Vomiting in Pregnancy and Hyperemesis Gravidarum
This review article outlines the prevalence of nausea and vomiting of pregnancy (NVP) and hyperemesis gravidarum (HG), definition of NVP and HG, aetiology, risk factors, complications of HG, recommended investigations, primary care management, hospital and ambulatory daycare, therapeutic management of HG supported by good clinical evidence, discharge planning, and importance of the multidisciplinary team to provide high quality care in patients with NVP and HG.
NVP affects up to 80% of pregnant women,1 and is one of the most common indications for hospital admission during pregnancy, with typical stays of between 3–4 days.2-4 NVP is defined as the symptom of nausea and/or vomiting during the first trimester of pregnancy where there are no other causes.5 It represents a continuous spectrum of severity – from the nausea and vomiting that occurs in most pregnancies to severe disorder of HG – and affects about 0.3–1% of pregnancies.6
HG is defined as persistent vomiting and severe nausea during pregnancy, which is sufficient to produce weight loss (greater than 5% of the body mass), fluid and electrolyte disturbances, dehydration, acidosis from malnutrition, and ketonuria. It is a diagnosis of exclusion with the differential diagnosis including urinary tract infection, gastroenteritis, hepatitis, pancreatitis, thyrotoxicosis, diabetes, and hypercalcaemia.5,7-8
The aetiological theories for NVP and HG range from the fetoprotective and genetic to the biochemical, immunological, and biosocial. They are primarily thought to be associated with rising levels of beta-human chorionic gonadotropin (hCG) hormone, and conditions with higher hCG levels, such as trophoblastic disease and multiple pregnancies, have been associated with increased severity of NVP.5
The risk factors for HG among pregnant women are:7
• Younger maternal age
• First pregnancy
• Multiple pregnancy
• Gestational trophoblastic disease
Nausea and vomiting is not usually harmful to the foetus. Women with nausea and vomiting in early pregnancy have a lower rate of miscarriage than women without these symptoms.12 On the other hand, NVP may have physical, psychological, and social impact on the mother. The greater the severity of symptoms, the greater the effect on the mother. NVP has been reported to reduce quality of life, impairing a woman’s ability to function on a day-to-day basis, and negatively affecting relationships with her partner and family.13-14 Women with HG are 3–6 times more likely to have low quality of life than women with NVP.15 Therefore, effective pharmacological and nonpharmacological treatments are essential to alleviate the s ymptoms caused by NVP, improve patient’s quality of life, and prevent the condition to progress to HG, which may have complications for both mother and foetus.
The complications of HG in terms of maternal and foetal risks are as follows:8
(i) Maternal risks
• Liver and renal failure
• Hyponatraemia and rapid reversal of hyponatraemia leading to central pontine myelinolysis
• Thiamine deficiency may lead to Wernicke’s encephalopathy
(ii) Foetal risks
• Intrauterine growth restriction
• Foetal death may ensue in cases with Wernicke’s encephalopathy
NVP and HG are associated with hyponatraemia, hypokalaemia, low serum urea, increased haematocrit, and ketonuria with a metabolic hypochloraemic alkalosis. If severe, metabolic acidaemia may develop. In two-thirds of patients with HG, there may be abnormal thyroid function tests (TFTs, based on a structural similarity between thyroid-stimulating hormone [TSH] and hCG) with biochemical thyrotoxicosis and raised free thyroxine levels with or without suppressed TSH level. These patients rarely have thyroid antibodies.5 The hyperthyroxinaemia is transient and resolves as the HG improves,15-16 and in most cases, treatment with antithyroid drugs is inappropriate.
Liver function tests (LFTs) are abnormal in up to 40% of women with HG,17 with the most likely abnormality being a rise in transaminases. Bilirubin levels can be slightly raised but without jaundice, and amylase levels can be mildly raised as well. These abnormalities improve as the HG resolves.5
An ultrasound scan should be scheduled to confirm viability and gestational age, and to rule out multiple pregnancy or trophoblastic disease.5,7In suspected cases of HG, the following investigations should be performed:5,7
• Urine dipstick: To detect ketones in the urine; and to confirm ketosis (dehydration).
• Midstream urine (MSU): To exclude urinary tract infection.
