Spotlight: nausea and vomiting in pregnancy

Introduction
Pathogenesis
Maternal and Fetal Factors in HG
Assessing women with NVP and HG
Management
Non-drug treatment
Admission criteria
Outlook
Conclusion
References

Introduction

Nausea and vomiting are common complaints during pregnancy, affecting 50-90% of women.¹  This is often referred to as ‘morning sickness’, though this is a misnomer, as nausea and vomiting in pregnancy (NVP) can occur at any time of the day or night.

Symptoms usually begin in the fourth to seventh week of gestation and subside by the 20^th week in 90% of women.²  The vast majority of women with NVP can be managed in primary care. Reassurance and advice are sufficient for many women suffering with NVP, though a proportion will require treatment with antiemetics.

Hyperemesis gravidarum (HG) is the most severe form of nausea and vomiting in pregnancy. HG affects less than 1% of women.³  There are several definitions of HG, but the main features are severe protracted nausea and vomiting associated with weight loss of more than 5% of pre-pregnancy weight, dehydration, electrolyte imbalances, ketosis and the need for hospital admission.

Risk factors for Hyperemesis Gravidarum

• Raised maternal BMI
• Multiple pregnancy
• HG in previous pregnancy

Pathogenesis

The pathogenesis of NVP is not fully understood and there are a variety of theories about aetiology. A combination of genetic, gastrointestinal, endocrine and psychosocial factors are probably involved.¹ 

HG is associated with high circulating levels of human chorionic gonadotrophin hormone (HCG), and women are more likely to experience NVP if their HCG levels are particularly elevated, for example, those with multiple or molar pregnancies.

Other theories propose that there is an evolutionary advantage associated with NVP, due to pregnant women expelling potentially noxious substances through vomiting.⁴ 

Helicobacter pylori infection has also been implicated as a possible cause, but the exact link is not established.

Maternal and fetal factors in HG

The psychological impact of HG on expectant mothers must not be underestimated. In a survey of 808 women from 23 countries, 15.2% had undergone at least one termination due to HG. Of women who had terminated a pregnancy due to HG,  prominent reasons given for the terminations were inability to care for the family and self (66.7%), fear that they or their baby could die (51.2%), or that the baby would be abnormal (22.0%).⁵ 

Primary care practitioners have an important part to play in supporting women with HG and allaying some of their fears. Women with HG can be reassured that HG is associated with lower risk of miscarriage.⁶  In a recent systematic review, no association was found between HG and perinatal death, nor between HG and congenital anomalies. There was, however, an increased risk of low birth weight and pre-term birth.⁷ 

Assessing women with NVP and HG

Clinical assessment of women with HG should include a thorough history, with questions such as:

• How often do you feel nauseated?
• Have you vomited? How many times?
• Are there any other associated symptoms?
• Have you been pregnant before? Did you have NVP in your previous pregnancy?
• When was your last menstrual period (LMP)?

Consider an alternative diagnosis if the history is not consistent with NVP. It is unusual for symptoms of NVP to begin after the first trimester, and alternative causes should be considered. Figure two outlines possible differential diagnoses for NVP.

Questions to evaluate the severity of symptoms:

• What is your weight compared with your pre-pregnancy weight?
• How are these symptoms impacting on your mood?
• How are the symptoms impacting on your home life?
• How is NVP impacting on work outside the home?
• Are you able to eat and drink?

Figure 2. Differential diagnosis of NVP

Gastrointestinal	Peptic ulcer disease Gastroenteritis Appendicitis Pancreatitis
Endocrine/Metabolic	Thyrotoxicosis Addison’s disease Hyperparathyroidism Diabetic ketoacidosis
Neurological	Space Occupying Lesion Migrane Vestibular disease
Pregnancy-associated conditions	Molar pregnancy Acute Fatty Liver of Pregnancy
Genitourinary	Urinary Tract Infection (UTI)
Psychological disorders	Bulimia nervosa
Cardiovascular	Myocardial Infarction

The PUQE questionnaire (figure three) is a validated scoring system which can be used to evaluate symptoms of NVP.⁸ 

This gives a score between 3 and 15. A score of 6 or less is mild NVP, 7-12 is moderate NVP and severe is 13 or more. PUQE can be a useful tool in monitoring symptoms and response to treatment.

