Ondansetron Compared With Metoclopramide for Hyperemesis Gravidarum: A Randomized Controlled Trial

Abas, Mohamed Norazam MD; Tan, Peng Chiong FRCOG; Azmi, Noor MOG; Omar, Siti Zawiah MOG

Obstetrics & Gynecology:
doi: 10.1097/AOG.0000000000000242
Contents: Original Research

OBJECTIVE: To compare ondansetron with metoclopramide in the treatment of hyperemesis gravidarum.

METHODS: We enrolled 160 women with hyperemesis gravidarum in a double-blind randomized trial. Participants were randomized to intravenous 4 mg ondansetron or 10 mg metoclopramide every 8 hours for 24 hours. Participants kept an emesis diary for 24 hours; at 24 hours, they expressed their well-being using a 10-point visual numeric rating scale and answered an adverse effects questionnaire. Nausea intensity was evaluated using a 10-point visual numeric rating scale at enrollment and at 8, 16, and 24 hours. Primary analysis was on an intention-to-treat basis.

RESULTS: Eighty women each were randomized to ondansetron or metoclopramide. Median well-being visual numeric rating scale scores were 9 (range, 5–10) compared with 9 (range, 4–10) (P=.33) and vomiting episodes in the first 24 hours were 1 (range, 0–9) compared with 2 (range, 0–23) (P=.38) for ondansetron compared with metoclopramide, respectively. Repeat-measures analysis of variance of nausea visual numeric rating scale showed no difference between study drugs (P=.22). Reported rates of drowsiness (12.5% compared with 30%; P=.01; number needed to treat to benefit, 6), xerostomia (10.0% compared with 23.8%; P<.01; number needed to treat to benefit, 8), and persistent ketonuria at 24 hours (12.5% compared with 30%; P=.01; number needed to treat to benefit, 6) were less frequent with ondansetron. Length of hospital stay was similar.

CONCLUSION: Ondansetron and metoclopramide demonstrated similar antiemetic and antinauseant effects in hyperemesis gravidarum. However, the overall profile, particularly regarding adverse effects, was better with ondansetron. In our setting, metoclopramide was significantly less expensive than ondansetron and remained a reasonable antiemetic choice.

CLINICAL TRIAL REGISTRATION: ISRCN Register, www.isrctn.org, ISRCTN00592566.


In Brief

The effect of ondansetron during hyperemesis gravidarum on vomiting, well-being, and nausea is similar, but drowsiness, xerostomia, and persistence of ketonuria are less frequent compared with the effects of metoclopramide.

Author Information

Department of Obstetrics and Gynecology, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, Malaysia.

Corresponding author: Peng Chiong Tan, FRCOG, Department of Obstetrics and Gynecology, University of Malaya, Faculty of Medicine, Lembah Pantai, Kuala Lumpur 50603, Malaysia; e-mail: pctan@um.edu.my.

Supported by a University of Malaya grant (grant reference number RG436/12HTM).

Financial Disclosure The authors did not report any potential conflicts of interest.

Article Outline

Nausea and vomiting affect approximately 70 to 85% of pregnancies.1 Hyperemesis gravidarum, a more serious form that requires hospitalization, affects 0.5 to 2% of pregnancies and, if intractable, may result in the need for pregnancy termination or even maternal death.2 The mainstays in the initial management of hyperemesis gravidarum are rehydration, correction of electrolyte imbalance, and symptom relief. The American College of Obstetricians and Gynecologists in their 2004 guideline recommends dimenhydrinate, metoclopramide, or promethazine as first-line alternatives, with ondansetron as a second-line parenteral antiemetic for hospitalized hyperemesis gravidarum.3

Metoclopramide has a better side effect profile compared with promethazine in hyperemesis gravidarum.4 It is commonly used for hyperemesis gravidarum5 and has an excellent safety profile.6,7 Ondansetron use for hyperemesis gravidarum was reported as early as 1992.8 A pilot study of 30 women showed that ondansetron is as effective as promethazine in hyperemesis gravidarum and is tolerated better.9 Although trial evidence of the superiority of ondansetron as an antiemetic in pregnancy is lacking,2 its use has been recommended10 and it is increasingly used as a first-line antiemetic for nausea and vomiting in pregnancy11 and hyperemesis gravidarum.5 Ondansetron does not appear to be an animal teratogen.12 Early pregnancy exposure to ondansetron in humans is not associated with major malformations.11 A major study published in 2013 showed that ondansetron use in pregnancy also has a reassuring safety profile.13 In a variety of settings like chemotherapy,14 radiotherapy,15 and after surgery,16,17 ondansetron is superior to metoclopramide as an antiemetic and is also tolerated better. We hypothesize that ondansetron may be more effective and better tolerated than metoclopramide as an antiemetic in hyperemesis gravidarum. We undertook a powered trial to compare these agents.

