scores are better indicators of severity. Assessment of urinary ketosis may mislead clinical judgement of hydration and nutrition status and should be avoided in the assessment or monitoring of NVP and HG.

TABLE 1. Features in the history, examination, and investigations to aid diagnosis and exclude other causes of severe nausea and vomiting in pregnancy.
History
  • Previous history of NVP/HG
  • Quantify severity using PUQE/HELP score: nausea, vomiting, ptyalism (hypersalivation), spitting, weight loss, inability to tolerate food and fluids, effect on quality of life and ability to perform daily activities
  • Ask about self-reported nutritional status or rapid weight loss
  • Ask about co-morbidities which may be complicated by lack of oral intake of essential medications such as epilepsy, diabetes, HIV, psychiatric conditions and hypoadrenalism.
  • Relevant surgical history such as gastric bypass, band or sleeve
  • History to exclude other causes:
  • abdominal pain
  • urinary symptoms
  • infection
  • drug history (prescription and/or recreational)
  • chronic Helicobacter pylori infection
Examination
  • Temperature
  • Heart rate (tachycardia in dehydration)
  • Blood pressure (hypotension in dehydration)
  • Oxygen saturations
  • Respiratory rate (tachypnoea in dehydration)
  • Abdominal examination
  • Weight
  • Signs of dehydration such as sunken eyes, dry lips and mouth, oliguria or anuria, tachycardia and hypotension
  • Signs of malnutrition or rapid weight loss (≥5% pre pregnancy weight), and muscle wasting as measured by mid-arm circumference1
  • Neurological signs such as confusion, nystagmus or ataxia which could indicate Wernicke's encephalopathy
Investigation
  • Urinalysis: Nitrites may indicate infection. The presence or absence of ketonuria in pregnancy is not an indicator of dehydration. Assessing urinary ketones does not have a use in the management of NVP or HG and may be misleading.
  • MSU (if dipstick indicates signs of UTI)
  • Urea and electrolytes: (to guide intravenous fluid and electrolyte replacement)
  • hypokalaemia/hyperkalaemia
  • hyponatraemia
  • chronic kidney disease
  • high creatinine / urea (acute kidney injury) due to dehydration
  • Full blood count:
  • infection
  • anaemia
  • raised haemoglobin and haematocrit
  • Blood glucose level:
  • diagnose diabetes
  • exclude diabetic ketoacidosis in patients with diabetes
  • Ultrasound scan:
  • assess if viable intrauterine pregnancy, multiple pregnancy or trophoblastic disease
  • In refractory cases or history of previous admissions, check:
  • TFTs: hypothyroid/hyperthyroid
  • LFTs: exclude other liver disease such as hepatitis or gallstones, monitor malnutrition
  • calcium and phosphate
  • amylase: exclude pancreatitis
  • VBG: exclude metabolic disturbances to monitor severity
  • 1 Malnutrition Universal Screening Tool (bapen.org.uk).
  • VBG venous blood gas; LFTs liver function tests; MSU midstream urine; TFTs thyroid function tests.

Severe malnutrition can be assessed with anthropometric measures such as mid-upper arm circumference (more useful with serial measurements) and validated nutrition screening tools such as the Malnutrition Universal Screening Tool (MUST) which can be adapted for pregnancy.28-33

5 HOW SHOULD WOMEN WITH NVP AND HG BE CARED FOR?

5.1 What initial clinical assessment and baseline investigations should be performed?

Recommendation Evidence quality Strength Rationale for the recommendation
Women with mild NVP should be cared for in the community with antiemetics. 4 D Since most women with NVP require only oral or intramuscular antiemetics, management in the community/primary care is appropriate to avoid unnecessary hospital admissions and disruption to the woman's life.34

Ambulatory day care should be used when community/primary care measures have failed.

2+ C If women are unable to tolerate oral antiemetics or oral fluids then ambulatory day care management is appropriate.
Inpatient care should be considered if there is at least one of the following:
  • Continued nausea and vomiting and inability to keep down oral antiemetics
  • Continued nausea and vomiting associated with clinical dehydration or weight loss (greater than 5% of body weight), despite oral antiemetics
  • Confirmed or suspected comorbidity (such as urinary tract infection and inability to tolerate oral antibiotics).
  • Comorbidities such as epilepsy, diabetes, HIV, hypoadrenalism or psychiatric disease where symptoms and inability to tolerate oral intake and medication could present further complications.
4 GPP

Women who have recurrent/on-going NVP/HG despite adequate ambulatory day care treatment should be cared for as inpatients because of the associated complications, in particular electrolyte imbalance and nutritional deficiencies.

Where inpatient care is required an ultrasound scan should be scheduled to confirm viability and gestational age, and to assess for multiple pregnancy or trophoblastic disease. Unless there are other medical reasons for an urgent scan, this can be scheduled for the next available appointment. 4 GPP Trophoblastic disease and multiple pregnancy are associated with an increased risk of HG but do not affect the initial care.

Women who have nausea and vomiting but are not dehydrated can be cared for in the community with antiemetics, reassurance, oral hydration and dietary advice (eat little and often to prevent an empty stomach). Women may benefit from rest and time off work. In areas where ‘acute care at home’ or ‘hospital at home’ services are operating to provide IV treatment in the community, these services can be utilised for IV rehydration at home for women who are unable to maintain hydration orally but who do not have co-morbidities or complications. Women may be reluctant to take, and non-specialist clinicians may be reluctant to prescribe, pharmacological treatments owing to concerns about teratogenic risk.35, 36 Women should be counselled that the benefits of antiemetics outweigh the risks, and that the absolute risk is low. Antiemetics are therefore appropriate and should be offered (see section 6.2.2).37 [Evidence level 4]

If women are unable to tolerate oral antiemetics or oral fluids then ambulatory day care management, which provides intravenous fluids, vitamins (especially B1- thiamine)38, 39 and parenteral antiemetics, is appropriate and should be offered. Thiamine stores in a previously healthy individual can deplete rapidly and cause symptoms of tachycardia, weakness and decreased deep tendon reflexes within one week without intake.39 Various rehydration regimens have been shown to be effective.40, 41 A randomised controlled trial (RCT) of 98 women showed that ambulatory day care management involving intravenous fluids and stepwise increments in antiemetic therapy versus inpatient care was acceptable to women and resulted in fewer days as an inpatient.42 In a study of 428 women who had ambulatory day care subcutaneous metoclopramide therapy (SMT), improvement in symptoms occurred in 89.3%.41 Those women for whom the SMT regimen failed (10.7%) had higher mean PUQE scores at the start of ambulatory day care treatment than those for whom it was successful (10.0 ± 3.0 versus 7.6 ± 2.8 respectively, P < 0.001). Moreover, they were more likely to have a PUQE score of 13 or higher, SMT was started earlier in pregnancy (9.7 ± 2.9 weeks versus 11.4 ± 3.2 weeks, P = 0.005) and they were more likely to need intravenous hydration (91.3% versus 65.2%, P < 0.001). In addition to the SMT regimen, women received adjuvant therapies at home such as intravenous hydration, subcutaneous ondansetron, histamine type-2 receptor blockers, and received total parenteral nutrition. Ambulatory day care management has been successfully and safely set up in units and is associated with high patient satisfaction.43 [Evidence level 2+]

5.2 How should women with NVP and HG be cared for?

5.2.1 What pharmacological therapeutic options are available and effective for women with NVP and HG?

Recommendation Evidence quality Strength Rationale for the recommendation

Combinations of different drugs should be used in women who do not respond to a single antiemetic. Suggested antiemetics for UK use are given in Appendix III.

