Hyperemesis Gravidarum

Context

Nausea and Vomiting of Pregnancy (NVP) is a very common condition which affects 90% of pregnant women.1 It has a wide range of severity with Hyperemesis Gravidarum (HG) at the most extreme end.

Presentations to the Emergency Department for NVP have been increasing year on year, with around 2.1% of all pregnant patients requiring a hospital admission, resulting in an estimated annual cost to the NHS of £62 million.2-3

NVP and HG can cause significant morbidity for both the mother and the fetus.

From a maternal perspective, it can severely impact quality of life during pregnancy, making day-to-day activities impossible, and resulting in increased rates of post-natal depression, anxiety and PTSD postpartum.4 It can be most significant in those with pre-existing conditions such as diabetes and epilepsy, where an inability to take oral medication can cause complications.

There is also an association between NVP and low birthweight, being small for gestational age, increased risk of resuscitation at birth or NICU admission.5

The most recent iteration of the RCOG Green Top Guideline on the topic of Nausea and Vomiting of pregnancy was updated in February 2024 with some key changes to both assessment and management of this condition.2 The full guideline can be accessed here.

Learning Bite

Nausea and Vomiting of Pregnancy is a common condition affecting up to 90% of pregnancies, with associated impacts on quality of life and morbidity for both the mother and the fetus.

Definition

Nausea and Vomiting of Pregnancy (NVP) is defined as the symptom of nausea and/or vomiting during pregnancy, with an onset prior to 16 weeks of gestation, and where there is no other cause.

• Onset is typically in the 4th to 7th weeks of gestation
• Symptoms typically peak at the 9th week
• Symptoms resolve by the 20th week for 90% of women

Hyperemesis Gravidarum is defined as a severe form of NVP which interferes with quality of life and the ability to eat and drink normally. HG affects approximately 0.3-3.6% of pregnant women.

“Morning sickness” is not considered an appropriate phrase to use clinically, as it is an inaccurate description of the condition and is felt to trivialise what can be a severely debilitating complication of pregnancy.

The latest RCOG Guideline places a greater emphasis on patient-focussed criteria, as opposed to strict objective measures such as weight loss and electrolyte imbalance.

Learning Bite

Nausea and Vomiting of Pregnancy is an umbrella term for a range of symptom severity, with Hyperemesis Gravidarum at the extreme end, affecting up to 3.6% of pregnancies.

It was previously thought that circulating hCG levels were responsible for the majority of symptoms. GI tract smooth muscle relaxation was also believed to contribute to symptoms of reflux.

The most recent research suggests that the primary cause of NVP is hypersensitivity to the vomiting hormone growth differentiation factor 15 (GDF15).6 GDF15 is produced through the activation of placental genes, resulting in a rise in circulating levels in the first half of pregnancy. GDF15 has been shown to act on the hindbrain directly triggering nausea and vomiting. Patients who go on to develop HG have been found to have particularly elevated levels of GDF15, with those who had low pre-pregnancy levels of the hormone at particular risk of symptoms.

Learning Bite

Hypersensitivity to increased levels of GDF15 is currently believed to be the primary cause of NVP and HG.

History Taking

There are a range of questions to ask in order to ascertain the patient’s severity of symptoms, the potential causes outwith their pregnancy, and their risk of complications secondary to NVP/HG.

Pregnancy history

• How many weeks pregnant are they?
• Do they have a midwife and have they had their dating scan?
• Have they been pregnant previously?
• Is there any past history of NVP/HG? Did this require admission to hospital?
• Were there any particular antiemetics which worked well for them previously?

This current episode of NVP

• How long have they had symptoms?
• How frequently are they feeling nauseated?
• How frequently are they vomiting?
• Are they managing to eat and drink, and how much?
• How are their symptoms impacting their daily life?
• Have they noticed any weight loss?
• Are they passing urine?
• Are they managing to keep down any medications they are taking?

You must also consider the other causes of vomiting in pregnancy. For example, do they have abdominal pain, any urinary symptoms, have they had a fever?

Past medical history

• Does the patient have any conditions which could be worsened by dehydration, electrolyte imbalance, or missed medication? e.g. diabetes, epilepsy
• Have they had any previous abdominal surgery? Particularly ask about C-Sections and gastric band procedures
• Do they take any regular medications? (don’t forget recreational drugs, particularly cannabis)

Severity Stratifying

There are two key stratifying tools used by the latest RCOG guideline:

1. Pregnancy-Unique Quantification of Emesis (PUQE)
2. HyperEmesis Level Prediction (HELP)

PUQE can help define if NVP is mild, moderate or severe.

