Hyperemesis Gravidarum DRAFT

Overview

Guidelines

• BNSSG - nausea and Vomiting in Pregnancy pathway - produced by Dr Yusra Khan (GP and Chair of the Medical Advisory Board of Pregnancy Sickness Support) and reviewed by Dr Cressida Bond (NBT Gynaecology Consultant) and Dr Abigail Oliver (Consultant Obstetrician and Gynaecologist St Michael’s Hill Hospital, Bristol). 
• RCOG Green-top No.69 guideline on Nausea and Vomiting in pregnancy and Hyperemesis Gravidarum should be referred to for further information.

The aetiology of NVP and HG has recently been discovered to be related to hypersensitivity to the vomiting hormone Growth Differentiation Factor 15 (GDF-15), previously this was thought to be associated with rising levels of hCG.

Nausea and Vomiting in Pregnancy (NVP)

NVP affects 90% of pregnancies^1. 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. Symptoms typically start between week 4 and 7 and can be graded as mild, moderate or severe. 

Hyperemesis Gravidarum (HG)

HG affects 0.3 - 3.6% of pregnancies^2. HG should be diagnosed when the nausea and/or vomiting is severe, begins before 16 weeks gestation, there is an inability to eat and drink normally and daily living activities are significantly limited³. 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 with the aim of achieving an improved recognition and diagnosis of HG.

Other Causes of Nausea and Vomiting in pregnancy.

If the onset of nausea and vomiting is in the 3rd trimester / postpartum period then please consider more serious conditions such as pre-eclampsia, HELLP or acute fatty liver of pregnancy.

Assessment in primary care

Please see the full BNSSG Nausea and Vomiting in Pregnancy pathway

PUQE - for assessment of NVP

The  Pregnancy-Unique Quantification of Emesis [PUQE] score can be used to determine whether the NVP is mild, moderate or severe⁴. 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^5.

Motherisk PUQE-24 Scoring system⁴

• 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?
• PUQE-24 score: Mild ≤ 6, Moderate = 7-12, Severe = 13-15 

HELP (HyperEmesis Level Prediction) score - for assessment of HG

HELP can be used 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.⁶

Urine and Blood tests are not required in primary care to guide need for admission

• Ketones - Urine dipstick test for ketones should not be used to diagnose or guide the management of NVP or HG.  Ketones reflect the catabolism of adipose tissue stores secondary to prolonged starvation rather than dehydration. A systematic review and meta-analysis found no correlation between the grade of ketonuria and the severity of HG⁷. Only a minority of patients with HG will actually have ketones. The diagnosis of dehydration should be based on history and examination not a urine dipstick test.
• A urine dipstick test should only be used if a UTI, DKA or pre-eclampsia is suspected.
• Blood tests do not need to be performed in primary care to guide need for admission.

Differential Diagnosis of vomiting in pregnancy

• Pregnancy related - NVP, HG, gestations trophoblastic disease, multiple pregnancy, acute fatty liver disease in pregnancy (AFLD)
• Gastrointestinal - pancreatitis, reflux oesophagitis, peptic ulcer, gastroenteritis, bowel obstruction, hepatitis, appendicitis, food intolerance.
• Urinary tract - UTI, calculi
• Metabolic - hypercalcaemia, Addison's disease, hyperparathyroidism, DKA
• Central Nervous System - migraine, raised intracranial pressure, Wernicke's encephalopathy
• ENT - labyrinthitis, Meniere's disease.
• Drug related - iron, opioids
• Psychosocial - eating disorder, social vulnerability.

Red Flags

Consider inpatient management via Gynaecology on call team (NBT) or Gynae registrar (St Michael's) with at least one of the following:

• Continued N&V and inability to keep down oral antiemetics, clinical dehydration and unsuccessful ambulatory care
• Any PUQE score and complications
• Continued N&V associated with weight loss (>5% body weight), despite oral antiemetics
• Confirmed or suspected comorbidity such as urinary tract infection with inability to tolerate oral antibiotics
• Comorbidity (epilepsy, diabetes mellitus, HIV, psychiatric disorders, hypoadrenalism) and unable to tolerate oral intake and medication hence could present with further complications.

Advise all women with nausea and vomiting in pregnancy to seek urgent medical advice if they experience:

• Very dark urine, or no urination for more than 8 hours
• Abdominal pain or fever
• Severe weakness or feeling faint
• Vomiting blood
• Repeated, unstoppable vomiting
• Inability to keep down food or fluids for 24 hours despite oral antiemetics
• Severe headache, visual problems, severe epigastric pain, sudden swelling of the face, hands, or feet (symptoms of pre-eclampsia). 