Figure 3. PUQE questionnaire 

In the last 12 hours for how long have you felt nauseated or sick to your stomach? Not at all 1 hour or less 2-3 hours 4-6 hours More than 6 hours Score=1 Score=2 Score=3 Score=4 Score=5 In the last 12 hours have you vomited or thrown up 7 or more times 5-6 3-4 1-2 I did not throw up Score=5 Score=4 Score=3 Score=2 Score=1 In the last 12 hours, how many times have you had retching or dry heaves without bringing anything up? No time 1-2 3-4 5-6 7 or more Score=1 Score=2 Score=3 Score=4 Score=5 (Total N+V score Mild< 6, Moderate 7-12, Severe >12)

Management

The psychosocial impact of NVP is significant and sometimes overlooked. In a study of 593 women with NVP, the majority described substantial effects on working, household duties and parenting activities. Findings from the study suggest NVP has a profound impact on women’s general sense of well-being and day to day activities.⁹ Primary care practitioners have a key role in providing advice and support.

Women with mild NVP can be managed with dietary and lifestyle advice in the majority of cases. Both non-drug and drug treatments can be helpful if symptoms do not settle with advice alone. At the most severe end of the spectrum, women with HG will require referral to secondary care for more aggressive management with intravenous fluid replacement, antiemetics and nutritional support.

Dietary changes

Women with NVP and HG should be advised to eat several small meals throughout the day instead of eating large meals. They should choose foods that are bland and low in fat, as fatty foods can delay gastric emptying.¹⁰ 

Advise women to avoid foods that trigger nausea and vomiting, such as foods which are strong-smelling. Some may find it helpful to sip drinks, such as sports rehydration drinks, over the course of the day, to ensure adequate fluid intake.

Lifestyle advice

Lying down when nauseated can help reduce symptoms of NVP. Women should be advised to try to avoid stress, which can worsen symptoms.  Physical activity should be gentle, as becoming too hot may exacerbate nausea.¹¹  Women who cook meals may find that cooking in a well-ventilated kitchen reduces exposure to strong smells, or may ask for help with meal preparation from family and friends.

Non-drug treatments

Ginger

Oral ginger supplements have been shown to be more effective than placebo in reducing symptoms of NVP in a systematic review of four RCTs.¹²  These can be purchased from high street health food shops and are generally well tolerated. There is no robust evidence regarding the maximum safe dose and duration of treatment. Alternatively, women can try ginger biscuits, which have been found to be better than placebo at reducing nausea.¹³  Ginger is less effective than Metoclopromide.¹⁴ 

Acupuncture and acupressure

Acupressure of the PC6 area (located approximately 2.5 finger breadths up from the wrist crease on the inside of the forearm) can help alleviate symptoms of nausea.¹⁵  Wristbands, finger pressure or electrical stimulation can be used to apply acupressure.  Acupuncture is safe in pregnancy,¹⁶  though the evidence for it in treating NVP is weak and further evaluation is needed.

Vitamin supplementation

Folic Acid

All pregnant women shoud be taking folic acid 400mcg OD in the first trimester as a minimum. Patients at higher risk, for example those with a history of neural tube defects, diabetes and patients taking enzyme-inducing anti-epileptic drugs such as phenytoin, carbamazepine, primidone, and phenobarbital should take folic acid 5mg OD.

Pyridoxine

Pyridoxine (Vitamin B6) is used as a first line treatment for NVP in many countries, often in combination with Doxylamine. At present this treatment is not widely used in the UK.

Thiamine

Thiamine (Vitamin B1) supplements are given routinely to women who are admitted to hospital with HG. Thiamine deficiency can lead to Wernicke’s encephalopathy. This is a medical emergency which is entirely preventable through adequate replacement of VitaminB1.

Other supplements

Supplements such as ferrous sulphate and ferrous fumarate can contribute to nausea in susceptible individuals. These drugs should be witheld temporarily in women with NVP or HG.

Antiemetics

Approximately 10% of women continue to experience significant nausea and vomiting in pregnancy, despite following advice on diet and lifestyle.^3 1  An analysis of 28 randomised trials into the treatment of HG showed that antiemetics reduce the frequency of nausea in early pregnancy and are more effective than placebo.¹⁷ 

The antiemetics used include H1 antagonists (cyclizine, promethazine), dopamine antagonists (metoclopromide, domperidone), phenothiazines (chlorpromazine, prochlorperazine) and 5HT3-receptor antagonists (ondansetron).