• Urea and electrolytes: Check hypokalaemia, hyponatraemia, dehydration, renal disease, and metabolic hypochloraemic alkalosis. The results can help to guide intravenous hydration.
• Full blood count: Check infection, anaemia, and haematocrit. Haematocrit will confirm the severity of dehydration.
• Blood glucose monitoring: Exclude diabetic ketoacidosis, if diabetic.
• Ultrasound scan: Confirm viable intrauterine pregnancy, and exclude multiple pregnancies and trophoblastic disease.
• In refractory cases or history of previous admissions, check:
– TFTs: Hypothyroid/hyperthyroid
– LFTs: Exclude other liver diseases such as hepatitis or gallstones, monitor malnutrition, and protracted vomiting can lead to transient and reversible derangement. The transaminase may increase, and serum albumin may decrease.
– Calcium and phosphate
– Amylase: To exclude pancreatitis
– Arterial blood gas: To exclude metabolic disturbances, to monitor severity
FROM COMMUNITY TO INPATIENT HOSPITAL CARE
Since most women with NVP only require oral antiemetics, management in the primary care is appropriate to avoid unnecessary hospital admissions and disruption to their lives.18 Women who have vomiting but are not dehydrated can be managed in the community with antiemetics, reassurance, oral hydration, and dietary advice.
If women are unable to tolerate oral antiemetics or fluids, then ambulatory daycare management is appropriate as per the local guideline, which provides parenteral fluids and vitamins (multi and B-complex), and antiemetics.19
Women who have recurrent NVP/HG despite adequate ambulatory daycare treatment should be managed as inpatients due to the associated complications such as electrolyte imbalance and nutritional deficiencies.5
Inpatient management should be considered if one of the following is present:5
• Continued nausea and vomiting, and inability to keep down oral antiemetics.
• Continued nausea and vomiting associated with ketonuria and/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).
The initial treatment for NVP is often conservative, including dietary changes and emotional support. Rest is advised as well as small, frequent meals that are high in carbohydrate and low in fat. Food or odour that trigger symptoms should be avoided. Drinking small amounts of water or other clear fluid regularly can also be helpful.
A Cochrane review,6 and other systematic reviews and meta-analyses20-22 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. However, many pregnant women still avoid pharmacological treatment for fear of harmful effects on their babies, and stay away from drugs that are considered safe. In 2016, the University of Hong Kong – Shenzhen Hospital Obstetric team surveyed 616 pregnant mothers from 6–14 weeks of pregnancy and found that 539 (87.5%) women suffered from varying degrees of NVP, but only six of them took medicine for thecondition.
Drugs use in NVP include antihistamines (H1 receptor antagonists) such as promethazine, cyclizine, and phenothiazines with prochlorperazine and chlorpromazine, and dopamine antagonists including metoclopramide23 and domperidone.
Because different drug classes have different mechanisms of action and therefore synergistic effects, combination of drugs from different classes should be used in women who do not respond to a single antiemetic. Furthermore, persistent vomiting may mean that oral doses of antiemetics are not absorbed and therefore the intravenous, rectal, subcutaneous, or intramuscular routes may be necessary and more effective.5
The general rules for drug treatments are:
• For women with persistent or severe HG, the parenteral or rectal route may be necessary and more effective than an oral regimen.5
• Clinicians should use drugs from different classes if the first-line treatment is not effective. Combinations of different drugs should be used in women who does not respond to a single antiemetic.5
• Women should be asked by their doctor or pharmacist about previous adverse reactions to antiemetic therapies so that the most appropriate treatment regimen can be decided.5
• It would be useful for the healthcare institute to have a clinical guideline in place as most of the drug used to treat NVP and HG are unlicensed.
(i) Antihistamine (H1 recepter antagonists) antiemetics have the best safety profile of all the commonly used drugs, so it should be the first-line of treatment for NVP and HG.5 Promethazine and cyclizine have been shown to be safe and effective treatments for NVP and HG. The recommended doses are:5
• Promethazine: 12.5–25 mg every 4–8 hours by PO, IM, IV, or PR route.
• Cyclizine: 50 mg thrice daily by PO, IM, or IV route.