If there are concerns that NVP/HG is having adverse consequences on the woman's mental health, consider discussion with or referral to Perinatal mental health services.

Referral

Assess and treat in primary care initially, following local guidelines on management in the Before Referral section below. If red flags have been excluded (see above) but secondary care management is still required then consider discussion with your local on call gynaecology team for ambulatory day care management in any of the following circumstances: 

St Michaels Hospital

The Ambulatory Hyperemesis Clinic is suitable for patients who are unable to tolerate oral antiemetics or fluids and are dehydrated.

The clinic is based on ward 78, St Michaels Hospital, Monday - Friday from 10am. It is run by the on-call team and referrals should be made to the gynaecology registrar.

• Referrals are accepted from GPs, midwives, EPC, ED and SWASFT
• Patients known to the service may call ward 78 if their symptoms recur and these should be triaged by the gynaecology registrar
• Referrals are accepted until 12pm, after which the patient will require either ward admission or an appointment for the following day. Please consider whether the patient can safely attend the following day and avoid an overnight stay

NBT

Patients requiring referral to the ambulatory day care unit or consideration for inpatient admission should be referred via the Gynaecology SHO. Referral ideally before midday is advised.

Before Referral

Management in Primary Care

Women with mild to moderate NVP (PUQE score 3-12) who are able to tolerate anti-emetics and maintain hydration should be managed in primary care. These cases are not associated with physical risks for the mother or foetus in the first trimester and often drug treatment is not required; advice on lifestyle measures can suffice.

GPs should not offer lifestyle advice as the mainstay of HG or severe NVP treatment, but rather as a means of preventing exacerbation of symptoms.

Lifestyle measures

• Rest
• Ginger -  encouraging patients with HG to use a ‘morning sickness’ cure, such as crackers or ginger, is inappropriate. Ginger is a therapeutic option for women with mild-to-moderate NVP, which is commonly improved by dietary changes.
• Acupressure and electrical stimulation - may have some benefit in alleviating nausea but less so vomiting.¹⁰
• Other complimentary therapies - there is no evidence of benefit from complementary therapies such as acupuncture or hypnosis in HG.¹¹

Anti-emetics

Anti-emetic treatment is definitely required for severe NVP and HG. Anti-emetics may not cure the symptoms but can palliate them until natural improvement occurs.

Please see the NVP Anti-emetic table for a step wise approach to medication. More detailed advice is also available in the Resources section below.

Other pharmacological treatments

Consider the need for: 

• Omeprazole/H2 receptor antagonists
• Laxatives-  patients commonly suffer from constipation with anti-emetics particularly Ondansetron.
• Thiamine - (100mg TDS) to prevent Wernicke’s encephalopathy in all women with prolonged vomiting > 3 weeks/severely reduced dietary intake. 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.
• Oral nutritional supplements - may supplement an inadequate food intake however may not be tolerated.
• Steroids - discuss with antenatal team if symptoms are not controlled on maximal anti-emetics and they remain dehydrated or there is continued weight loss. See further notes in resource section.

Psychological Support

NVP and HG can have profound psychosocial effects on women and their families. A UK wide survey of 5071 participants found a quarter of those suffering HG occasionally reported suicidal ideation and 6.6% frequently 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 of these awful outcomes were associated with perceived poor care from their healthcare providers²⁷. Around 10% of women with HG will terminate a wanted pregnancy²⁸ due to the condition. Pregnancy Sickness Support found that most of these women had not been offered the full range of treatments available with less than 10% being offered steroids.²⁹

Evidence shows that consequences may persist beyond pregnancy, with reports of post-traumatic stress symptoms in up to 20% of women with HG.³⁰

A depression and anxiety screen should be performed (the PHQ-9 and GAD-7questionnaires can be useful here) and the following avenues of support should be considered:

• Support via the GP and midwife: holistic approach, facilitation of fit notes (e.g more than a few weeks). Note, the intractable nausea can be markedly more debilitating than vomiting.
• Referral to the Pregnancy Sickness Support charity (helpline coordinator, online forum, volunteer support)pregnancysicknesssupport.org.uk
• Referral to AWP Primary Care Liaison Service (PCLS)
• https://www.nhs.uk/mental-health/nhs-voluntary-charity-services/charity-and-voluntary-services/get-help-from-mental-health-helplines/
• Books: “Hyperemesis Gravidarum – The Definitive Guide” and “How to be an HG Hero!”
• Maternity Action
• helpher.org: The Hyperemesis Education and Research Foundation- based in the United States, collaborates internationally.
• UK Teratology information service (UKTIS)
• Best use of medicines in pregnancy (BUMPS)

