Clinical Topic A-Z Clinical Speciality

Nausea/vomiting in pregnancy

Nausea/vomiting in pregnancy
D009325Nausea
D014839Vomiting
D011247Pregnancy
D006939Hyperemesis Gravidarum
PregnancyWomen's health
2013-06-01Last revised in June 2013

Nausea/vomiting in pregnancy - Summary

The majority of women vomit or feel nauseated in early pregnancy. Symptoms usually begin before 9 weeks of gestation, and usually improve, resolving by 16 weeks of gestation in 90% of women.

Hyperemesis gravidarum is a diagnosis of exclusion characterized by prolonged and severe nausea and vomiting, dehydration, ketosis, and body weight loss in pregnancy.

Complications are more likely in women with severe vomiting and include:

Maternal — weight loss, dehydration, hyponatraemia, vitamin deficiencies, Mallory-Weiss tear or oesophageal rupture, increased risk of venous thromboembolism.

Fetal — possible higher incidence of low birthweight babies (if hyperemesis gravidarum).

Conditions causing nausea and vomiting in pregnancy include:

Genito-urinary conditions such as urinary tract infection, pyelonephritis, ovarian torsion.

Endocrine conditions such as thyrotoxicosis, diabetic ketoacidosis, Addison's disease.

Gastrointestinal conditions such as gastritis, peptic ulcer, pancreatitis, bowel obstruction, hepatitis, cholelithiasis, appendicitis.

Neurological conditions such as vestibular disease, migraine.

Other pregnancy-related conditions such as acute fatty liver of pregnancy, pre-eclampsia.

Women with nausea and vomiting in pregnancy do not usually require laboratory evaluation unless symptoms are severe, prolonged (in terms of overall duration during pregnancy), or extended (in terms of frequency during each day).

Management includes:

Asking about the the nausea and vomiting (e.g. onset, duration, frequency, effect of food, associated symptoms, co-existing conditions, and effect of mood and quality of life).

If nausea or vomiting is affecting fluid and food intake, monitoring weight, checking for dehydration, testing the urine for ketones, and pelvic ultrasound to assess for predisposing multiple or molar pregnancy.

Offering appropriate self-care advice (e.g. rest, adequate fluid intake, and small frequent meals). Some women find ginger or acupressure helps symptoms.

Considering the need for an oral anti-emetic (off-label use) if self-care advice fails and the woman has persistent symptoms. All anti-emetics are unlicensed for treatment of nausea and vomiting in pregnancy.

Early treatment with an anti-emetic is likely to be more effective and is essential to improve the woman's quality of life, symptoms, and reduce morbidity to the fetus.

Hospital admission should be arranged if:

Symptoms are severe despite 24 hours of oral anti-emetic drug treatment (e.g. inability to tolerate liquids without vomiting).

There is evidence of dehydration, ketones in the urine, or suspicion of medical complications.

The following treatments are not recommended for nausea and vomiting during pregnancy: acustimulation, acupuncture, herbal remedies, homeopathy, hypnosis, hypnotherapy, psychotherapy, and multivitamins (including pyridoxine).

Have I got the right topic?

156months720monthsFemale

This CKS topic covers the management of nausea and vomiting in pregnancy, in primary care.

This CKS topic does not cover other causes of nausea and vomiting (obstetric and non-obstetric), or dyspepsia during pregnancy.

There are separate CKS topics on Dyspepsia - pregnancy-associated and Gastroenteritis.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary health care.

How up-to-date is this topic?

How up-to-date is this topic?

Changes

Last revised in June 2013

September 2013 — minor update to the text to reflect current recommendations regarding metoclopramide [EMA, 2013].

January - June 2013 — reviewed. A literature search was conducted in December 2012 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs and observational studies published since the last revision of the topic. There is one change to the recommendations – ondansetron is now recommended as a second-line anti-emetic.

Previous changes

August 2012 — minor update. Minor typographical error corrected.

March 2011 — topic structure revised to ensure consistency across CKS topics — no changes to clinical recommendations have been made.

November 2008 — update to text regarding the use of ginger and acupressure during pregnancy. These are now recommended by the National institute for Health and Clinical Excellence. Issued in December 2008.

August 2008 — minor update to text regarding the safety of promethazine in pregnancy.

February to May 2008 — converted from CKS guidance to CKS topic structure. The evidence base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence.

There are no major changes to the recommendations.

October 2005 — minor technical update. Issued in November 2005.

March 2005 — reviewed. Validated in June 2005 and issued in July 2005.

December 2001 — reviewed. Validated in March 2002 and issued in April 2002.

January 1999 — written, replacing the guidance on Hyperemesis of pregnancy. Validated in March 1999 and issued in August 1999.

Update

New evidence

Evidence-based guidelines

No new evidence-based guidelines since 1 December 2012.

HTAs (Health Technology Assessments)

No new HTAs since 1 December 2012.

