Review Severe nausea and vomiting of pregnancy: should it be treated with appropriate pharmacotherapy?

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1 /toag Severe nausea and vomiting of pregnancy: should it be treated with appropriate pharmacotherapy? Authors Roger Gadsby / Tony Barnie-Adshead Key content: Severe nausea and vomiting occurs in up to 30% of pregnant women and it can cause significant morbidity. There are over admissions per year for hyperemesis gravidarum in England. Safe, effective treatments for severe nausea and vomiting of pregnancy are available. Early treatment is important to prevent the development of hyperemesis gravidarum. Treatment algorithms have been developed in other countries. Learning objectives: To recognise that severe nausea and vomiting of pregnancy often occurs after midday, so the term morning sickness is inappropriate. To increase knowledge of the evidence for safe, effective treatment of the condition. To understand that effective management is important. Ethical issues: There are concerns about teratogenicity when prescribing pharmacological therapy: severe pregnancy sickness may, therefore, go untreated. Lack of treatment may be associated with increased admissions for hyperemesis gravidarum. Keywords antihistamines / doxylamine / hyperemesis gravidarum / pyridoxine / teratogenicity Please cite this article as: Gadsby R, Barnie-Adshead T. Severe nausea and vomiting of pregnancy: should it be treated with appropriate pharmacotherapy? The Obstetrician & Gynaecologist. Author details Roger Gadsby MBE FRCGP General Practitioner (Nuneaton); and Associate Clinical Professor Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK r.gadsby@warwick.ac.uk (corresponding author) Tony Barnie-Adshead FRCGP Retired General Practitioner Nuneaton, Warwickshire, UK 107

2 The Obstetrician & Gynaecologist Introduction Although nausea and vomiting of pregnancy (NVP) is now rarely life threatening, it can have a profound effect on the quality of women s lives. Severe NVP can cause feelings of depression, 1 difficulties between partners, 1 less effective parenting 2 and concern for the health of the unborn child. 1 Some women have such severe NVP that they are less likely to have another child, 1 or they consider terminating subsequent pregnancies. 1 In some women the condition is so intolerable that they actually elect to have a termination of the current pregnancy. 3 Between 1979 and 1992 in England and Wales, excessive vomiting of pregnancy was the stated cause of between 25 and 59 terminations per year 3 and from 1992 to 2001 in England there were between 15 and 37 terminations each year. 4 Approximately 30% of pregnant working women need time off from paid employment because of NVP. 5 They need additional rest and some report that they cannot carry out their household duties or parenting activities satisfactorily. 2 Women with severe NVP have to endure persistent nausea, which many describe as being intolerable, and it can lead to them being unable to cook, shop, eat a satisfactory diet or attend social activities for fear of vomiting. 6 Morning sickness is a misleading name for the condition, as only 13% of women with the condition have symptoms exclusively in the mornings: in the majority, symptoms occur both before and after midday. A more appropriate term, therefore, would be episodic nausea and vomiting of pregnancy. 7 Prevalence of severe nausea and vomiting of pregnancy Approximately 80% of pregnant women have some degree of NVP 5 and the disorder becomes severe in approximately 30% of pregnant women with symptoms: 20% have hours of nausea per pregnancy and a further 10% have hours, which may be associated with vomiting at least 40 times. 5 Approximately % have such severe NVP that they require hospital admission for rehydration and correction of electrolyte imbalance: this condition is termed hyperemesis gravidarum. 7 The continuing significance of pregnancy sickness is reflected in the increasing number of admissions for hyperemesis gravidarum in England. Between the years 1989/1990 and 2003/2004, the finished admission episodes for a primary diagnosis of excessive vomiting in pregnancy (International Classification of Diseases [ICD]-9 643, ICD ) in England rose from 8637 to , 8 an almost three-fold increase. Between the years 2004/5 and 2005/6, admissions for ICD rose from to In the year 2006/7, the total admissions for ICD stood at Information about the effect of treatment of NVP on admission rates for hyperemesis gravidarum has been documented in publications from Canada where, between 1983 and 1989, there was a rise in admission rates for hyperemesis gravidarum after Bendectin (pyridoxine [vitamin B 6 ] and doxylamine) (Merrell Dow, Bridgewater NJ, USA), an effective treatment for NVP, was withdrawn from the market in Rates of admission then began to decline between 1990 and 1995, which was associated with increasing prescription of the similar drug Diclectin (doxylamine 10 mg with pyridoxine 10 mg) (Duchesnay Inc., Blainville QC, Canada), a safe, effective treatment for NVP. 11 In view of this Canadian experience, it can be argued that in England the implementation of a strategy to offer early effective treatment for NVP would reduce admission rates for hyperemesis gravidarum. In their clinical guidelines on the management of NVP, 12 the Society of Obstetricians and Gynaecologists of Canada suggest that costs, including hospital admissions, visits to health professionals and time lost from work, can be reduced if NVP is treated early. Similarly, in their practice bulletin on the clinical management of NVP, 13 the American College of Obstetricians and Gynecologists state that once symptoms of NVP progress, treatment can become more difficult, therefore, treatment in the early stages can prevent more serious complications, including hospital admission. Management of severe nausea and vomiting of pregnancy Efficacy and safety of antihistamines In a Cochrane review 14 of therapies for NVP published in 2002, 23 randomised controlled trials of various treatments were reviewed. The analysis of all anti-emetic drugs, using data from 13 trials, showed a beneficial reduction in the incidence of nausea. In four trials they caused more drowsiness than placebo. Three trials compared Bendectin (the H1 receptor antagonist antihistamine doxylamine 10 mg and pyridoxine 10 mg combination tablet) with placebo and showed a reduction in nausea similar to that achieved by all the anti-emetics so combined. 14 The trial in which four tablets of Bendectin were administered per day showed the greatest benefit. 15 A further Cochrane review was published in It reviewed the evidence included in the