4 GPP Various drug classes have different mechanisms of action and work synergistically, therefore, combination antiemetics should be used in women who do not respond to a single agent. Some women may require combinations of two or more medications from first- and second- line options (see Appendix III)
A delayed-release combination of doxylamine and pyridoxine (vitamin B6) is the only licensed treatment of NVP in the UK so can be used first-line for mild-moderate NVP requiring treatment. 2++ B A larger improvement in PUQE score from baseline to day 15 and increased wellbeing has been reported as compared with placebo.44
For women with persistent or severe HG, the parenteral, transdermal, or rectal route may be necessary and more effective than an oral regimen. 2− D
Corticosteroids should be reserved for cases where standard therapies have been ineffective and used in combination with antiemetics. 1+ A Systematic review suggests a beneficial effect for steroids.45

Clinicians should use antiemetics with which they are familiar and should use drugs from different classes if the first drug is not effective or only partially effective. Many women will require a combination of two or more antiemetics.46

A slow-release combination of doxylamine and pyridoxine (vitamin B6) called Xonvea®™ is the only licensed treatment of NVP in the UK.44 A delayed-release formulation containing 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride has been available in Canada since 1979 and since 2013 in the USA. The combination of doxylamine and pyridoxine resulted in a larger improvement in PUQE score from baseline to day 15 compared with placebo (mean difference −0.90, 95% CI −1.55 to −0.25; P = 0.006) in a randomised double-blind multicentre trial of 256 women. There was also a significantly larger increase in wellbeing score with active treatment (+1.0, P = 0.005). Although no high quality evidence exists to suggest that delayed release formulations are more effective than other antiemetics in treating NVP, evidence from other fields, such as chemotherapy nausea and vomiting management supports their use to create stable blood levels of the drug.44 [Evidence level 2++]

A study of 1037 admissions46 for HG demonstrated that antihistamines were more commonly prescribed in combination with other antiemetics at hospital discharge after a first admission and that combinations of dopamine antagonists and serotonin antagonists are common after second and subsequent admissions. Furthermore, persistent vomiting may mean that oral doses of antiemetics are not absorbed and therefore the sublingual, intravenous, rectal, transcutaneous, subcutaneous or intramuscular routes may be necessary and more effective (see Appendix III). [Evidence level 2++]

Three small randomised studies47-49 have shown ondansetron to be superior to doxylamine and pyridoxine in reducing nausea and vomiting,47 equally effective as metoclopramide, but with fewer adverse effects,48 and more effective than metoclopramide at reducing severe vomiting.49 [Evidence level 2++] Because there are large amounts of safety data for doxylamine/pyridoxine and the antihistamines in general have fewer adverse effects than ondansetron (which may cause constipation) the antihistamines remain first line over ondansetron which is second line (see Appendix III).

A Cochrane systematic review including two RCTs demonstrated that treatment with ondansetron was associated with improvement in symptoms of all severities.50 [Evidence level 2++]

There are small studies of the use of Granisetron with limited evidence as yet of its use.51, 52 [Evidence level 3]

There is no association between the degree of NVP at 12 weeks and vitamin B6 levels measured at 15 weeks.53 A Cochrane review concluded that there is a lack of consistent evidence that pyridoxine is an effective therapy for NVP.54 Furthermore, a placebo-controlled trial of its use in HG did not demonstrate any improvement in nausea, vomiting or rehospitalisation in 46 women given 20 mg orally three times a day in addition to intravenous fluids, intravenous metoclopramide three times a day and oral thiamine, compared with the control group given placebo in addition to standard therapy.55 A matched non-randomised study demonstrated that the combination of doxylamine and pyridoxine was significantly more effective than pyridoxine alone.56 [Evidence level 2++]

Corticosteroids have resulted in dramatic and rapid improvement in case series of women with refractory HG.57 The results of randomised studies are conflicting58 and the largest study failed to show improvement in the primary outcome of rehospitalisation (however, both groups also received metoclopramide and promethazine).59, 60 Case selection and route and dose of corticosteroid administration may explain the different results, with beneficial results being described in more severe cases. A systematic review and meta-analysis identified five trials of 310 women and showed no effect on readmission rates, with one study showing reduced vomiting and one showing improved wellbeing.45 [Evidence level 1+]

Corticosteroids should not be used until conventional treatment with intravenous fluid replacement and regular antiemetics has been proven to be ineffective. The suggested dose is IV hydrocortisone 100 mg twice daily, and once clinical improvement occurs conversion to oral prednisolone 40–50 mg daily, with the dose gradually tapered until the lowest maintenance dose that controls the symptoms is reached. In most cases prednisolone needs to be continued until the gestational age at which HG would have resolved and in some extreme cases, prednisolone is continued until birth.34 Women receiving corticosteroids should be screened for gestational diabetes.

There are no trials of community use of ginger for severe NVP and HG. A large cross-sectional survey of 512 women with HG found that ginger foodstuffs or over the counter tablets have little or no efficacy but caused unpleasant adverse effects and worsening of symptoms in over half (54%) of participants. Recommendations by a healthcare professional (HCP) to try ginger was found to cause a loss of trust in the HCP and damaged clinician-patient relationships. Because prior awareness and self-administration of ginger as a home remedy prior to seeking medical help was extremely high HCPs should not suggest it and doing so may delay access to effective treatment.61

5.2.2 What is the safety of the pharmacological agents used to treat NVP and HG? (See Appendix APPENDIX III)

Recommendation Evidence quality Strength Rationale for the recommendation
First line - There are safety data for antiemetics such as anti (H1) histamines, phenothiazines and pyridoxine-doxylamine (Xonvea®) and they should be prescribed initially when required for NVP and HG (Appendix III). 2++ A Cochrane review reports no increased risk of congenital malformations or other adverse pregnancy outcomes.62
Second line - There is evidence that ondansetron is safe. Its use should not be discouraged if first line antiemetics are ineffective. Women can be reassured regarding a very small increase in the absolute risk of orofacial clefting with ondansetron use in the first trimester, which should be balanced with the risks of poorly managed HG. 2++ B Absolute risk of orofacial clefting increases from a background risk of 11 cases per 10 000 births to 14 cases per 10 000 births with ondansetron (infographic from Irish Medicines in Pregnancy Service in Appendix IV).