Economic appraisals

No new economic appraisals relevant to England since 1 December 2012.

Systematic reviews and meta-analyses

Systematic reviews published since the last revision of this topic:

Maltepe, C. and Koren, G. (2013) The management of nausea and vomiting of pregnancy and hyperemesis gravidarum: a meta analysis. Journal of Population Therapeutics and Clinical Pharmacology 20(2), e184-e192. [Abstract]

Thomson, M., Corbin, R., and Leung, L. (2014) Effects of ginger for nausea and vomiting in early pregnancy: a meta-analysis. Journal of the American Board of Family Medicine 27(1), 115-122. [Abstract] [Free Full-text]

Viljoen, E., Visser, J., Koen, N. and Musekiwa, A. (2014) A systematic review and meta-analysis of the effect and safety of ginger in the treatment of pregnancy-associated nausea and vomiting. Nutrition Journal13(1), 20. [Abstract] [Free Full-text]

Primary evidence

No new randomized controlled trials published in the major journals since 1 December 2012.

Observational studies published since the last revision of this topic:

Pasternak, B., Svanstrom, H., Molgaard-Nielsen, D., et al. (2013) Metoclopramide in pregnancy and risk of major congenital malformations and fetal death. JAMA 310(15), 1601-1611.

New policies

No new national policies or guidelines since 1 December 2012.

New safety alerts

No new safety alerts since 1 December 2012.

Changes in product availability

No changes in product availability since 1 December 2012.

Goals and outcome measures

Goals

To reassure the woman that nausea and vomiting are normal in pregnancy

To reduce nausea and vomiting

To reduce time off work and other lifestyle disruptions caused by symptoms

To prevent complications

Background information

Definition

What is it?

Most women feel nauseated or vomit in early pregnancy [Whitehead et al, 1992]. These symptoms are commonly referred to as 'morning sickness', but symptoms can occur at any time during the day [Jarvis and Nelson-Piercy, 2011].

A UK study found that nausea and vomiting occur throughout the day in many pregnant women; of 292 women with symptoms, only 3.8% experienced nausea only in the morning. A similar pattern was observed for women with vomiting [Gadsby et al, 1993].

Symptoms manifest before 9 weeks of gestation in almost all affected women and usually improve as the pregnancy progresses, resolving by 16 weeks of gestation in 90% of women [ACOG, 2004; Festin, 2009].

Hyperemesis gravidarum is a diagnosis of exclusion characterized by prolonged and severe nausea and vomiting, dehydration, electrolyte imbalance, ketosis, the need for admission to hospital, and body weight loss of more than 5% of pre-pregnancy weight [ACOG, 2004; Jarvis and Nelson-Piercy, 2011].

Causes

What causes it?

The cause of nausea and vomiting in pregnancy is uncertain [Niebyl, 2010]. Several associated factors may influence its development, but some causative mechanisms have also been suggested:

Human chorionic gonadotrophin (hCG)

There is general agreement that the stimulus for nausea and vomiting in pregnancy is of placental origin. The hCG theory is supported by the temporal relationship between nausea and vomiting and hCG levels. In addition, nausea and vomiting are associated with multiple pregnancies and molar pregnancy, both of which involve increased levels of hCG.

Oestrogen

Nausea and vomiting in pregnancy are more common when estradiol levels are increased. When levels are decreased, nausea and vomiting are less common.

Nutritional deficiency

Women with hyperemesis gravidarum have been shown to be deficient in vitamin B6, and it has been considered whether this is a possible aetiology.

Evolutionary adaptation

It has been suggested that nausea and vomiting are a mechanism to prevent the woman eating potentially harmful foods. The temporary aversions to tastes and smells that some pregnant women experience may support this theory.

Gastric dysfunction

In pregnant women, oesophageal, gastric, and small-bowel motility are impaired because of smooth-muscle relaxation due to increased levels of progesterone. Delayed gastric emptying in pregnancy may also contribute to nausea and vomiting.

Vestibular and olfactory system

It is postulated that a pregnancy stimulus may lower the threshold for vestibular-mediated nausea and vomiting in some women. Hyperacuity of the olfactory system is thought to be due to increasing oestrogen concentrations in early pregnancy.

Psychological influences

Less favoured is the theory that nausea and vomiting in pregnancy are an abnormal response to stress or are associated with negative feelings about the pregnancy. It has been suggested that psychological symptoms may be a result, rather than a cause, of nausea and vomiting in pregnancy.

[ACOG, 2004; Davis, 2004; Festin, 2009; Matthews et al, 2010; Jarvis and Nelson-Piercy, 2011]

Associated factors

What are the associated factors?

Several factors are associated with the development of nausea and vomiting in pregnancy, the majority of which are not modifiable:

Increased placental mass (for example advanced molar gestation, multiple gestation).

Female fetus.

History of nausea and vomiting in previous pregnancies.

History of motion sickness.

History of migraines.