(ii) If antihistamine (H1 recepter antagonists) antiemetics do not work, phenothiazines5 can be used which also have good safety and efficacy data for management of NVP and HG. The recommended doses are:5,40
• Prochlorperazine 5–10 mg every 6–8 hours by PO; 12.5 mg every 8 hours by IM/IV; 25 mg daily by PR; and 3 mg twice a day by buccal route.
• Chlorpromazine 10–25 mg every 4–6 hours by PO, IV, or IM; or 50–100 mg every 6–8 hours by PR.
(iii) If antihistamine antiemetics and phenothiazines are not able to control the symptoms of NVP and HG, metoclopramide and domperidone are also safe and effective alternative treatments.5 These can be used as an add-on therapy. The recommended dosages are:5,40
• Metoclopramide 5–10 mg every 8 hours by PO, IV, or IM (maximum duration is 5 days).
• Domperidone 10 mg every 8 hours by PO; or 30–60 mg every 8 hours by PR.
Due to the risk of extrapyramidal effects with metoclopramide, it should not be used as the first-line therapy.5 A review of metoclopramide24 by the European Medicines Agency’s 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 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.25
Both phenothiazines and metoclopramide can cause extrapyramidal symptoms and oculogyric crises as side effects. If these occur, there should be prompt cessation of the medications.5
(iv) There is evidence that ondansetron is safe and effective for the management of NVP and HG, but because data are limited, it should be used as third-line therapy.5
Studies on the safety of ondansetron are mixed. A large retrospective analysis26 of data from the Danish Birth Registry of 608,385 pregnancies found no increased risk of major birth defect, stillbirth, preterm labour, or small-for-gestational age. However, a case-control study27 with 4,524 cases and 5,859 controls found a twofold increased risk of cleft palate, although the authors suggest that this association may be due to the large number of variables investigated. For these reasons, the use of ondansetron should be limited to patients who are not adequately managed on first- to third-line antiemetics, and if possible, to be used after the first trimester of pregnancy.
Three small randomized studies have shown ondansetron to be equally effective but with fewer adverse effects than metoclopramide28 and more effective in reducing severe vomiting.29
Ondansetron should be used with caution. When used together with other drugs that affect serotonin levels, it may contribute to the development of serotonin syndrome in susceptible patients.30
The recommended doses of ondansetron are:5,40
• Ondansetron 4–8 mg every 6–8 hours by PO; 8 mg over 15 minutes every 12 hours by IV; or 16 mg once daily by PR.
(v) Corticosteroids should not be used until conventional treatment with intravenous fluid replacement and regular antiemetics have failed.5 Corticosteroids have resulted in dramatic and rapid improvement in case series of women with refractory HG.31 The results of randomized studies are conflicting,32 and the largest study failed to show improvement in the primary outcome of rehospitalisation (however, both groups also received metoclopramide and promethazine).33-34 Case selection and route, and dose of corticosteroid administration may explain the different results, with beneficial results being described in more severe cases of HG. A prospective, double-blind study35 of 40 women who were admitted to intensive care unit with severe HG demonstrated that daily intravenous hydrocortisone 300 mg was superior to intravenous metoclopramide in reducing vomiting and recurrence.
The suggested doses are:5,8
• Intravenous hydrocortisone 100 mg twice daily, and once clinical improvement occurs, convert to oral prednisolone 40–50 mg daily, with the dose gradually tapered until the lowest maintenance dose that controls the symptoms is reached. The weaning regimen is to step down the dosage weekly to finally reduce the dose to 5–10 mg daily.
In most cases, prednisolone needs to be continued until the gestational age at which HG would have typically resolved, and in some extreme cases, this occurs at delivery.18
(vi) Pyridoxine is not recommended for HG.There is no association between the degree of NVP at 12 weeks and vitamin B6 levels measured at 15 weeks.36 A Cochrane review6 concluded that there is lack of consistent evidence that pyridoxine is an effective therapy for NVP. Furthermore, a placebo-controlled trial37 of pyridoxine in HG did not demonstrate any improvement in nausea, vomiting, or rehospitalisation in 46 women who were given 20 mg orally thrice daily in addition to intravenous fluids, intravenous metoclopramide thrice daily, and oral thiamine compared with control group given placebo in addition to standard therapy.