Additional second line – Metoclopramide is safe and can be used alone or in combination with other antiemetics.

2++

B

Drug-induced extrapyramidal symptoms and oculogyric crises can occur with the use of phenothiazines and metoclopramide.
Because of the risk of extrapyramidal effects metoclopramide should be used as second-line therapy. Intravenous doses should be administered by slow bolus injection over at least 3 minutes to help minimise these. 2+ C Dystonic reactions have been shown to be significantly less common in non-pregnant patients receiving a slow infusion as opposed to a bolus injection of 10 mg of metoclopramide.
Women should be asked about previous adverse reactions to antiemetic therapies. If adverse reactions occur, there should be prompt cessation of the medications. 4 GPP Women should not be prescribed medications that have caused previous adverse reactions.

All the antiemetics discussed above can and should be used with confidence in primary and secondary care to manage women's symptoms.

A Cochrane review63, other systematic reviews and meta-analyses37, 64-66 and birth registry data37 have reported on the safety and efficacy of many antiemetics for use in NVP and HG, with no increased risk of teratogenesis or other adverse pregnancy outcomes. These drugs include: antihistamines (H1 receptor antagonists) such as promethazine, cyclizine, cinnarizine, pyridoxine-doxylamine (Xonvea®)67 and dimenhydrinate; phenothiazines including prochlorperazine, chlorpromazine and perphenazine; and dopamine antagonists including metoclopramide68 and domperidone. Because there are no clear data supporting increased efficacy of one class of antiemetic over others the suggested step wise approach (Appendix III) is based predominantly on safety data6. [Evidence level 2++]

Use of ondansetron for NVP/HG is increasing69 as is the body of literature to support no overall increased risk of congenital malformations.70-73 However, conflicting findings from large epidemiological studies (some of which have shown a small increased risk of either cardiac defects74 or orofacial clefting70) have, controversially, led to warnings from the European Medicines Authority to avoid ondansetron in the first trimester. The Medicines and Healthcare products Regulatory Agency (MHRA) did not issue a warning. The UK Teratology Information Service (UKTIS) have published a systematic review of the literature that concludes ‘currently available data do not provide evidence that ondansetron use in the first trimester of pregnancy is associated with an increase in the overall malformation rate.’73 They summarised the data for congenital malformations ‘Twelve studies, including one meta-analysis of data from seven studies, collectively including more than 97 000 unique first trimester-exposed pregnancies have assessed the overall malformation rate following maternal ondansetron use in pregnancy.70, 75-85 The majority of these studies,70, 75, 80-84 including the largest and most statistically robust (more than 88 000 first trimester exposures)70 and the meta-analysis,85 did not identify increased risks in comparison with disease-matched and/or healthy or population unexposed controls.’ [Evidence level 2++]

Two large cohort studies form the majority of the data in the meta-analysis.74, 70, 85 Although one study74 found a significant risk of cardiac defects (adjusted OR 1.43, 95% CI 1.28–1.61), the larger (1.8 million pregnancy cohort of which almost 5% [88 467 women] were exposed to ondansetron during the first trimester) study70 did not find a significant association for cardiac defects after adjusting for pre-defined confounding factors (adjusted relative risk [aRR] 0.99, 95% CI 0.93–1.06). However, a small increased risk of orofacial clefting was noted71 (aRR 1.24, 95% CI 1.03–1.48). It is important to put this into context as the background risk of orofacial clefting is low, and therefore the increase in absolute risk is small. If the increase in risk is real, then ondansetron represents an additional three oral clefts per 10 000 births (14 cases per 10 000 births with ondansetron exposure versus 11 cases per 10 000 births in the unexposed population, see Appendix IV for visual risk summary). [Evidence level 2++]

A limitation of these two cohort studies is that they compare women with severe NVP and HG taking ondansetron to women who do not have severe NVP and HG. This leaves open the possibility that any effects are confounded by indication, nor do they consider the competing risks to women with severe NVP and HG of leaving their illness poorly controlled. A study comparing women with HG taking ondansetron with women with HG taking other antiemetics found no increased risk of major malformations in the ondansetron group.86 A study85 comparing women with HG taking ondansetron vs those with HG not taking ondansetron found a higher rate of terminations of pregnancy in those not taking ondansetron and higher rate of live birth in those taking ondansetron.

Due to the risk of extrapyramidal effects with metoclopramide it should be used as second-line therapy. A review of metoclopramide,87 conducted by the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use, has confirmed the risks of short-term extrapyramidal disorders and tardive dyskinesia, particularly in young people. The review recommends metoclopramide should only be prescribed for short-term use (maximum dose of 30 mg in 24 hours or 0.5 mg/kg body weight in 24 hours [whichever is lowest] and maximum duration of 5 days) and that intravenous doses should be administered by slow bolus injection over at least 3 minutes to help minimise these risks. Dystonic reactions have been shown to be significantly less common in non-pregnant patients receiving a slow infusion as opposed to a bolus injection of 10 mg of metoclopramide.88 Notwithstanding the EMA's recommendation the authors of this guideline recommend that it can be prescribed for more than five days in those women who gain symptomatic relief from it. [Evidence level 2++]

Data confirm that corticosteroid use in the first trimester is not associated with an increase in risk of congenital malformations overall and specifically no increase in orofacial clefting, cardiac defects or hypospadias following first trimester use of corticosteroids.89 Data on corticosteroids use in the first trimester is limited to a maximum of approximately 3500 exposures, and therefore is less well studied in comparison to other anti-emetic medication. [Evidence level 2++]

5.2.3 What adverse effects can occur from NVP and HG and how can they be prevented?

Recommendation Evidence quality Strength Rationale for the recommendation
Urea and serum electrolyte levels should be checked daily in women requiring intravenous fluids. 4 GPP NVP can be associated with electrolyte imbalances.
Histamine type-2 receptor blockers or proton pump inhibitors may be used for women developing gastro-oesophageal reflux disease, oesophagitis or gastritis. 4 D

Recurrent intractable vomiting may lead to gastro-oesophageal reflux disease, oesophagitis or gastritis.