Family history (first-degree relatives) of nausea and vomiting in pregnancy.

History of nausea with oestrogen-containing oral contraceptives.

Young maternal age.

First pregnancy.

Obesity.

Stress.

Being seropositive for Helicobacter pylori. This is associated with an increased risk of hyperemesis gravidarum.

For more information on potential causal mechanisms, see Causes.

[ACOG, 2004; Davis, 2004; Festin, 2009]

Prevalence

How common is it?

It is thought that nausea and vomiting affects up to 90% of pregnant women and that about 35% of these women have clinically significant symptoms [Jarvis and Nelson-Piercy, 2011].

A UK prospective study of nausea and vomiting during pregnancy found that of the 266 pregnant women studied [Gadsby et al, 1993]:

Around half had both nausea and vomiting.

Nausea without vomiting was experienced by 28%.

The incidence of hyperemesis gravidarum is around 0.5–2% of pregnancies. Figures vary because of different diagnostic criteria and ethnic variation in study populations [ACOG, 2004].

Complications

What are the complications?

Maternal complications:

Most women with nausea and vomiting in pregnancy do not experience severe complications. However, the symptoms can significantly affect their lives, in terms of [Davis, 2004; Festin, 2009]:

Loss of productivity at home and in employment.

Psychosocial morbidity (for example depression), especially in women with hyperemesis gravidarum.

Medical complications are more likely to occur in women with severe vomiting or hyperemesis gravidarum and include [Kuscu and Koyuncu, 2002; ACOG, 2004; Davis, 2004; Jarvis and Nelson-Piercy, 2011]:

Metabolic complications:

Weight loss.

Dehydration.

Acidosis.

Abnormal liver function test results.

Hyponatraemia (plasma sodium levels < 120 mmol/L), which may cause lethargy, seizures, and respiratory arrest.

Vitamin deficiencies (e.g. pyridoxine [vitamin B6]; cyanocobalamin [vitamin B12], which may cause peripheral neuropathy; and thiamine [vitamin B1] which may cause Wernicke's encephalopathy).

Mechanical complications:

Retinal haemorrhage.

Splenic avulsion.

Mallory–Weiss tears or oesophageal rupture.

Pneumothorax.

The combination of immobility and dehydration associated with hyperemesis gravidarum may increase a woman's risk of venous thromboembolism [CMACE, 2011].

Today, maternal death from nausea and vomiting is very rare, but until 60 years ago, nausea and vomiting was an important cause of maternal mortality [ACOG, 2004].

Fetal complications:

Mild or moderate nausea and vomiting have little apparent effect on pregnancy outcome; nausea and vomiting may even be predictors of successful pregnancy outcome [Davis, 2004]:

A lower rate of miscarriage has been documented among women with nausea and vomiting during pregnancy compared with controls. This is thought to be related to robust placental synthesis in a healthy pregnancy [ACOG, 2004].

In women with hyperemesis gravidarum, an increased risk of malformations is unlikely. However, a higher incidence of low birthweight babies has been documented, particularly if the mother had low pregnancy weight gain (< 7 kg) [ACOG, 2004; Dodds et al, 2006; Jarvis and Nelson-Piercy, 2011].

Fetal death is very rare and is usually limited to extreme cases of hyperemesis [ACOG, 2004].

Diagnosis

Diagnosis of nausea and vomiting in pregnancy

Diagnosis

How do I know my patient has it?

Nausea and vomiting in pregnancy are usually diagnosed on the basis of symptoms alone. Laboratory investigations are not required in uncomplicated cases:

Women may report nausea, vomiting, or both. Symptoms are usually mild and self-limiting.

Symptoms manifest before 9 weeks of gestation in almost all affected women.

If nausea and vomiting starts at 12 weeks of gestation or later, this is usually not caused by pregnancy and another cause should be sought.

A minority of women, for whom symptoms are more severe, will require further assessment. This group includes women with hyperemesis gravidarum, which commonly presents with:

Persistent vomiting not related to other causes.

Weight loss (usually at least 5% of pre-pregnancy body weight).

Signs of acute starvation (usually large ketonuria).

Basis for recommendation

Basis for recommendation

This recommendation is based on a US practice bulletin [ACOG, 2004] and expert opinion from 2 review articles [Davis, 2004; Jarvis and Nelson-Piercy, 2011].

Differential diagnosis

What else might it be?

Findings which may suggest an alternative diagnosis include:

Abdominal pain or tenderness (more than mild epigastric tenderness after retching).

Fever.

Headache or abnormal neurological examination.

Goitre.

Conditions causing nausea and vomiting in pregnancy:

Genito-urinary conditions — urinary tract infection, uraemia, pyelonephritis, ovarian torsion.

Metabolic disorders and endocrine conditions — hypercalcaemia, thyrotoxicosis, diabetic ketoacidosis, Addison's disease.