Recurrence in subsequent pregnancy

The recurrence rate of HG in subsequent pregnancy is very high at 70–80%: 26% report more severe symptoms, 44% less severe symptoms and 30% experience the same degree of severity.⁹ The patient and GP should agree a pre-emptive care plan focusing on:

• Starting an anti-emetic as soon as the woman has a positive pregnancy test as this reduces the severity and duration of symptoms. This should be a first line anti-emetic that the patient found useful in her last pregnancy. A Canadian study where women took anti-emetics pre-emptively was associated with lower recurrence rates of HG, significant improvement in PUQE score of NVP severity compared to the previous pregnancy.³¹
• The criteria and route for admission should be agreed.
• Aim for a healthy body mass index (BMI) aiming for the higher end of normal as weight loss is likely to occur with severe NVP/HG. A low BMI is associated with a greater number of admissions and a high BMI is associated with increased symptoms of NVP.
• Financial, employment and domestic concerns should be discussed and resolved, where possible, prior to conceiving.¹⁰

Resources

Further reading

1. RCOG 2024 Green-top guideline. The Management of Nausea and Vomiting in Pregnancy and Hyperemesis Gravidarum (Green‐top Guideline No. 69) (wiley.com)
2. For professionals: UKTIS. Treatment of nausea and vomiting in pregnancy https://uktis.org/monographs/treatment-of-nausea-and-vomiting-in-pregnancy/

References

Please see attached list of references

Further evidence for lifestyle treatments

• Rest: A survey of 114 women found that rest was noted by most respondents to be the only effective management strategy apart from antiemetic medications⁸. A structured daily diary can be useful in identifying periods of reduced nausea so eating and drinking can be planned for these times.
• Ginger: Encouraging patients with HG to use a ‘morning sickness’ cure, such as crackers or ginger, is inappropriate. Ginger is a therapeutic option for women with mild-to-moderate NVP, which is commonly improved by dietary changes; however, HG requires medical treatment including medications and intravenous fluids. A self-selected internet-based survey of 512 women hospitalised with HG within a one-year period and collectively experiencing 965 HG pregnancies, concluded that ginger was unhelpful in controlling HG symptoms. It also caused unpleasant side-effects, worsening of mood, breakdown of the doctor–patient relationship and a delay in receiving effective management with worsening and longer duration of symptoms.⁹
• Acupressure and electrical stimulation: a systematic review comprising 14 studies and meta-analysis showed that acupressure and electrical stimulation at the pericardium 6 point may have some benefit in alleviating nausea but less so vomiting.¹⁰
• There is no evidence of benefit from complementary therapies such as acupuncture or hypnosis in HG.¹¹

^{Further notes on pharmacological treatments}

• A slow-release combination of doxylamine and pyridoxine (vitamin B6) called Xonvea is the only licensed treatment of NVP in the UK¹².  Anti-emetics are on the BNSSG formulary within their licensed indications and apart from Xonvea, prescribing these in NVP/HG is off label. However, clinicians should feel comfortable using these medications given their long-standing use and evidence of safety in the condition. A Cochrane review¹³, systematic reviews^14,15 and birth registry¹⁶ data have all concluded the safety of anti-emetics such as H1 receptor antagonists (Cyclizine, Xonvea), Phenothiazines (Prochlorperazine) and dopamine agonists (Metoclopramide)

• Doxylamine/pyridoxine (Xonvea) can only be started in secondary care at present for the treatment of nausea and vomiting of pregnancy in patients aged 18 years or over who do not respond to conservative management and for who a trial of first and second line antiemetics has not controlled symptoms. 