Thiamine supplementation (either oral 100 mg tds or intravenous as part of vitamin B complex (Pabrinex®)) should be given to all women admitted with vomiting, or severely reduced dietary intake, especially before administration of dextrose or parenteral nutrition. 4 D

NVP/HG can lead to Wernicke encephalopathy due to vitamin B1 (thiamine) deficiency.

Women admitted with HG should be offered thromboprophylaxis with low-molecular-weight heparin and those being managed in the community should be assessed for VTE risk (see GTG 37a). Graduated compression stockings should be used when low-molecular-weight heparin is contra-indicated (as per GTG 37a). Thromboprophylaxis can be discontinued upon discharge providing no other indications exist for continuation of thromboprophylaxis.

3

C

Women with HG have increased risk of venous thromboembolism with odds ratio 2.5 (95% CI 2–3.2).90

Women with previous or current NVP or HG should consider avoiding iron-containing preparations if these exacerbate symptoms or consider alternative route of administering iron.

4

D

Oral iron can cause nausea and vomiting and constipation.

Women should be questioned about their bowel habits and offered laxatives if constipated, and particularly if ondansetron is used. 4 GPP Women with NVP or HG commonly suffer with constipation because of reduced food and fluid intake and if treated with ondansetron.91
Women should be offered treatment with proton pump inhibitors for Gastro-oesophageal reflux. 4 GPP The treatment of gastro-oesophageal reflux, along with anti-emetic therapy, has been associated with reduced PUQE-24 scores and improved quality of life scores.92

Inability to tolerate oral fluids and excessive vomiting due to NVP and HG can affect other medical conditions requiring oral medication, such as epilepsy, psychiatric conditions, hypoadrenalism and HIV. It is vital to prescribe antiemetics for women with the above co-morbidities. Medication times may need to be adjusted so women can take them when symptoms are better controlled.

HG increases risks in some conditions such as those with diabetes mellitus, or a history of gastric band, gastric bypass and gastric sleeve surgery. Specialist advice is required for these women. A previous history of gastric reduction surgery may cause malabsorption of oral medication and increase the risk of nutrient and vitamin deficiency, particularly thiamine and vitamin K.

In women requiring intravenous fluids, daily monitoring of fluid and serum electrolyte levels is important to recognise and treat hyponatraemia and hypokalaemia.34, 93

Oesophago-gastroduodenoscopy is safe in pregnancy and indicated in cases of haematemesis or severe epigastric pain. A therapeutic trial with a proton pump inhibitor is appropriate for treatment and prevention and is safe in pregnancy.94, 95

Wernicke encephalopathy due to vitamin B1 (thiamine) deficiency classically presents with blurred vision, unsteadiness and confusion/memory problems/drowsiness and on examination there is usually nystagmus, ophthalmoplegia, hyporeflexia or areflexia, gait and/or finger–nose ataxia. In HG, the presentation tends to be episodic and of slow onset. Wernicke encephalopathy is a potentially fatal medical emergency. In the context of HG, it is preventable and studies have stressed the association between Wernicke encephalopathy and administration of intravenous dextrose and parenteral nutrition.96 A systematic review of 177 cases found that chronic cognitive disorders occurred in 65.4%, pregnancy loss in 50%, and maternal death in 5% of cases.96 Therefore thiamine supplementation is recommended for all women admitted with HG. [Evidence level 2++]

A Canadian study97 using hospital discharge data found an adjusted odds ratio for deep vein thrombosis of 4.4 (95% CI 2.4–8.4) in women with HG. However, since women with HG are only at markedly increased risk while persistently vomiting, thromboprophylaxis can be discontinued at discharge or when the HG resolves.98

In a Canadian prospective cohort study, two-thirds of 97 women who discontinued iron supplements reported improvement in their severity of NVP.99

6 HOW SHOULD WOMEN WITH NVP AND HG BE OFFERED ONGOING ANTENATAL CARE?

Recommendation Evidence quality Strength Rationale for the recommendation

Women should only be discharged once

  • appropriate antiemetic therapy has been tolerated
  • adequate oral nutrition and hydration has been tolerated
  • management of concurrent conditions is completed

4 GPP

Failure to ensure this will increase the chance of readmission.

At the time of discharge, it is essential that women are advised to continue with their antiemetics where appropriate and that they know how to access further care. 4 D Continued treatment may reduce the need for hospital readmission.
Women with severe NVP or HG who have continued symptoms into the late second or the third trimester should be offered serial scans to monitor fetal growth. 2+ B Women with low pregnancy weight gain are at increased risk of preterm birth and low birth weight.

Almost one third of women will be readmitted within the same pregnancy.100 Therefore, at the time of discharge it is essential that women are advised to continue with their antiemetics where appropriate and that they know how to access further care if their symptoms and/or signs recur (e.g. persistent vomiting, dehydration). Rehydration and a review of antiemetic treatment should ideally be undertaken in an ambulatory day care setting.101 Better communication and advice about the safety of antiemetics may enable general practitioners to adequately support women with HG.101, 102 [Evidence level 2–]

Level of ketones should not be used to inform clinical decision making about treatments or hydration status.27 [Evidence level 2+]

An observational study has shown that women with HG and low pregnancy weight gain (less than 7 kg during pregnancy) are at an increased risk of preterm birth (aRR 3.0, 95% CI 1.9–4.3) and low birthweight (less than 2500g; aRR 2.8, 95% CI 1.7–4.3).103 [Evidence level 2+]

A population-based cohort study using secondary healthcare records demonstrated that HG was significantly associated with low birthweight (OR 1.12, 99% CI 1.08–1.17), small-for-gestational-age (OR 1.06, 99% CI 1.01–1.11) babies, and babies more likely to undergo resuscitation or intensive care treatment, albeit with small absolute risk.104 The Cambridge Baby Growth Study also found that vomiting during the first and second trimesters of pregnancy was associated with a higher risk of low birthweight (OR 3.5 95% CI 1.2–10.8 P = 0.03) even when vomiting was not perceived to be severe enough to warrant treatment.105 [Evidence level 2+]

6.1 What are optimal rehydration regimens for ambulatory and inpatient care?

Recommendation Evidence quality Strength Rationale for the recommendation
Normal saline (0.9% NaCl) with additional potassium chloride in each bag, with administration guided by daily monitoring of electrolytes, is the most appropriate intravenous hydration. 3 C There is no evidence to determine which fluid regimen is most appropriate but given that most women admitted to hospital with HG are hyponatraemic, hypochloraemic and hypokalaemic, it seems appropriate to use normal saline (0.9% NaCl) and potassium chloride.

The use of dextrose infusions for fluid replacement in NVP and HG is not recommended.

4 D Intravenous fluid and electrolyte replacement is likely to be the most important intervention in the treatment of those requiring ambulatory or inpatient care for NVP. General guidance on fluid management in adults can be found in NICE Clinical Guideline 174.106 Dextrose-containing solutions may precipitate Wernicke encephalopathy in thiamine deficient states.