Gastrointestinal conditions — gastritis, peptic ulcer, pancreatitis, bowel obstruction, hepatitis, cholelithiasis, appendicitis. See the CKS topic on Dyspepsia - pregnancy-associated.

Neurological disorders — vestibular disease, migraine.

Other pregnancy-related conditions — acute fatty liver of pregnancy, pre-eclampsia (consider pre-eclampsia if the onset of nausea and vomiting is in the second half of pregnancy).

Drug-induced vomiting — for example iron or opioids.

Psychological disorders — for example eating disorders.

Basis for recommendation

Basis for recommendation

This information is based on a US practice bulletin [ACOG, 2004] and expert opinion in review articles [Eliakim et al, 2000; Jarvis and Nelson-Piercy, 2011].

Management

Management

Scenario: Management : covers the assessment of a woman with nausea and vomiting, and discusses self-care advice, when to consider drug treatment and when admission to hospital or referral is appropriate.

Scenario: Management

Scenario: Management of nausea and vomiting in pregnancy

156months720monthsFemale

Assessment

What assessment is required?

Women with nausea and vomiting in pregnancy do not usually require laboratory evaluation unless symptoms are severe, prolonged (in terms of overall duration during pregnancy), or extended (in terms of frequency during each day).

Enquire about:

The onset, duration, and frequency of nausea and vomiting.

Whether food and drinks are being tolerated.

Associated symptoms (for example weight loss, abdominal pain).

Any co-existing conditions (for example diabetes) which may be adversely affected by nausea and vomiting.

The effect on the woman's life (for example work, home situation and support, ability to care for her family).

The effect on the woman's mood, with further assessment if appropriate.

If there are concerns that the woman is showing signs of depression, see the CKS topic on Depression - antenatal and postnatal.

If a woman has nausea or vomiting of sufficient severity to affect fluid and food intake:

Monitor her weight.

Examine for signs of dehydration (for example tachycardia, postural hypotension).

Test the urine for ketones — urinalysis may show elevated specific gravity or ketone levels, or both.

Consider assessing for signs of hypokalaemia (muscle weakness), hypercalcaemia, hypocalcaemia (Chvostek's or Trousseau's sign), or thyrotoxicosis.

Consider ultrasonography to identify predisposing factors (for example multiple or molar pregnancy).

Measurement of serum human chorionic gonadotrophin is not recommended.

Further blood tests (for example full blood count, urea and electrolytes, liver function tests, and thyroid function tests) are not routinely recommended in primary care; if they are thought to be necessary, admission to hospital may be more appropriate.

If features suggest an alternative cause of nausea and vomiting, exclude alternative diagnoses (see Differential diagnosis).

Basis for recommendation

Basis for recommendation

This recommendation is pragmatic advice, taking into account a clinical management guideline from the American College of Obstetricians and Gynaecologists [ACOG, 2004], and an evidence-based review of nausea and vomiting in pregnancy [Davis, 2004].

Most women can eat and drink sufficiently to avoid use of anti-emetics or intravenous fluids, or admission to hospital [Jarvis and Nelson-Piercy, 2011].

Measuring serum human chorionic gonadotrophin is not recommended because it is not thought to be helpful in determining whether vomiting is caused by hyperemesis gravidarum [ACOG, 2004].

CKS suggests that if a woman is sufficiently unwell that further investigations (for example full blood count, urea and electrolytes, liver function tests and thyroid function tests) are being considered, it is more appropriate to do these as part of a secondary care assessment. Therefore, blood tests are not discussed in detail.

Admission and specialist advice

When should I admit to hospital or seek specialist advice?

Admit to hospital if:

Symptoms are severe despite 24 hours of medication (for example inability to tolerate liquids without vomiting).

There is evidence of dehydration or suspicion of medical complications.

There is continuing nausea and vomiting and the woman is unable to keep down oral antiemetics.

Seek specialist advice from an obstetrician if the woman has elevated urine ketone levels, or weight loss of greater than 5% of pre-pregnancy body weight despite drug treatment.

Have a lower threshold for admitting to hospital or seeking specialist advice if the woman has a co-existing condition (for example diabetes) which may be adversely affected by nausea and vomiting.

Basis for recommendation

Basis for recommendation

This recommendation is pragmatic advice, taking into account a clinical management guideline from the American College of Obstetricians and Gynaecologists [ACOG, 2004] and published expert opinion [Jarvis and Nelson-Piercy, 2011].

Offering advice

What advice should I offer?

Reassure the woman that nausea and vomiting are a normal part of pregnancy and that pregnancy outcomes are generally better for women who have nausea and vomiting in early pregnancy.

Advise rest and drinking little and often rather than large amounts, as this may help to prevent vomiting.

The following may also be tried:

Eating small, frequent meals high in carbohydrate and low in fat (cold meals may be more easily tolerated if nausea is smell-related).

Eating plain biscuits about 20 minutes before getting up.

Ginger.

Acupressure.