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The trial was conducted in a full-service, state-funded university hospital open to the public in Kuala Lumpur, Malaysia. Ethics approval was obtained from the University Malaya Medical Center Medical Ethics Committee (approval date 24 August 2011, reference number 871.2). University of Malaya provided a grant (grant reference number RG436/12HTM) for the trial. The trial is registered with ISRCTN (identifier ISRCTN00592566). This trial was performed in compliance with the Declaration of Helsinki on human studies. Written informed consent was obtained from all participants.

The diagnosis of hyperemesis gravidarum required the presence of nausea and intractable vomiting sufficient to cause dehydration and metabolic disturbance of a severity to require hospitalization, occurrence early in pregnancy, and with no other obvious cause. Women hospitalized for the first time with this diagnosis were approached and enrolled by their providers. In our center, initial inpatient treatment at first hospitalization for hyperemesis gravidarum typically included intravenous rehydration with normal saline solution at the rate of 3 L over the course of 24 hours (with potassium chloride added if required for hypokalemia), oral thiamine 10 mg daily, and an intravenous antiemetic.

Inclusion criteria were clinical diagnosis of hyperemesis gravidarum with clinical dehydration and ketonuria (of 2+ or greater) on urine dipstick and gestation of 16 weeks or less. Exclusion criteria were multiple gestations, established nonviable pregnancy, any preexisting medical condition that could be associated with nausea and vomiting, and known allergy to metoclopramide or ondansetron.

Providers counseled consented and enrolled participants regarding their enrolment into the trial. Participants were randomized by the sequential opening of numbered, sealed, and opaque envelopes stating allocation to “drug A” or “drug B” on a one-to-one ratio. The envelopes were prepared by an author (M.N.A.) in random blocks of four or eight using a computer-generated randomization sequence obtained from http://www.random.org.

Study drugs (4 mg ondansetron or 10 mg metoclopramide) were diluted in 100 mL normal saline by an author (M.N.A.) and the standard 100-mL normal saline packs were labeled as A or B. Except for the label, study drug packs were identical and contained colorless fluid. Drug packs prepared in advance were kept in the ward refrigerator at 4°C and discarded if unused after 24 hours. We swapped labeling of A and B for ondansetron and metoclopramide periodically to prevent inadvertent elucidation of allocation from consistent drug effects. The label swaps were not revealed to providers. We chose a 4-mg dose of ondansetron because a meta-analysis found no evidence that ondansetron is more effective in doses larger than 4 mg.18

The allocated trial drug was infused over the course of approximately 10 minutes through an indwelling intravenous catheter as soon as possible after randomization, and then every 8 hours for a course of four doses over the next 24 hours. Participants were asked to record in a diary vomiting episodes as they occurred and to record nausea intensity using the 10-point visual numeric rating scale (high score denoting worse nausea) at enrollment (before administration of study drug) and then every 8 hours at each study drug dose administration. At 24 hours, participants were instructed to record their well-being over the course of the study period by using a 10-point visual numeric rating scale (higher score indicates better well-being) and to respond to a questionnaire with “yes” or “no” answers regarding symptoms they had experienced during the preceding 24 hours of study.

At the conclusion of the 24-hour main study period, the trial drug was stopped and open-label treatment of metoclopramide (intravenously or orally) was started if an antiemetic was still needed. Women who had responded well to treatment were switched to an oral antiemetic; the intravenous route was typically reserved for suboptimal responders. Participants received standard care for hyperemesis gravidarum as has been described for the management of hyperemesis gravidarum patients in our hospital.19

The predetermined primary outcomes were well-being (using a 10-point visual numeric rating scale, with higher score indicating greater well-being) and vomiting episodes in the 24-hour study period. Secondary outcomes included visual numeric rating scale scores for nausea at recruitment and at 8, 16, and 24 hours, responses on the symptoms questionnaire, ketonuria status at 24 hours, treatment curtailment (not completing four study drug doses as per protocol for any reason and separately because of adverse events) during the study period, open-label use of intravenous metoclopramide after the study, and length of hospital stay.