The most important intervention is likely to be appropriate intravenous fluid and electrolyte replacement. General adult fluid management guidance can be found in NICE Clinical Guideline 174.106 IV fluids have been shown to reduce vomiting and are therefore valuable for both outpatient and inpatient management of the symptoms of HG and severe NVP as well as associated dehydration and electrolyte disorders. Women in the placebo arm of controlled trials for NVP demonstrated a significant improvement in nausea with supportive treatment including IV fluids without antiemetics107, 108.

Dextrose-containing solutions can precipitate Wernicke encephalopathy in thiamine-deficient states (see section 7.1); hence, they should be avoided, and high (e.g. 100 mg) doses of parenteral thiamine should be given to prevent Wernicke encephalopathy. Dextrose containing fluids are appropriate for nausea and vomiting in the third trimester to prevent and treat starvation ketosis.109 [Evidence level 3]

6.2 What is the effect of NVP and HG on the quality of life of the woman and family?

Recommendation Evidence quality Strength Rationale for the recommendation

A woman's quality of life can be adversely affected by NVP and HG and practitioners should assess the severity of a woman's symptoms in relation to her quality of life and social situation.

2– C NVP has been reported to reduce quality of life, impairing a woman's ability to function on a day-to-day basis, and negatively affects relationships with her partner and family.

Practitioners should carry out a full assessment of both physical and mental health status during the pregnancy and refer for psychological support if necessary.

2+ C

Depressive symptoms and poor mental health are associated with severity of NVP.

Acknowledgement by healthcare professionals of the effect of these physical symptoms on patients’ mental health is likely to lead to an improved patient experience.

Pre-existing mental health conditions may be exacerbated by HG particularly where prescribed oral medications are not being taken or kept down because of vomiting, therefore consideration to alternative routes of administration, proactive use of antiemetics and appropriate referrals should be considered.

Information about patient support groups should be provided to all women admitted with nausea and vomiting in pregnancy.

4

4

GPP

GPP

Many women and their partners find support groups (e.g. Pregnancy Sickness Support) online or in person extremely helpful.

6.2.1 Effect of HG on daily functioning

NVP has been reported to reduce quality of life, impairing a woman's ability to function on a day-to-day basis, and negatively affects relationships with her partner and family.110-130 Women with HG are three to six times more likely than women with NVP to have low quality of life.24 Constant nausea is the symptom that most adversely affects quality of life.118, 131 Furthermore, causes of stress as a consequence of NVP include lack of understanding and support, inability to eat healthily, regret for the loss of a positive pregnancy experience, financial pressures, absence from work, isolation, inability to care for family, others’ belief that it is psychosomatic and perception that doctors are reluctant to provide treatment.112, 132, 133 Perceived stress positively correlated with NVP and negatively correlated with social support in a cross-sectional study of 243 women.134 It has been recommended that social support is necessary as an adjunct to treatment and the circle of support should be expanded to include family, friends and healthcare professionals.135 A cohort study of 648 women found that having support from at least three other persons was protective in women with NVP.112 [Evidence level 2–]

Information about patient support groups (e.g. Pregnancy Sickness Support) should be provided as many women and their partners find this form of support helpful.136-138 [Evidence level 4]

A follow-up appointment for antenatal care is important in women with HG. Psychological and social support should be organised depending upon the clinical and social circumstances. [Evidence level 4]

6.2.2 Effect of HG on mental health

The erroneous belief in the psychogenic aetiology of HG is still prevalent among healthcare professionals137, 139-143 and such attitudes towards women contribute to a worse experience for NVP and HG sufferers.137, 140, 143-145 Women often struggle to obtain treatment for NVP and HG, are dissatisfied with communication during their appointments and found healthcare professionals dismissive and unsympathetic.143, 146-149 A cohort study of 808 women demonstrated that women who feel that their healthcare professional is unsympathetic report more depression and anxiety.140 A review paper recommends an integrated approach which addresses both physical and psychological suffering in HG.150 The theory of psychogenic aetiology proposed by Fairweather has been severely criticised for poor methodology and bias.97, 151-153 Studies have failed to find a convincing association between a prior history of psychological poor health and having HG.154-160 Similarly, these suggest that poor mental health can be exacerbated by HG rather than being caused by it.114, 139, 144, 150, 157, 160-163 [Evidence level 2+]

Depressive symptoms and poor mental health are associated with severity of NVP.164, 165 Poor psychological health of women with HG is considered as the demoralisation of suffering from a prolonged, severe chronic illness and in this regard it is similar to mental health problems suffered in other chronic illnesses.140 [Evidence level 2+]

Pre-existing mental health conditions may be exacerbated by HG particularly where prescribed oral medications are not being taken or kept down due to vomiting, therefore consideration to alternative routes of administration, aggressive use of antiemetics and appropriate referrals should be considered. [Evidence level 4]

Clinical assessment should be considered for depression, anxiety and postnatal depression with appropriate referral. Depression and poor psychological health have been found to be associated with NVP and HG in numerous studies,112, 113, 130, 144, 154-157, 161, 164-169 including a systematic review and meta-analysis, but resulted from the disease and were not the cause of HG or NVP.126 A UK wide survey of 5071 participants found a quarter of those suffering HG occasionally reported suicidal ideation and 6.6% regularly considered suicide due to the severity of the condition, 4.9% had a termination of pregnancy (TOP) due to HG and 52.1% considered TOP due to HG. Both suicidal ideation and TOP of a wanted pregnancy were associated with perceived poor care from their healthcare providers. Those reporting extremely poor perception of both primary and secondary care were less likely to have been offered medication compared with those reporting excellent care.170 [Evidence level 2++]

A cohort study of 648 women found that symptoms of major depression are associated with moderate and severe NVP but prior history of depression is not a determinant.112, 162 [Evidence level 2–]

Poor mental health can persist post-partum and HG is a risk factor for postpartum PTSD.169, 171, 172 [Evidence level 2+]

Pregnancy sickness specific counselling may be helpful either during or after pregnancy.173 Measures that address NVP, poor social support and depression are warranted throughout pregnancy.112 A prospective cohort study of 367 women suggests that practitioners could improve their management of NVP by addressing symptoms and life situation.115 [Evidence level 3]

7 HOW SHOULD WOMEN WITH NVP AND HG BE CARED FOR WHEN STANDARD TREATMENT MEASURES DO NOT CONTROL SYMPTOMS OF NAUSEA AND VOMITING?