Avoiding any foods or smells that trigger symptoms.

Avoiding drinking cold, tart, or sweet beverages.

Support from family and friends is also regarded as helpful (for example assistance with household responsibilities and child care).

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.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion [SOGC, 2002; SOGC, 2011].

Dietary changes:

There is no published evidence that dietary changes relieve nausea and vomiting during pregnancy; however, they have been traditionally recommended.

Ginger and P6 (wrist) acupressure:

Ginger and P6 (wrist) acupressure are recommended to treat nausea and vomiting in pregnancy by the National Institute for Health and Clinical Excellence [NICE, 2008]. Ginger and P6 (wrist) acupressure have been used for many years to treat nausea and vomiting in pregnancy, unfortunately there is little strong or consistent evidence that they are effective [Matthews et al, 2010]. The UK Teratology Information Service (UKTIS) have reviewed the safety data for both of these treatments [UKTIS, 2012a]:

Ginger — UKTIS identified three observational studies that found no evidence of an increased risk of congenital malformations associated with ginger when taken during pregnancy.

P6 (wrist) acupressure — UKTIS found no theoretical concerns about the safety of acupressure in pregnancy, although no data were located that specifically assessed its safety.

Rest:

Sleep requirements increase in early pregnancy. Because fatigue seems to exacerbate nausea and vomiting during pregnancy, encourage women to increase their rest, especially while they are symptomatic.

Seeking specialist advice:

The recommendation about when women should be advised to seek specialist advice is based on an evidence-based review of nausea and vomiting in pregnancy [Davis, 2004].

Considering drug treatment

When should I consider drug treatment?

Consider drug treatment with an anti-emetic if initial treatments such as dietary advice or rest have failed and the woman has persistent symptoms.

Early treatment with an anti-emetic is likely to be more effective and is essential to improve the woman's quality of life, symptoms, and reduce morbidity to the fetus.

Basis for recommendation

Basis for recommendation

These recommendations are based on published expert opinion [Kuscu and Koyuncu, 2002; SOGC, 2002; Jarvis and Nelson-Piercy, 2011] and expert opinion from the Royal College of Obstetricians and Gynaecologists [RCOG, Personal Communication, 2013].

It is generally accepted that all drugs should be avoided if possible during the first trimester [BNF 65, 2013]. However, CKS acknowledges that there will be circumstances in which the benefits of medication outweigh potential risks.

Feedback from CKS expert reviewers [RCOG, Personal Communication, 2013] and published expert opinion [Jarvis and Nelson-Piercy, 2011] recommends early treatment with anti-emetics. It is thought that early treatment with an anti-emetic is more effective, and avoids hyperemesis which can lead to maternal metabolic disturbances, and placental dysfunction.

Choice of drug treatment

Which drug treatments should be used?

All anti-emetics are unlicensed for treatment of nausea and vomiting in pregnancy.

If an anti-emetic is required in pregnancy, prescribe oral promethazine or oral cyclizine, and reassess after 24 hours.

If the response to the treatment is good:

Continue treatment with the chosen anti-emetic (promethazine or cyclizine).

Review the woman once a week thereafter.

If the response to treatment is inadequate, the woman is not dehydrated, and there is no ketonuria:

Switch to another anti-emetic such as oral metoclopramide, oral prochlorperazine, or oral ondansetron.

Metoclopramide is not licensed for people under 20 years old and is known to cause oculogyric crisis, especially in young adults. Treatment with metoclopramide should not be prescribed for longer than 5 days.

At the time of writing, ondansetron is significantly more expensive than metoclopramide or prochlorperazine.

Reassess after 24 hours.

Seek specialist advice if the response to a second anti-emetic is poor.

Continue with the second anti-emetic if the response to treatment is good.

Review the woman once a week thereafter.

Decide when to stop medication using a pragmatic approach (for example it may be possible to stop anti-emetic medication at around 12–16 weeks, by which time symptoms have usually improved) in conjunction with clinical judgement (for example severity of symptoms, response to treatment in previous pregnancies, preference of the woman).

Seek specialist advice from an obstetrician or gynaecologist if:

Response to anti-emetics is inadequate.

The woman is dehydrated or has ketonuria despite drug treatment.

Basis for recommendation

Basis for recommendation

Choice of anti-emetic

Expert opinion from reviewers of this CKS topic agreed that promethazine and cyclizine could be used first-line in primary care, and that prochlorperazine and metoclopramide were suitable second-line choices. Published expert opinion [Jarvis and Nelson-Piercy, 2011] and feedback from CKS expert reviewers [RCOG, Personal Communication, 2013] also suggests that ondansetron may be considered second-line.

Evidence suggests that there is no increase in the occurrence of congenital malformations with promethazine, cyclizine, prochlorperazine, metoclopramide, or ondansetron [UKTIS, 2012a]. However a single study has shown an increased risk of isolated cleft palate following first trimester exposure to ondansetron, although most of the currently available data provide no evidence that exposure to ondansetron during pregnancy is associated with an increase in overall congenital malformation rate or other adverse pregnancy outcomes [UKTIS, 2012b].