A previous trial comparing ondansetron and metoclopramide in hyperemesis gravidarum was not available to provide pilot data for sample size estimation at trial inception. Therefore, we based our sample size calculation on the assumption that ondansetron will improve well-being score (using a 10-point visual numeric rating scale) at 24 hours by 1 unit compared with metoclopramide. Assuming that the well-being visual numeric rating scale would have a standard deviation of 2 units and setting recruitment ratio at one to one, α at 0.05, and power at 80%, 64 women were required in each arm. Factoring in the possibility that the visual numeric rating scale score might not be normally distributed and that the Mann-Whitney U test might have to be applied in preference to the Student t test for data analysis, we increased the enrollment target by 10%. A 10% dropout rate was also factored in, resulting in a calculated sample size of a total of 158 women for a suitably powered trial.

Data were entered into SPSS 17. Analysis was by intention to treat. The normality of distribution of continuous variables was checked with the one-sample Kolmogorov-Smirnov test. The Student t test was applied in the analyses of normally distributed continuous variables, with the Mann-Whitney U test used in preference if data distribution was not normal. Two-by-two categorical datasets were analyzed by Fisher exact test and larger categorical datasets were analyzed by the χ2 test. Ordinal variables were analyzed by the Mann-Whitney U test. Repeated-measures analysis of variance was applied to the series of nausea visual numeric rating scale scores. Numbers needed to treat were generated using GraphPad QuickCalc software if the bivariate analyses were significant. All tests were two- sided and P<.05 was considered significant.

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The trial recruited from 5 November 2011 to 4 August 2012. Figure 1 depicts the recruitment flow of trial participants. Patients admitted for hyperemesis gravidarum are included in the flow chart as potential recruits during the periods when the trial was recruiting. One hundred sixty women were recruited and randomized (80 in each arm). Recruitment ceased when the targeted sample size was attained. The allocated study drug was administered as planned to all participants. One patient randomized to ondansetron withdrew after receiving two doses of the study drug because of safety concerns about antiemetics (antiemetic use was discontinued altogether by her provider because she had responded well at that point), but she cooperated with answering the adverse symptom questionnaire. Another patient assigned to metoclopramide had development of prominent skin rashes that were assumed to be drug-related after receiving two doses of study drug (antiemetic use was also discontinued by the provider), and she also cooperated with questionnaire answering. Concealment of study drug allocation was maintained in these two cases. Five participants partially completed their nausea visual numeric rating scale or well-being score sheets. There were 14 cases with routine urine cultures revealing a significant (105 colony conforming units/mL or more) pure growth of uropathogenic bacterium. We included these cases in the primary analysis because the positive cultures probably represented asymptomatic bacteriuria of pregnancy rather than being a major contributor to symptoms of nausea and vomiting.20 All available data were included in the intention-to-treat analysis.

Table 1 depicts the characteristics of the participants stratified according to randomization to ondansetron or metoclopramide. Participant characteristics across the two arms were similar. In addition to the characteristics shown in Table 1, all other parameters from the renal function test and full blood count were similar, as were the liver function test parameters when performed (data not shown).