7.1 What is the role of the multidisciplinary team?

Recommendation Evidence quality Strength Rationale for the recommendation
In women with severe NVP or HG, input should be sought from other allied professionals. 4 D There are many facets to severe NVP and HG and a holistic approach to assessment and treatment should be adopted.

Involvement of the mental health team in the woman's care may improve quality of life and the ability to cope with the impact of a complicated pregnancy.110 Emotional support and psychological or psychiatric care may be required126, 174 with targeted interventions specifically designed to treat mental health issues occurring as a result of HG.154, 161, 175, 176 [Evidence level 2–]

Dieticians should be consulted regarding the role of nutritional support. Oral nutritional supplements may supplement an inadequate food intake or provide a more balanced nutritional intake where women are only able to tolerate a limited range of foods. All care should be holistic and culturally sensitive particularly in those with multimorbidity, social deprivation and other marginalised groups.

7.2 When should enteral and parenteral nutrition be considered and what are the risks to the woman and fetus?

Recommendation Evidence quality Strength Rationale for the recommendation
When all other medical therapies have failed to sufficiently manage symptoms, enteral tube feeding or parenteral treatment should be considered with a referral to gastroenterology and a multidisciplinary approach in parallel to ongoing medical therapies. 3 D Total parenteral nutrition is a high-risk intervention; however, it may be useful in refractory cases to ensure sufficient nutritional intake.

Parenteral nutrition should only be considered as a multidisciplinary approach when all other treatments have failed to sufficiently control symptoms as it is inconvenient, expensive and can be associated with serious complications such as thrombosis, metabolic disturbances and infection.177, 178 A single nonrandomised study has shown that total parenteral nutrition (TPN) was associated with a decreased risk of perinatal morbidity compared with those with HG who did not receive TPN.179 [Evidence level 2+]

There are no defined criteria for starting parenteral or enteral tube feeding. Their effectiveness is not well established. Anecdotally, they can be effective and are often employed as a last resort when all other medical therapy has failed and the only other practical option is TOP.180, 181 Close monitoring of metabolic and electrolyte balance, related complications (including refeeding syndrome)182 and nutritional requirements are needed with a multidisciplinary approach. [Evidence level 2–]

Enteral tube feeding options to consider include nasogastric, nasoduodenal or nasojejunal tubes, or percutaneous endoscopic gastrostomy or gastrojejunostomy feeding, all of which should only be considered in consultation with gastroenterology and with a multidisciplinary approach. Parenteral feeding with a peripherally inserted central catheter (PICC line) is often better tolerated than enteral feeding; however, it carries a higher risk of infection and vascular complications.183 [Evidence level 2+]

In some women, feeding by nasogastric or percutaneous endoscopic gastrostomy tube increases the risk of nausea and vomiting. It may be tolerated in the short term but not in protracted HG.184 A recent randomised controlled trial recruited 116 women hospitalised for HG between 5 and 20 weeks and allocated them to either enteral (nasogastric) tube feeding (n=59) or standard care (n=57). Outcomes did not differ between the groups and adherence to protocol was low due to adverse effects in the enteral tube feeding arm. Many women could not tolerate tube feeding due to discomfort suggesting it is poorly tolerated as an early routine treatment. [Evidence level 2+]

In nasojejunal feeding, the tube is inserted endoscopically or under radiological guidance to the jejunum and feeding can be administered by a continuous infusion. One study showed that although the majority of women improved greatly within 48 hours, ongoing vomiting and retching can dislodge gastric and postpyloric feeding tubes.184 [Evidence level 3]

Feeding via a percutaneous endoscopic gastrojejunostomy (PEG-J), placed under general anaesthetic in the second trimester,185-187 has been shown to be an effective, safe and well-tolerated treatment of HG. In the majority of women, the tube is removed after birth. The risk of early dislodgement is minimised compared with nasoenteric placement.187 Potential complications of percutaneous endoscopic gastrojejunostomy include tube dislodgement, obstruction or migration, cutaneous or intra-abdominal abscesses, fistula formation, pneumatosis, occlusion and intestinal ischaemia. [Evidence level 2+]

7.3 When should termination of pregnancy be discussed?

Recommendation Evidence quality Strength Rationale for the recommendation
All therapeutic measures should have been offered before considering termination of pregnancy. 2– C HG is associated with a higher risk of termination of pregnancy. As many as 10% of women with HG undergo termination of pregnancy due to the severity of symptoms, who would not otherwise have chosen to.188

Around 10% of women with HG will terminate a wanted pregnancy, due to the condition.137, 170 Pregnancy Sickness Support in the UK found that many of these women have not been offered the full range of treatments available and fewer than 10% had been offered steroids.188 [Evidence level 2–]

Treatment options of antiemetics, corticosteroids, enteral tube and parenteral feeding, and correction of electrolyte or metabolic disturbances should be considered before deciding that the only option is TOP.189, 190 Consider seeking psychiatric opinion if there are concerns regarding mental health, and the decision for TOP needs to be multidisciplinary, with documentation of therapeutic failure if this is the reason for the termination. Women should be offered counselling before and after a decision of pregnancy termination is made. [Evidence level 2–]

In a survey of 808 women who had TOP secondary to HG, 123 (15.2%) had at least one termination due to HG, and 49 (6.1%) had multiple terminations.190 Common reasons given for the terminations were inability to care for the family and self (66.7%), fear that they and their baby could die (51.2%), or that the baby would be abnormal (22%). In one study, women who underwent a pregnancy termination were more likely to report a negative attitude from their caregiver. Initiation of a prompt and responsive treatment plan may reduce this.180 Rarely, HG or its treatment may lead to life-threatening illness and TOP is seen as the only option.96, 191 [Evidence level 4]

8 WHAT ARE THE LONG-TERM EFFECTS OF NVP AND HG?

8.1 What are the long-term effects of NVP and HG on women?

Recommendation Evidence quality Strength Rationale for the recommendation

There is no evidence of significant impact on long-term all-cause mortality.

2++

B

In a large population cohort study from Norway, HG was not associated with an increased risk of long-term all-cause mortality.192

Women who experience HG in pregnancy are at increased risk of PND, anxiety and PTSD postpartum.

2++ B

Systematic review has shown a significantly increased risk of depression and anxiety in women with HG which extended into the postnatal period.126 A subsequent two-point case control study demonstrated long-lasting psychological morbidity associated with HG.169

Women with previous HG should be advised that there is a risk of recurrence in future pregnancies. 2++ B The reported rates of recurrence varied from 15% to 81%.