A recently published observational study that reviewed 1,849 women exposed to ondansetron during pregnancy found that ondansetron was not associated with a significantly increased risk of adverse fetal outcomes [Pasternak et al, 2013].

Promethazine and cyclizine may be preferred because they are the most studied drugs [Mahadevan and Kane, 2006; Schaefer et al, 2007].

Although there are fewer data available for prochlorperazine, metoclopramide, and ondansetron they are also considered safe in pregnancy [Schaefer et al, 2007; RCOG, Personal Communication, 2013], however metoclopramide is associated with an increased risk of extrapyramidal side-effects in children and young adults [BNF 65, 2013].

Following a review by the European Medicines Agency metoclopramide should not be taken for longer than 5 days [EMA, 2013]. The EMA review confirmed the well-known risks of neurological effects such as short-term extrapyramidal effects associated with metoclopramide. The risk of acute (short-term) neurological effects is higher in children, although tardive dyskinesia was reported more often in the elderly, and the risk is increased at high doses or with long-term treatment. The EMA states that the risks outweighed the benefits of metoclopramide in conditions requiring long-term treatment. There have also been very rare cases of serious effects on the heart or circulation, particularly after injection.

Treatment review

Expert opinion from reviewers of this CKS topic suggest women who have nausea and vomiting in pregnancy should be reviewed 24 hours after treatment with an anti-emetic has commenced, and once a week thereafter [RCOG, Personal Communication, 2013]. The British National Formulary advises seeking specialist advice if symptoms do not resolve in 24–48 hours [BNF 65, 2013].

Duration of treatment

CKS could find no evidence regarding duration of treatment. Expert opinion from reviewers of this CKS topic states that there is no evidence to recommend a short time period of treatment and therapy should be stepped up until it is effective then continued until symptoms resolve [RCOG, Personal Communication, 2013]. CKS has therefore recommended a pragmatic approach with the use of clinical judgement as it is recognized that circumstances will vary depending on the individual.

Treatments not recommended

Pyridoxine — Although there is no evidence that pyridoxine (used alone or in combination with doxylamine) is associated with an increased risk of congenital malformations [UKTIS, 2012b], high doses of pyridoxine (greater than 50 mg daily) are known to cause peripheral neuropathy [Dalton and Dalton, 1987]. High doses of pyridoxine (up to 80 mg daily) are required to treat nausea and vomiting in pregnancy, and the Committee on Toxicity of Chemicals in Food in the UK recommends a maximum daily dose of 10 mg [DH, 1997]. Therefore CKS has not recommended the use of pyridoxine for nausea and vomiting.

Herbal treatments, homeopathy, hypnosis, hypnotherapy, psychotherapy — there is either no published evidence or limited evidence that these treatments are effective and safe to use in pregnancy.

Follow up

What follow up is required?

Women with mild symptoms usually do not require routine follow up.

If the woman's symptoms are severe enough to require medication (see Considering drug treatment), follow up after 24 hours:

Check for dehydration (for example infrequent urination, dry mucous membranes, lightheadedness).

Check for ketones in the urine.

Assess response to medication.

Consider admitting to hospital depending on the clinical findings and the effect of medication. See Admission and specialist advice.

Basis for recommendation

Basis for recommendation

CKS could find no guidelines on the referral of women with nausea and vomiting in pregnancy; therefore, the recommendations on when to follow up are pragmatic advice.

Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://medicines.org.uk/emc), or the British National Formulary (BNF) (www.bnf.org).

Prescribing drug treatments

How should drug treatments be prescribed?

Promethazine is available as promethazine hydrochloride or promethazine teoclate. Either preparation may be used:

Promethazine hydrochloride is available in two strengths — 10 mg or 25 mg tablets. Prescribe up to 25 mg as one dose at bedtime, and repeat in the morning if necessary. The 10 mg tablets can also be titrated up to a dose that gives optimal effect.

Promethazine teoclate is available as 25 mg tablets. Prescribe 25 mg at bedtime. The dose may be increased to 100 mg daily.

Cyclizine: prescribe 50 mg up to three times a day.

Prochlorperazine:

Oral tablets: prescribe up to 10 mg three times a day.

Buccal tablets: prescribe 3 to 6 mg twice a day.

Metoclopramide: prescribe 10 mg three times a day.

Ondansetron: prescribe 8 mg twice a day.

[UKMI, 2012; ABPI Medicines Compendium, 2012b; BNF 65, 2013]

Cyclizine and promethazine

Prescribing cyclizine and promethazine

What issues should I consider before prescribing cyclizine and promethazine?

Promethazine and cyclizine may cause drowsiness. The degree of sedation varies among individuals and depends on the dose given, but if affected, the woman should avoid driving or performing skilled tasks. Drowsiness may diminish after a few days of treatment.