• Suggested anti-emetic combinations include, but are not limited to (triple therapy is often required for HG):
  • Cyclizine + prochlorperazine
  • Cyclizine + metoclopramide
  • Prochlorperazine + metoclopramide

• Metoclopramide should be used as a second line agent due to the risk of extrapyramidal side effects and tardive dyskinesia particularly in young people. Please see August 2013 MHRA safety advice regarding prolonged use of Metoclopramide.
• In the BNF under the “Important Safety Information” it states that the 5-day ruling does not apply to unlicensed use of Metoclopramide. As treating NVP/HG is an unlicensed use, this means that the 5-day ruling should not be applied in this instance. If patients have not experienced any extrapyramidal side-effects, please explain to patients regarding the unlicensed use of this medication if prescribed for >5 days
• It should be noted that phenothiazines can also increase the risk of oculogyric crisis hence this should be discussed with the patient if Metoclopramide is prescribed alongside Prochlorperazine.¹⁷ 
• Combining Metoclopramide and Cyclizine could lead to additive side effects such as asthenia, drowsiness, hypotension and movement disorders. Please ask patients to monitor for side effects.
• Cyclizine (and other anticholinergics e.g. Buscopan/Xonvea) may antagonise some of the effects of Metoclopramide. Cyclizine may have mutual antagonism with Metoclopramide on digestive tract motility.
• Due to the prokinetic effect of Metoclopramide, the absorption of certain drugs may be modified. If clinically indicated to co-prescribe, consider differential timing of administration.
• Ondansetron: The European Medicines Agency (EMA) issued a controversial warning that Ondansetron should not be used in the first trimester and should not be used in women of child-bearing age without contraception. This was based on two large epidemiological studies which showed a small increased risk of cardiac defects¹⁸ and orofacial clefting¹⁹. The MHRA did not endorse this and the UK Teratology Information Service (UKTIS) published a systematic review concluding that currently available data does not show that Ondansetron use in the first trimester is associated with an increased overall malformation rate.²⁰ In conclusion, Ondansetron use should not be discouraged if first-line anti-emetics are ineffective. However, the decision to use Ondansetron should be made with the patient fully informed regarding the very small increase in the absolute risk of orofacial clefting with Ondansetron use in the first trimester (an additional three oral clefts per 10, 000 births (14 per 10,000 births with Ondansetron use versus 11 cases per 10, 000 birth in unexposed women).²¹
• The following patient information leaflets can be sent to patients about safety of anti-emetics in pregnancy:

https://www.pregnancysicknesssupport.org.uk/get-help/treatments/

https://www.medicinesinpregnancy.org/Medicine--pregnancy/Morning-Sickness/

• After prescribing an anti-emetic, a review of symptoms is required after 24-72 hours. A pragmatic stepwise approach should be followed adding in a further anti-emetic if symptoms remain uncontrolled; co-existent use of up to 3 anti-emetics from first and second-line options (different drug classes) may be required at which point specialist advice may be sought. When uptitrating anti-emetics, add drugs as opposed to replacing them because they have not proved effective initially on lone use²².
• The symptoms peak between 7 and 9 weeks from the last menstrual period hence additional anti-emetics are likely to be required at this point
• 90% of mild to moderate NVP cases resolve by 20 weeks²³; the majority of HG patients continue to have symptoms after 16 weeks²⁴ with 1 to 2% of patients enduring symptoms until delivery²⁵ Symptoms of NVP and HG should resolve rapidly after the birth. Persistent nausea and vomiting post-delivery requires investigation.
• If a woman feels her symptoms have been controlled for a reasonable period of time (eg 2-3 weeks) and she is now able to function at a pre-pregnancy level, a gradual reduction in anti-emetics can be trialled. It is important to note that 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 K¹¹.

• Please see cautions, contraindications, common side-effects and interactions of common anti-emetics in this link (appx 2, page 17). This is a guide rather than an exhaustive list. Please use other resources, such as the BNF
• Steroids - discuss with antenatal team if symptoms are not controlled on maximal anti-emetics and they remain dehydrated or there is continued weight loss. In hospital, patients are started on intravenous hydrocortisone 100mg BD converting to oral prednisolone 40-50mg OD tapering by 5mg per week to the lowest maintenance dose that controls symptoms¹¹. One should aim to stop steroids at the gestational age at which HG usually improves (16-24 weeks). For patients taking steroids, BP and glucose monitoring should be performed as there is an increased rate of hypertension and gestational diabetes respectively. There can also be a risk of adrenal suppression. Omeprazole and Vitamin D should also be prescribed with steroids.

Efforts are made to ensure the accuracy and agreement of these guidelines, including any content uploaded, referred to or linked to from the system. However, BNSSG ICB cannot guarantee this. This guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer, in accordance with the mental capacity act, and informed by the summary of product characteristics of any drugs they are considering. Practitioners are required to perform their duties in accordance with the law and their regulators and nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.

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