Women who experience HG in pregnancy are at increased risk of postnatal depression (PND), anxiety and post-traumatic stress disorder (PTSD) postpartum.126 [Evidence level 2++]

Symptoms of NVP and HG should resolve rapidly after the birth. Where symptoms do not resolve further investigation should occur with referrals to endocrinology and gastroenterology as appropriate. Case reports have highlighted hyperparathyroidism as a potential differential diagnosis for HG which does not resolve postnatally.193 [Evidence level 4]

A systematic review published in 2019 found five eligible studies reporting on 40 350 women with HG which investigated the chance of recurrence of HG in subsequent pregnancies.7 The quality of the five studies was low and meta-analysis was not possible due to clinical and statistical heterogeneity. The reported rates of recurrence varied from 15% to 81%. The paper concluded that a prospective longitudinal cohort study using an agreed definition of HG and outcomes meaningful to patients is required to establish the true recurrence rate of HG.9 [Evidence level 2++]

8.2 What are the long-term effects of NVP and HG on the infant and child?

Mild-moderate NVP does not appear to have a negative long-term effect on the developing fetus and may have a protective effect for the pregnancy.194 [Evidence level 2+]

In contrast a recent systematic review and meta-analysis of nineteen studies with 619 cases showed an association with a small increase in adverse health outcomes of children born to women who had suffered with HG.195 A recent meta-analysis suggested a small increase in the risk of certain adverse health outcomes in infants born to women who suffered with HG including anxiety disorder, testicular cancer (aged up to 40 years), attention deficit hyperactivity disorder and autism, however there was considerable heterogeneity between individual studies. [Evidence level 2–]

8.3 What advice should be given about future pregnancies?

Recommendation Evidence quality Strength Rationale for the recommendation
Early use of lifestyle/dietary modifications and antiemetics that were useful in the index pregnancy is advisable to reduce the risk of NVP and HG in the current pregnancy. 2+ B There is a lower recurrence risk with pre-emptive antiemetics before symptoms begin.

The self-reported recurrence risk of HG is extremely high (89%).6-9

A Canadian study comparing women with NVP (PUQE score of 13 and above) who took pre-emptive antiemetics before pregnancy or before the onset of symptoms with those who did not, reported a lower recurrence rate of HG in the group that took pre-emptive antiemetics.111 There was also a significant improvement in the PUQE score of NVP severity compared with the previous pregnancy in the pre-emptive group. Women who have experienced severe NVP in a previous pregnancy may benefit from initiating dietary and lifestyle changes, such as arranging childcare to facilitate rest and adjusting to a “little and often” diet, and commencing antiemetics before or immediately at the start of symptoms in a subsequent pregnancy.111 [Evidence level 2++]

A small randomised study in women with previous NVP demonstrated that pre-emptive treatment with antiemetics resulted in fewer women with moderate to severe NVP.196 [Evidence level 2++]

Women who have experienced HG in two or more pregnancies reported that earlier use of antiemetics was a factor in reducing the number of hospital admissions they had in the second pregnancy.149 [Evidence level 3]

9 RECOMMENDATIONS FOR FUTURE RESEARCH

A James Lind Alliance Priority Setting Partnership has reported 26 priorities for research.197 Recommendations based on this guideline are:
  • To establish optimum dose and route of administration for ondansetron to maximise efficacy with the least adverse effects
  • To evaluate the feasibility, cost efficiency and patient satisfaction of community/home based rehydration treatment
  • To establish the most effective combinations of therapies to maximise efficacy with the least adverse effects
  • To develop and assess interventions to reduce the risk of negative psychological outcomes
  • To evaluate the effect of pre-emptive intervention on the severity and duration of symptoms in subsequent pregnancies
  • To explore the effect of socioeconomic factors and ethnicity on access to appropriate care and management of HG

All future research should use the Core Outcome Set for Hyperemesis Gravidarum research.197

10 AUDITABLE TOPICS

  • Percentage of women with access to recommended first and second line antiemetic HG treatment (100%)
  • Percentage of women prescribed appropriate rehydration regimes and VTE risk assessment (100%)
  • Service evaluation – incidence of termination of wanted pregnancy due to NVP/HG

11 USEFUL LINKS AND SUPPORT GROUPS

FUNDING INFORMATION

All those involved in the development of the Green-top Guidelines, including the Guidelines Committee, Guidelines Committee co-chairs, guideline developers, peer reviewers and other reviewers, are unpaid volunteers and receive no direct funding for their work in producing the guideline. The exception to this are the RCOG staff involved who are salaried employees of the College and Guidelines Committee members who receive reimbursement for expenses for attending Guidelines Committee meetings. Please see more information on travel expense rules on the RCOG website.

CONFLICT OF INTEREST STATEMENT

CNP reports payment from UCB (manufacturer of Cimzia®) for advisory board participation, and speaker and chairing fees from Sanofi and UCB. MS reports speaker fees from Alliance Healthcare. RG is Trustee and Treasurer at Pregnancy Sickness Support, and reports a consultancy fee from Exeltis. MN has been supported by an NIHR-funded research training fellowship, and reports speaker fees from Exceltis. CD, MOH and KH have declared no conflicts of interests. Full disclosures of interest for the Guidelines Committee and peer reviewers are available to view online as supporting information.

APPENDIX I: : Explanation of guidelines and evidence levels

Clinical guidelines are ‘systematically developed statements which assist clinicians and patients in making decisions about appropriate treatment for specific conditions’. Each guideline is systematically developed using a standardised methodology. Exact details of this process can be found in the RCOG handbook Developing a Green-top Guideline: Guidance for developers. These recommendations are not intended to dictate an exclusive course of management or treatment. They must be evaluated with reference to individual patient needs, resources and limitations unique to the institution and variations in local populations. It is hoped that this process of local ownership will help to incorporate these guidelines into routine practice. Attention is drawn to areas of clinical uncertainty where further research may be indicated.

The evidence used in this guideline was graded using the scheme below and the recommendations formulated in a similar fashion with a standardised grading scheme.

Classification of evidence levels

1++ High-quality meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a very low risk of bias
1+ Well-conducted meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a low risk of bias
1– Meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a high risk of bias
2++

High-quality systematic reviews of case–control or cohort studies or high-quality case–control or cohort studies with a very low risk of confounding, bias or chance and a high probability that the relationship is causal

2+

Well-conducted case–control or cohort studies with a low risk of confounding, bias or chance and a moderate probability that the relationship is causal

2–

Case–control or cohort studies with a high risk of confounding, bias or chance and a significant risk that the relationship is not causal

3 Non-analytical studies, e.g. case reports, case series
4 Expert opinion

Grades of Recommendation

A At least one meta-analysis, systematic reviews or RCT rated as 1++, and directly applicable to the target population; or a systematic review of RCTs or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population and demonstrating overall consistency of results
B A body of evidence including studies rated as 2++ directly applicable to the target population, and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 1++ or 1+
C A body of evidence including studies rated as 2+ directly applicable to the target population, and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 2++
D

Evidence level 3 or 4; or Extrapolated evidence from studies rated as 2+

Good Practice Points

GPP Recommended best practice based on the clinical experience of the guideline development group.