Less common adverse effects include headache; psychomotor impairment; and antimuscarinic effects, such as urinary retention, dry mouth, blurred vision, and gastrointestinal disturbances.

The use of promethazine in the 2 weeks before delivery may cause irritability and excitement in the neonate.

[Schaefer et al, 2007; ABPI Medicines Compendium, 2011; ABPI Medicines Compendium, 2013b; BNF 65, 2013]

Advice about cyclizine and promethazine

What advice should I give to women about cyclizine and promethazine?

Reassure the woman that cyclizine and promethazine are suitable for use in pregnancy:

No increased risks of congenital abnormalities, above the background rate for the population, have been reported when cyclizine or promethazine have been used in therapeutic doses [Schaefer et al, 2007; UKTIS, 2012a].

Advise the woman that cyclizine and promethazine may make them feel excessively drowsy, and if affected they should not drive or operate machinery [BNF 65, 2013].

Explain that the drowsiness diminishes after a few days.

Metoclopramide

Prescribing metoclopramide

What issues should I consider before prescribing metoclopramide?

Metoclopramide is not suitable for women younger than 20 years of age because it can induce acute dystonic reactions involving facial and skeletal muscle spasms and oculogyric crises:

These reactions are more common in younger people (particularly girls and young women) and people who are taking other drugs known to cause extrapyramidal effects. They generally occur within a few days of starting treatment and subside within 24 hours of stopping metoclopramide. Injection of procyclidine, 5–10 mg intravenously or intramuscularly, will abort a dystonic attack.

Other adverse effects include drowsiness, restlessness, and diarrhoea.

Following a review by the European Medicines Agency metoclopramide should not be taken for longer than 5 days [EMA, 2013].

The EMA review confirmed the well-known risks of neurological effects such as short-term extrapyramidal effects associated with metoclopramide. The risk of acute (short-term) neurological effects is higher in children, although tardive dyskinesia was reported more often in the elderly, and the risk is increased at high doses or with long-term treatment. The EMA states that the risks outweighed the benefits of metoclopramide in conditions requiring long-term treatment. There have also been very rare cases of serious effects on the heart or circulation, particularly after injection.

[ABPI Medicines Compendium, 2013a]

Advice about metoclopramide

What advice should I give to women about metoclopramide?

Reassure the woman that metoclopramide is suitable for use in pregnancy:

No increased risks of congenital abnormalities above the background rate for the population have been reported when metoclopramide has been used in therapeutic doses [Schaefer et al, 2007; UKTIS, 2012a].

One cohort study has shown a higher incidence of premature delivery after metoclopramide exposure [UKTIS, 2012a].

Discuss the possibility of extrapyramidal adverse effects, explaining that they are possible but unlikely at the prescribed dose.

Prochlorperazine

Prescribing prochlorperazine

What issues should I consider before prescribing prochlorperazine?

The most commonly reported adverse effects are nervous system disorders:

Acute dystonia or dyskinesia are usually transitory and are more common in children and young adults. These effects usually occur within the first 4 days of treatment.

Prochlorperazine may cause drowsiness but is less sedating than cyclizine and promethazine. The degree of sedation varies among individuals and depends on the dose given, but if affected, the person should avoid driving or performing skilled tasks. Anticholinergic adverse effects may also occur (for example blurred vision and dry mouth).

[ABPI Medicines Compendium, 2012a]

Advice about prochlorperazine

What advice should I give to women about prochlorperazine?

Reassure the woman that prochlorperazine is suitable for use in pregnancy:

No increased risks of congenital abnormalities above the background rate for the population have been reported when prochlorperazine is used in therapeutic doses [Schaefer et al, 2007; UKTIS, 2012a].

Discuss the possibility of extrapyramidal adverse effects, explaining that they are possible but unlikely at the prescribed dose.

Explain that prochlorperazine can be sedating; if affected, the woman should not drive or operate machinery.

Ondansetron

Ondansetron

Prescribing ondansetron

Prescribing ondansetron

Contra-indications and precautions

Transient ECG changes, including QT interval prolongation and cases of Torsade de Pointes, have been reported in people taking ondansetron. Ondansetron should be administered with caution to people who have or may develop prolongation of QT interval.

Adverse effects

The most common adverse effects of ondansetron include constipation, headache, and flushing.

Other less common adverse effects include hiccups, hypotension, bradycardia, chest pain, arrhythmias, movement disorders, and seizures.

[ABPI Medicines Compendium, 2012b; BNF 65, 2013]

Advice about ondansetron

Advice about ondansetron

Reassure the woman that ondansetron is suitable for use in pregnancy:

Most studies have found no increased risks of congenital abnormalities above the background rate for the population when ondansetron is used in therapeutic doses [UKTIS, 2012b; Pasternak et al, 2013].