3 review and papers published since then. The authors state that they found only limited evidence from trials to support the use of pharmacological agents, including pyridoxine, antihistamines and other anti-emetic agents, to relieve mild to moderate nausea and vomiting. A related Cochrane review is going to examine their use in women with more severe symptoms. In the UK, Bendectin was marketed under the trade name Debendox (Merrell Dow). The production of the drug was halted in June 1983 after 27 years of use because of exhaustive defence costs against liability suits for fetal defects. All the defences were successful. The manufacturer estimated that Bendectin had been used in approximately 33 million pregnancies: ample basis for epidemiological studies of cause and effect. 17 Diclectin has been available in Canada since The safety of antihistamines in early pregnancy has been the subject of extensive investigation. A review of 24 studies, 18 with over participating women, indicated that there is no positive association between the use of H1 blocker antihistamines in the first trimester and rates of major malformations. The conclusion was that this review had an unprecedented power to refute suggestions of teratogenic potential of this class of drugs. An antenatal guideline published by the National Institute for Health and Clinical Excellence (NICE) in June states that, if a woman requests or would like to consider treatment for NVP, antihistamines should be used. This is the only pharmacological treatment for NVP mentioned in the recommendation section. Efficacy and safety of pyridoxine There is evidence that pyridoxine is effective in treating NVP. In one randomised controlled trial, pregnant women received either 25 mg pyridoxine or placebo three times a day: in the pyridoxine group there was a significant reduction in the mean nausea score and in the number of participants with vomiting. In another randomised controlled trial 21 of 342 pregnant women who received either 10 mg pyridoxine or placebo three times a day, there was a significant decrease in the mean nausea score in the treated group. There was also a greater reduction in the mean number of vomiting episodes in the treated group, but this did not reach statistical significance. The Cochrane review of on the treatment of NVP considered these two pyridoxine trials and concluded that pyridoxine is effective in reducing nausea. Many women with severe NVP say that nausea is the most distressing symptom of the condition. 22 The treatment of nausea should, therefore, be a high priority in the management of NVP. The safety of pyridoxine has been investigated in a cohort study 23 which found no association between pyridoxine and major malformations. Pyridoxine has also been shown to be non-teratogenic when combined with doxylamine, 10 mg of each up to four times a day. 12,13,17 Recommendations in management guidelines Both Canadian and American guidelines recommend early recognition and management of NVP. They suggest that a doxylamine/pyridoxine combination should be standard care, or first-line treatment, since there is very strong evidence to support its safety and efficacy, and a treatment algorithm has been published in both countries. 12,13 In the NICE antenatal guideline, 19 the guideline development group reviewing treatments for NVP quoted the efficacy and safety data for antihistamines and pyridoxine as mentioned above. 20, 21 However, the group stated that concerns about the possible toxicity of pyridoxine in high doses have not yet been resolved and so they do not recommend pyridoxine for the treatment for NVP. Nevertheless, the safety and efficacy of pyridoxine at up to 40 mg per day in combination with an H1 receptor antagonist antihistamine for the treatment of NVP are clearly affirmed in the American and Canadian guidelines. Pyridoxine at up to 40 mg daily should, therefore, be considered as part of the initial standard treatment for NVP. Other issues of recommendation and licence The National Health Service Clinical Knowledge Summary for NVP 24 states that all anti-emetics (including antihistamines) are unlicensed for the treatment of NVP in the UK. They state that if an anti-emetic is required in pregnancy, oral promethazine or oral cyclizine (H1 receptor antagonist antihistamines) can be taken. These are available without a prescription in the UK, but the information leaflet in the drug packs states: Do not take if you are pregnant unless they have been recommended by a doctor. Lack of an approved or licensed drug for symptoms of NVP can be associated with unwarranted and preventable adverse health effects from severe NVP. 25 In a Canadian observational study, 25 there was evidence that the majority of women with NVP 109