Figure 1: Pregnancy-Unique Quantification of Emesis. Appendix IIa of the Green-top Guideline No.69.2

HELP score is more useful for tracking the trend of HG to monitor response to treatment.

Figure 2: HyperEmesis Level Prediction Score. Appendix IIb of the Green-top Guideline No.69.2

Urinalysis

• Ketonuria is not an indicator of dehydration severity, may be misleading, and should no longer be used
• Urinalysis can still be utilised to both confirm pregnancy and assess for the presence of nitrates which may indicate infection.

Bloods

• FBC

To assess for potential infection, anaemia and raised haematocrit (suggesting haemoconcentration due to dehydration)

• U&E

To identify the presence of AKI, the need for electrolyte replacement and guide IV fluid replacement

• Venous Blood Gas/Bedside glucose

Identify undiagnosed diabetes

Assess for possible DKA in patients with T1DM

• Can also consider TFT, LFT, Calcium, Phosphate, Amylase

Especially if suspicious for alternative causes of nausea and vomiting.

Imaging

Imaging is not required for all patients, but a pelvic ultrasound may be indicated to assess for viable pregnancy, multiple pregnancy and trophoblastic disease (molar pregnancy).

CT imaging may be required in a small number of patients to assess for alternative surgical causes of nausea and vomiting. This would usually be in the case of additional symptoms suggestive of a surgical pathology such as abdominal pain and fever. Consideration of the patient’s gestation and the pre-test probability of an alternative cause should be considered, as well as a discussion with both the patient and the relevant on-call teams, including O&G, General Surgery and Urology. Abdominal ultrasound or KUB ultrasound may be considered alternatively.

Learning Bite

Measurement of ketones in the urine is no longer recommended by RCOG Guidance, as it has been shown to be a very unreliable indicator of dehydration severity.

Summary of Management

RCEM and RCOG have produced the following resource to guide clinicians in the ED through the initial assessment, investigations, severity scoring and management of patients presenting with NVP.

Figure 3: Treatment algorithm for NVP and HG in the Emergency Department. Appendix V of the Green Top Guideline 69.2

Many patients can be managed safely in the community. The mainstay of treatment is oral antiemetics, oral rehydration, dietary advice to eat little and often, and rest with time off work.

Some Obstetric centres may be able to facilitate IV therapies via an Ambulatory Clinic, thereby avoiding admission, but this will depend on your local service provision.

Red flags that would warrant referral for admission

• Any PUQE score plus complications
• Inability to tolerate oral intake
• Unresponsiveness to outpatient or Emergency Department management
• Clinical dehydration
• Weight loss of >5%
• Comorbidities such as urinary tract infection, epilepsy, diabetes, HIV, hypoadrenalism, or psychiatric disorders; being exacerbated by uncontrolled nausea and vomiting. An inability to take regular medications would be concerning.

Intravenous Fluids

When oral fluids cannot be tolerated then IV fluid replacement can be very effective at both rehydrating the pregnant patient and treating their nausea.

0.9%NaCl + Potassium chloride is the primary fluid choice.

The use of Dextrose for fluid replacement is NOT recommended due to the increased risk of precipitating Wernicke’s Encephalopathy.

Antiemetics

The prescribing of antiemetics in pregnancy can cause confusion and anxiety in the clinicians caring for patients with NVP due to concerns about the teratogenic effects. However, the absolute risk is low and the benefits outweigh the risks of leaving NVP untreated.

Oral antiemetics should be used in the first instance but may be insufficient to manage the patient’s symptoms. There are a variety of IM and IV antiemetics available.

Drugs from different classes can be safely combined when single agent therapy is not enough.

First line

• Doxylamine and Pyridoxine (vitamin B6) brand name “Xonvea” 20/20mg PO at night, increase to additional 10/10mg in morning and 10/10mg at lunchtime if required.
• Cyclizine 50mg PO, IM or IV 8 hourly
• Prochlorperazine 5–10mg 6–8 hourly PO (or 3mg buccal); 12.5mg 8 hourly IM/IV; 25mg PR daily
• Promethazine 12.5–25mg 4–8 hourly PO, IM or IV
• Chlorpromazine 10–25mg 4–6 hourly PO, IM or IV

Second line

• Metoclopramide 5–10mg 8 hourly PO, IV/IM/SC
• Domperidone 10mg 8 hourly PO; 30mg 12 hourly PR
• Ondansetron 4mg 8 hourly or 8 mg 12 hourly PO; 8mg over 15 minutes 12 hourly IV; 16mg daily PR

Third line – this is for the O&G service to consider commencing and is not appropriate for ED teams to start without seeking specialist input

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

Safety Data on Antiemetics

Concerns about the safety of antiemetics has resulted in many patients having their symptoms inadequately treated out of a concern for medication teratogenicity.