However, a single study has shown an increased risk of isolated cleft palate following first-trimester exposure to ondansetron [UKTIS, 2012b] .

Evidence

Evidence

Supporting evidence

Recommended treatments

Evidence on treatments recommended in primary care

The UK Teratology Information Service (UKTIS) has reviewed the evidence on the safety of treatments for nausea and vomiting in pregnancy [UKTIS, 2012a]. A brief summary on the safety of treatments recommended in primary care is provided in Table 1.

A more detailed summary can be found on the Toxbase website (www.toxbase.org)

Table 1 . Summary of the UKTIS evidence on safety of treatments recommended in primary care to treat nausea and vomiting in pregnancy.
Medicine Evidence on safety in pregnancy
Antihistamines (H1receptor antagonists) — cyclizine and promethazine Extensively used during pregnancy. Large amount of safety data available regarding antihistamines in general. No increase in rate of major congenital malformations observed. Published data specifically for cyclizine are limited, but no increase in congenital malformations has been reported with either cyclizine or promethazine use during pregnancy. Other pregnancy outcomes have not been studied for either drug.
Metoclopramide Fetal exposure data limited to one large case control and a small cohort study. No increase in congenital malformations in exposed pregnancies. A cohort study showed higher incidence of premature delivery after metoclopramide exposure. Use in younger adults has been associated with dystonias and should therefore not be routinely used as first-line treatment.
Ondansetron A single study has shown an increased risk of isolated cleft palate following first trimester exposure to ondansetron, however most of the currently available data provide no evidence that exposure to ondansetron during pregnancy is associated with an increase in overall congenital malformation rate or other adverse pregnancy outcomes, although it should be noted that these data are limited.
Phenothiazines (including prochorperazine) A large meta-analysis examining pregnancy outcomes after exposure to various and multiple phenothiazines did not provide evidence of increased risk of congenital malformations. Neither did a case-control study examining outcomes after exposure specifically to prochlorperazine.
Ginger One population-based case-control study and two cohort studies did not provide evidence of increased congenital malformation rates.
Acupressure No theoretical concerns about safety of acupressure in pregnancy, although no data were located that specifically assessed safety.
Data from: [UKTIS, 2012a]

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of nausea and vomiting in pregnancy.

Search dates

January 2008 - December 2012

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

exp Nausea/, exp Vomiting/, nausea.tw., vomit$.tw., emesis.tw.,

exp Pregnancy/, Hyperemesis Gravidarum/, preg$.tw., (hyperemesis adj gravidarum).tw., antenatal.tw.

Table 1 . Key to search terms.
Search commands Explanation
/ indicates a MeSh subject heading with all subheadings selected
.tw indicates a search for a term in the title or abstract
exp indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree
$ indicates that the search term was truncated (e.g. wart$ searches for wart and warts)
Sources of guidelines

National Institute for Health and Care Excellence (NICE)

Scottish Intercollegiate Guidelines Network (SIGN)

Royal College of Physicians

Royal College of General Practitioners

Royal College of Nursing

NICE Evidence

Health Protection Agency

World Health Organization

National Guidelines Clearinghouse

Guidelines International Network

TRIP database

GAIN

NHS Scotland National Patient Pathways

New Zealand Guidelines Group

Agency for Healthcare Research and Quality

Institute for Clinical Systems Improvement

National Health and Medical Research Council (Australia)

Royal Australian College of General Practitioners

British Columbia Medical Association

Canadian Medical Association

Alberta Medical Association

University of Michigan Medical School

Michigan Quality Improvement Consortium

Singapore Ministry of Health

National Resource for Infection Control

Patient UK Guideline links

UK Ambulance Service Clinical Practice Guidelines

RefHELP NHS Lothian Referral Guidelines

Medline (with guideline filter)

Driver and Vehicle Licensing Agency

NHS Health at Work (occupational health practice)

Sources of systematic reviews and meta-analyses

The Cochrane Library :

Systematic reviews

Protocols

Database of Abstracts of Reviews of Effects

Medline (with systematic review filter)

EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

NIHR Health Technology Assessment programme

The Cochrane Library :

NHS Economic Evaluations

Health Technology Assessments

Canadian Agency for Drugs and Technologies in Health

International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

The Cochrane Library :

Central Register of Controlled Trials

Medline (with randomized controlled trial filter)

EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Bandolier

Drug & Therapeutics Bulletin

TRIP database

Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

Department of Health

Health Management Information Consortium (HMIC)

Patient experiences

Healthtalkonline

BMJ - Patient Journeys

Patient.co.uk - Patient Support Groups

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

British National Formulary (BNF)

electronic Medicines Compendium (eMC)

European Medicines Agency (EMEA)

LactMed

Medicines and Healthcare products Regulatory Agency (MHRA)

REPROTOX

Scottish Medicines Consortium

Stockley's Drug Interactions

TERIS

TOXBASE

Micromedex

UK Medicines Information

References

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