4 The Obstetrician & Gynaecologist do not receive appropriate treatment because of misinformation and misconception related to teratogenic risk. Pre-emptive treatment Some women say they are less likely to want another pregnancy because of the severe NVP they suffered previously; 1 some women ask healthcare professionals if anything can be done to ensure that they do not have to endure similar symptoms in their next pregnancy. In a recent study, women who had a history of severe NVP with or without hyperemesis gravidarum were offered anti-emetic therapy either as soon as they became aware of the present pregnancy or no later than the beginning of NVP symptoms. A control group of 35 women with similar histories of NVP did not receive pre-emptive treatment. Nausea and vomiting of pregnancy in the pre-emptive therapy group was improved significantly compared with the control group. In the pre-emptive group, only 8 women experienced hyperemesis gravidarum in the index pregnancy compared with 18 in their previous pregnancy. In contrast, 80% of women in the control group experienced severe NVP again. The authors suggest that further research is needed to define optimal dosages and to clarify whether single or combined anti-emetics are most effective for pre-emptive treatment of recurrent severe forms of NVP. Certainly one should choose medications known to be safe and avoid drugs for which evidence of safety and effectiveness is inconclusive. 25 Conclusion (See Box 1 for a summary of recommendations and guidelines.) There is good evidence for the safety and effectiveness of an H1 receptor antagonist antihistamine with pyridoxine in the treatment of pregnancy nausea and vomiting. The best-attested treatment for efficacy and safety is doxylamine 10 mg with pyridoxine 10 mg (Diclectin) up to four times a day. In the UK, the closest equivalent available is Avomine (promethazine teoclate) (Manx Healthcare, Warwick, Warwickshire, UK) tablets 25 mg (up to 100 mg daily) or cyclizine 50 mg (up to 150 mg daily) plus, in each case, pyroxidine 10 mg (up to 40 mg daily). Any woman who develops symptoms of NVP and finds no help from lifestyle measures should be considered for safe, effective oral treatment as soon as the condition reaches a level of severity that impairs her quality of life. This is often about 2 weeks after the onset of NVP. For women who have had severe NVP or hyperemesis gravidarum in a previous pregnancy, pre-emptive treatment with safe and effective medication started as soon as NVP develops has been shown in one study 26 to reduce the risk of developing severe symptoms in the current pregnancy. In reducing the incidence of hyperemesis gravidarum, a most unpleasant and medically significant condition, pre-emptive treatment could reduce hospital admissions and hence costs to the National Health Service. Disclosure of interests Dr Gadsby and Dr Barnie-Adshead are trustees of the charity Pregnancy Sickness Support (Charity Number ), which provides information and support to women suffering from NVP. The charity has received financial support from a number of donors, including Duchesnay Inc. of Canada, who make Diclectin, which is available to treat pregnancy sickness symptoms in Canada. Box 1 Summary of recommendations and guidelines regarding management of NVP Society of Obstetricians and Gynaecologists of Canada 12 American College of Obstetricians and Gynecologists 13 National Institute for Health and Clinical Excellence 18 The National Health Service Clinical Knowledge Summary for NVP 23 Early recognition and management recommended. Costs, including hospital admissions, visits to health professionals and time lost from work, can be reduced if treated early. A doxylamine/pyridoxine combination should be standard care or first-line treatment, since there is very strong evidence to support its safety and efficacy. Guidelines include a treatment algorithm. Early recognition and management recommended. Once symptoms progress, treatment can become more difficult, therefore, treatment in the early stages can prevent more serious complications, including hospital admission. A doxylamine/pyridoxine combination should be standard care or first-line treatment, since there is very strong evidence to support its safety and efficacy. Guidelines include a treatment algorithm. If a woman requests or would like to consider treatment, antihistamines should be used (the only pharmacological treatment mentioned in the recommendation section). Concerns about the possible toxicity of pyridoxine in high doses have not yet been resolved: they do not recommend pyridoxine. All anti-emetics (including antihistamines) are unlicensed for the treatment of NVP in the UK. If an anti-emetic is required in pregnancy, oral promethazine or oral cyclizine (H1 receptor antagonist antihistamines) can be taken. These are available without a prescription in the UK, but the information leaflet in the drug packs states: Do not take if you are pregnant unless they have been recommended by a doctor. 110

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