APPENDIX IIa: : Pregnancy-Unique Quantification of Emesis (PUQE) index

Total score is sum of replies to each of the three questions. PUQE-24 Score: Mild 6; Moderate = 7–12; Severe = 13–15.

Motherisk PUQE-24 scoring system
In the last 24 hours, for how long have you felt nauseated or sick to your stomach? Not at all (1) 1 hour or less (2) 2–3 hours (3) 4–6 hours (4) More than 6 hours (5)
In the last 24 hours have you vomited or thrown up? I did not throw up (1)

1–2 times (2)

3–4 times (3) 5–6 times (4) 7 or more times (5)
In the last 24 hours how many times have you had retching or dry heaves without bringing anything up? No time (1) 1–2 times (2) 3–4 times (3) 5–6 times (4) 7 or more times (5)
PUQE-24 Score: Mild 6; Moderate = 7–12; Severe = 13–15.

How many hours have you slept out of 24 hours? Why?

On a scale of 0 to 10, how would you rate your wellbeing?

0 (worst possible) 10 (The best you felt before pregnancy)

Can you tell me what causes you to feel that way?

APPENDIX IIb:: HELP (HyperEmesis Level Prediction Score)

APPENDIX III: : Recommended antiemetic therapies and dosages

Recommended antiemetic therapies and dosages

First line

Doxylamine and Pyridoxine (vitamin B6) 20/20mg PO at night, increase to additional 10/10 mg in morning and 10/10mg at lunchtime if required.

Cyclizine 50 mg PO, IM or IV 8 hourly

Prochlorperazine 5–10 mg 6–8 hourly PO (or 3 mg buccal); 12.5 mg 8 hourly IM/IV; 25 mg PR daily

Promethazine 12.5–25 mg 4–8 hourly PO, IM or IV

Chlorpromazine 10–25 mg 4–6 hourly PO, IM or IV

Second line

Metoclopramide 5–10 mg 8 hourly PO, IV/IM/SC

Domperidone 10 mg 8 hourly PO; 30 mg 12 hourly PR

Ondansetron 4 mg 8 hourly or 8 mg 12 hourly PO; 8 mg over 15 minutes 12 hourly IV; 16 mg daily PR

(Women taking ondansetron may require laxatives if constipation develops)

Third line

Hydrocortisone 100 mg twice daily IV and once clinical improvement occurs, convert to prednisolone 40–50 mg daily PO, with the dose gradually tapered (by 5-10 mg per week) until the lowest maintenance dose that controls the symptoms is reached

(Corticosteroids should be reserved for cases where standard therapies have failed; when initiated they should be prescribed in addition to previously started effective antiemetics. Women taking corticosteroids should have their blood pressure monitored and a screen for diabetes mellitus)

IM intramuscular; IV intravenous; PO by mouth; PR by rectum.

APPENDIX IV: :198

Visual risk summary

APPENDIX V: : Treatment algorithms for NVP and HG in primary care (Vai and ii), ambulatory care (Vb), emergency department (Vc) and inpatient care (Vd)

This guideline was produced on behalf of the Royal College of Obstetricians and Gynaecologists by:

Professor C Nelson-Piercy FRCP FRCOG, London; Dr C Dean PhD, Patient Representative (Pregnancy Sickness Support); Dr M Shehmar FRCOG, Birmingham; Dr R Gadsby, Coventry; Ms M O'Hara, Patient Representative (Pregnancy Sickness Support); Dr K Hodson FRCGP, Newcastle Upon Tyne; Dr M Nana, MRCP. NIHR clinical research fellow and obstetric medicine registrar, King’s College London.

Acknowledgement Dr Gemma Holder MRCP (neonatalogy), Dr Ziva Mrevlje (enteral nutrition) and Dr Amanda Farrow (emergency medicine) for their invaluable help.

The following organisations have endorsed this guideline:Royal College of Emergency Medicine (RCEM); Association of Early Pregnancy Units (AEPU); and General Practitioners Championing Perinatal Care (GPCPC); and it has been supported by the Royal College of General Practitioners (RCGP).

The following organisations and individuals submitted comments at peer review:

R Buabeng, HG Support for All; A Burnett, Black Baby Loss Awareness Week; E M Crookes, RCOG Women's Network; S Elbeshbeshy MRCOG, Diametta Egypt; M Fejzo, Los Angeles USA; B Goulden MRCP, London; S Ibuanokpe, London; G Kumar FRCOG, London; B Laverick, MRCOG; S Lowe FRACP, Sydney Australia; K Maslin British Dietetic Association Maternal and Fertility Nutrition Group; D Montague-Coast Fair Treatment for the Women of Wales (FTWW); M Mouyis FRCP, Luton and Dunstable University Hospital; F Nyazika, Liverpool; D Ofili-Yebovi MRCOG, London; M Pilling MRCOG; P Prinja, Royal Wolverhampton NHS Trust; J Ross FRCOG, London; L Salmon Pregnancy Sickness Support; A Self MRCOG, West Midlands; J Shakespeare FRCGP, General Practitioners championing Perinatal Care (GPCPC); V Sudhakar, Kettering General Hospital NHS Foundation Trust.

Committee lead reviewers were: Dr M Annappa FRCOG1, Lincolnshire; Dr L Knight MRCOG, Exeter3; Dr P Timmons MRCOG, Norwich2; Dr M Savvidou FRCOG, London4

1 Until June 2021 2 From June 2021 3Until June 2023 4From June 2023

The chairs of the Guidelines Committee were: Dr MA Ledingham MRCOG, Glasgow3; Dr B Magowan FRCOG, Melrose3; Mr A McKelvey FROCG, Norwich4 and Dr N Potdar FRCOG, Leicester4.

3until June 2019, 4from June 2019

The final version is the responsibility of the Guidelines Committee of the RCOG.

The review process will commence in 2027, unless otherwise indicated.

DISCLAIMER

The Royal College of Obstetricians and Gynaecologists produces guidelines as an educational aid to good clinical practice. They present recognised methods and techniques of clinical practice, based on published evidence, for consideration by obstetricians and gynaecologists and other relevant health professionals. The ultimate judgement regarding a particular clinical procedure or treatment plan must be made by the doctor or other attendant in the light of clinical data presented by the patient and the diagnostic and treatment options available.

This means that RCOG Guidelines are unlike protocols or guidelines issued by employers, as they are not intended to be prescriptive directions defining a single course of management. Departure from the local prescriptive protocols or guidelines should be fully documented in the patient's case notes at the time the relevant decision is taken.