There is no good evidence that any one anti-emetic is superior to another,¹  and clinicians should prescribe the antiemetic that they are most familiar with, and take into account individual patient factors and potential side-effects associated with the medication. All antiemetics have the potential to cause drowsiness, but this is most frequently observed with phenothiazines. Oculogyric crises and extrapyramidal side-effects can be caused by metoclopromide and phenothiazines.¹ 

Ondansetron may cause constipation. Women should be warned of these side-effects. If there is no significant improvement in NVP with the first antiemetic prescribed, a second antiemetics is indicated. In this instance, it is good practice to prescribe a drug from another drug class. Antiemetics to be prescribed in NVP are listed in figure 4, in order of preferred use.

The safety and efficacy of the commonly used drugs in NVP has been formally evaluated, and there is no evidence for increased teratogenesis or adverse outcomes for women who take these drugs in pregnancy.^18 19 

Figure 4. Suggested antiemetics for NVP

Cyclizine 50 mg orally, intramuscularly, or intravenously, three times daily Metoclopramide 10 mg orally, intramuscularly, or intravenously, three times daily Prochlorperazine 5 mg orally, 12.5 mg intramuscularly or intravenously, three times daily; 25 mg rectally, followed if necessary six hours later by an oral dose Promethazine 25 mg orally, at night Chlorpromazine 10-25 mg orally up to three times daily; 25 mg intramuscularly, three times daily Domperidone 10 mg orally, four times daily; 30-60 mg rectally, three times daily Ondansetron 4-8 mg orally, intramuscularly, or by slow intravenous infusion, two to three times daily

Corticosteroids

Oral and intravenous corticosteroids are used in secondary care. Their used is reserved for severe and intractable cases of HG only. Patients with HG who are discharged from hospital on oral corticosteroids should have the dose gradually weaned.

Adjunctive treatments

Women with NVP may also complain of symptoms of heartburn and acid reflux. Gastroesophageal reflux disease is associated with an increased severity of NVP, and co-existing gastritis and oesophagitis should be addressed. Lifestyle interventions should be tried initially, and antacids, proton pump inhibitors (PPIs) and H2 €“receptor antagonists (e.g. Ranitidine) can be given to those with resistant symtptoms. These drugs are all safe to use in pregnancy.²⁰ .

Patients with HG who are hospitalised should all be assessed for risk of developing venous thromboembolism (VTE), and low molecular weight heparin (LMWH) should be prescribed where appropriate.

Admission criteria

Despite effective treatment in primary care, some women require referral to secondary care. Arrangements will vary according to local policy. Some hospitals have ambulatory care arrangements for patients with HG, enabling women to attend hospital for assessment and treatment, but to remains as outpatients.

Referral to secondary care is appropriate if:

• Continued nausea and vomiting associated with ketonuria or weight loss (>5% body weight), despite oral antiemetics
• Continued nausea and vomiting and inability to keep down oral antiemetics
• Confirmed or suspected comorbidity (such as confirmed urinary tract infection and unable to tolerate oral antibiotics)(1)

Outlook

Women with HG and NVP can be directed to support groups such as Pregnancy Sickness Support Group²¹  for additional information and advice. Resources such as this can be very helpful to women with NVP and their families. Women who are planning future pregnancies can be advised that recurrence rates for HG vary, and lie somewhere between 15%²²  and 81%.²³  They can be advised that there is some evidence that women who have experienced severe NVP in a previous pregnancy benefit from taking antiemetics before or immediately at the start of symptoms in subsequent pregnancies.24

Conclusion

In summary, the vast majority of women with NVP can be managed in primary care with lifestyle and dietary advice, and antiemetics. Symptomatic women should be encouraged to take antiemetics when indicated and reassured regarding their safety. Women with HG should be referred to secondary care for further assessment and treatment.

Authors

• Dr Francesca Neuberger, Fellow in Obstetric Medicine
• Prof Catherine Nelson-Piercy, Professor of Obstetric Medicine, Imperial College Healthcare NHS Trust

References

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5. Poursharif B, Korst LM, Macgibbon KW et al. Elective pregnancy termination in a large cohort of women with hyperemesis gravidarum.  Contraception 2007; 76 (6): 451-5.
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8. Koren G, Piwko C, Ahn E et al. Validation studies of the Pregnancy Unique-Quantification of Emesis (PUQE) scores.  J Obstet Gynaecol 2005; 25(3): 241-4.
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20. Law R, Maltepe C, Bozzo P et al. Treatment of heartburn and acid reflux associated with nausea and vomiting during pregnancy.  Can Fam Physician 2010;56(2):143-144.
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This article was first published in our sister publication Journal of Women’s Health