Most women admitted to hospital with HG are hyponatraemic, hypochloraemic, hypokalaemic, and ketotic. The 0.9% sodium chloride (150 mmol/L sodium) with 20 or 40 mmol potassium chloride or Hartmann’s solution (sodium chloride 0.6%; 131 mmol/L sodium) are appropriate intravenous (IV) fluids to be infused for patients with NVP or HG.7-8 The regimen is guided by the investigation results.7 Dextrose or dextrose/saline IV fluids are not recommended, as dextrose may precipitate Wernicke’s encephalopathy in thiamine-deficient states.5,7 If dextrose IV fluid is required for HG patients, it should be administered daily, and high (eg, 100 mg) doses of parenteral thiamine5 should be given to prevent Wernicke’s encephalopathy.
Wernicke’s encephalopathy is caused by a deficiency of vitamin B1 and commonly seen in patients with persistent vomiting. Wernicke’s encephalopathy classically presents with blurred vision, unsteadiness, and confusion, memory problems, or drowsiness, and on examination, there is usually nystagmus, ophthalmoplegia, hyporeflexia or areflexia, gait, and/or finger-nose ataxia.5 In HG, the presentation tends to be episodic and of slow onset. Wernicke’s encephalopathy is potentially fatal but reversible medical emergency.
Thiamine supplementation should be given to all women who are diagnosed with NVP and HG. The inability to eat can lead to thiamine deficiency which results in Wernicke’s encephalopathy and subsequently Korsakoff’s psychosis.5,7
The recommended doses are:8
• 25–50 mg thrice daily by PO or 100 mg once weekly by IV (dilute into 100 mL sodium chloride 0.9% to be given by IV infusion over 30–60 minutes).
Give 5 mg orally once daily, only for patients who are less than 12 weeks’ gestation. For women with severe vomiting and nausea symptoms, a dose higher than the normal dose (400 micrograms once a day) is used.
H2 receptor antagonists or proton pump inhibitors
Recurrent intractable vomiting may lead to gastroesophageal reflux disease, oesophagitis, or gastritis. Histamine H2 receptor antagonists or proton pump inhibitors are safe to use38 for women developing these medical problems, and can be used for the prevention of stress-induced ulcer due to vomiting.
Patients with HG are at an increased risk of developing deep vein thrombosis (DVT) due to dehydration and lack of mobility.5,7 Thromboprophylaxis with low-molecular-weight heparin should be considered in severe cases of HG. In addition, all patients with HG should be measured and fitted for TED stockings to reduce the risk of DVT. Since women with HG are only at markedly increased risk while persistently vomiting, thromboprophylaxis can be discontinued at discharge or when the HG resolves.39
Enteral or parenteral nutrient
When all other medical therapies have failed, enteral, or parenteral treatment should be considered.5 Whilst on parenteral nutrient, close monitoring of metabolic and electrolyte balance, related complications, and nutritional requirements are required.
DISCHARGE PLANNING AND MANAGEMENT
Women with NVP and HG should have an individualised management plan in place when they are discharged from hospital.5 Women with severe NVP or HG who have continued symptoms into the late second or third trimester should be offered serial scans to monitor foetal growth.5
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 (eg, persistent vomiting, dehydration, or ketonuria). Better communication and advice about the safety of antiemetics may enable general practitioners to adequately support women with HG. Pharmacists can play an important role in patient counselling on discharged medications to improve patient compliance and optimisation of drug use.
Most cases of NVP can be managed with diet and lifestyle measures alone. On the other hand, those with more severe symptoms may need pharmacologic therapy. In view of the good clinical evidence to use antiemetic drugs for management of HG as off-label uses, we would like to encourage the clinicians to prescribe the antiemetic drugs in NVP and HG patients when clinically appropriate, with effective patient counselling to enhance patient compliance.
There are many facets to severe NVP and HG, and a holistic approach to assessment and treatment should be adopted. Therefore, input from a multidisciplinary team including obstetricians, midwives, nurses, dieticians, pharmacists, endocrinologists, nutritionists, gastroenterologists, and mental health team will be beneficial to improve the quality of life of these groups of patients.
About the authors
Christina Leung is a Senior Pharmacist (Clinical Pharmacist-in-Charge), The University of Hong Kong – Shenzhen, Shenzhen China.
Dr Robert Chin is a Consultant Gynaecologist in the Department of Obstetrics and Gynaecology, The University of Hong Kong – Shenzhen, Shenzhen China.