The current guidance is that the absolute risk of causing conditions such as cleft palate are incredibly low.

Antihistamines, Phenothiazines and Pyridoxine-Doxylamine all have good safety data.

Ondansetron has a very small increase in the absolute risk of orofacial clefting when used in the first trimester (from 11 per 10,000 births background rate, to 14 per 10,000 births).7

Figure 4: Visual risk summary of the use of Ondansetron in pregnancy. Appendix IX of the Green Top Guideline 69.2

Metoclopramide is safe and can be used as a standalone agent or in combination with other agents. There is a small risk of extrapyramidal side effects and oculogyric crisis, so it should be utilised as a 2nd line agent.

Other Medications to Consider

PPI such as Omeprazole or Lansoprazole for GORD symptoms

Thiamine supplementation (either oral 100 mg TDS or IV Pabrinex)

Laxatives if constipated

Pregnancy specific VTE risk assessment should be performed in all patients.

Mental Health Considerations

Women can be left feeling dismissed, with delays to adequate treatment for their NVP which can negatively impact on their mental health. Inversely those who are treated with compassion and empathy respond far better to their treatment even if their symptoms remain severe.

Patients with NVP and HG report higher rates of depression and anxiety.

For those with pre-existing mental health conditions, vomiting can result in them being unable to take their usual medications, thereby further exacerbating their prior illness.

One UK survey found that 25% of those with HG reported suicidal ideation, with 6% regularly considering suicide due to their symptoms, and the impact it has on their life.8 In the Emergency Department we have a responsibility to consider the impact NVP and HG can have on a patient’s mental health, and direct to appropriate services as required.

• Ensure there is a focus on the patient’s subjective symptoms and experience Objective measurements such as weight loss values can be useful but don’t fully assess the quality-of-life impact that this condition can have.
• Ketonuria is no longer used as an assessment tool in NVP and HG.
• The PUQE score can help stratify the severity of symptoms, and guide management.
• There are a wide range of antiemetic choices that can be used in a stepwise manner. A combination approach is often needed.
• The absolute risk of teratogenic effects of anti-emetics such as Ondansetron are very low. The risk of harm from untreated NVP and HG far outweighs the risk of teratogenicity.
• Patients can suffer with severe mental health consequences from NVP and HG. It is important to assess their mental health and provide onward support as needed.

1. Gadsby R, Rawson V, Dziadulewicz E, Rousseau B, Collings H. Nausea and vomiting of pregnancy and resource implications: the NVP Impact Study. Br J Gen Pract. 2019 Mar;69(680):e217-e223.
2. Nelson-Piercy C, Dean C, Shehmar M, et al. The Management of Nausea and Vomiting in Pregnancy and Hyperemesis Gravidarum (Green-top Guideline No. 69). BJOG. 2024 Jun;131(7):e1-e30.
3. Fiaschi L, Nelson-Piercy C, et al. Clinical management of nausea and vomiting in pregnancy and hyperemesis gravidarum across primary and secondary care: a population-based study. BJOG. 2019 Sep;126(10):1201-1211.
4. Mitchell-Jones N, Gallos I, et al. Psychological morbidity associated with hyperemesis gravidarum: a systematic review and meta-analysis. BJOG. 2017 Jan;124(1):20-30.
5. Fiaschi L, Nelson-Piercy C, et al. Adverse Maternal and Birth Outcomes in Women Admitted to Hospital for Hyperemesis Gravidarum: a Population-Based Cohort Study. Paediatr Perinat Epidemiol. 2018 Jan;32(1):40-51.
6. Fejzo M, Rocha N, Cimino I, et al. GDF15 linked to maternal risk of nausea and vomiting during pregnancy. Nature. 2024 Jan;625(7996):760-767.
7. Irish Medicines in Pregnancy Service: Position Statement on Ondansetron Use in Pregnancy. 23 October 2019. 
8. Nana M, Tydeman F, Bevan G, et al. Hyperemesis gravidarum is associated with increased rates of termination of pregnancy and suicidal ideation: results from a survey completed by >5000 participants. Am J Obstet Gynecol. 2021 Jun;224(6):629-631.