Table 2 depicts the outcomes analyses stratified according to randomization to ondansetron or metoclopramide. For the two primary outcomes, results were similar: median (range) well-being visual numeric rating scale scores were 9 (5–10) compared with 9 (4–10) (P=.33), and vomiting episodes in the first 24 hours were 1 (0–9) compared with 2 (0–23) (P=.38) for ondansetron and metoclopramide, respectively. Of the secondary outcomes, nausea visual numeric rating scale scores at 8, 16, and 24 hours after randomization were not significantly different when assessed separately at each time point. Repeated-measures analysis of variance also showed no difference across the trial arms (P=.22) for nausea visual numeric rating scale scores, although generally across both arms, nausea score lessened significantly over time (P<.001). Of the yes or no responses to the questionnaire regarding symptoms at the end of the 24-hour study period, drowsiness (12.5% compared with 30%; P=.01; number needed to treat [NNT] to benefit, 6) and xerostomia (dry mouth; 10.0% compared with 23.8%; P<.01; NNT to benefit, 8) were less frequently reported after allocation to ondansetron than after allocation to metoclopramide. Ketonuria was less likely to be present at 24 hours (12.5% compared with 30%; P=.01; NNT to benefit, 6) for the ondansetron arm. The rates of overall treatment curtailment and treatment curtailment attributable to adverse events, absence of vomiting, need for continuation with open-label intravenous antiemetic, and the length of hospital stay were not different between the trial arms. Difficulty sleeping, dizziness, diarrhea, headache, palpitations, and skin rash were reported in similar proportions across the trial arms. Six women did not receive the full four doses of the allocated study drug in the 24-hour study period as per trial protocol: four from the ondansetron arm (three had declined further antiemetic because they felt fully recovered and one withdrew from the trial because of safety concerns about antiemetic use) and two from the metoclopramide arm (one declined further antiemetic because she felt fully recovered and one had stopped using the study drug because of prominent skin rashes presumed to be an allergic drug reaction). Excluding the 14 cases of significant bacteriuria from the analysis did not materially affect the findings (Appendix 1, available online at http://links.lww.com/AOG/A492, and Appendix 2, available online at http://links.lww.com/AOG/A493).

Post hoc, considering overall well-being (mean± standard deviation) visual numeric rating scale of 8.7±1.1 compared with 8.3±1.6 for ondansetron and metoclopramide, the calculated statistical power of our study was only 44.9%. However, a small difference of 0.4 on a 10-point visual numeric rating scale in our view was not likely to be clinically relevant. Our sample size was calculated with a β set at 0.2 and α of 0.05 to evaluate the well-being difference of 1 unit of the 10-point visual numeric rating scale (a standard deviation of 2 units in visual numeric rating scale score distribution was assumed). Given that the actual standard deviation in the well-being visual numeric rating scale scores was narrower (1.1 compared with 1.6 for ondansetron compared with metoclopramide, respectively), the power of the trial to detect a one-unit difference in well-being score is actually 99.6% (calculator accessible via http://www.dssresearch.com/KnowledgeCenter/toolkitcalculators/statisticalpowercalculators.aspx). There was no known major unintended harm.

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Intravenous ondansetron or metoclopramide are now recommended first-line alternatives as antiemetic therapy for severe nausea and vomiting in pregnancy with associated dehydration according to a 2010 clinical practice article.10 In this randomized trial of these two agents used as intravenous therapy for 24 hours for hyperemesis gravidarum, no differences in efficacy or well-being were noted. Women in the metoclopramide arm had more minor side effects. This is in contrast to previous observational or retrospective studies of these drugs with different administration routes used for hyperemesis gravidarum.

A trial of 83 women with hyperemesis gravidarum compared oral ondansetron with oral metoclopramide and found that ondansetron reduced vomiting but not nausea.21

A retrospective database analysis comparing outpatient continuous subcutaneous infusion of ondansetron or metoclopramide for hyperemesis gravidarum showed that regime alteration from metoclopramide to ondansetron (31.8%) was more frequent than alteration from ondansetron to metoclopramide (4.4%; P<.001), with persistent severe symptoms or side effects being the major indications for regime alteration.22 Our data also demonstrated that ondansetron was better-tolerated over a 24-hour period.

Our trial design of a 24-hour primary assessment period is justified by the fact that the majority of our participants responded rapidly to therapy and intravenous antiemetic therapy was discontinued by 24 hours. For antiemesis after cesarean delivery, ondansetron compared with metoclopramide or placebo has been shown to be associated with less nausea and higher patient satisfaction, but there was no difference in vomiting frequency.23 In our trial, nausea visual numeric rating scale was not significantly different between the trial arms.

In 2009, the U.S. Food and Drug Administration (FDA) issued a black box warning (accessible on http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm170934.htm) indicating that prolonged (more than 12 weeks) use of metoclopramide is associated with tardive dyskinesia. In June 2012, the FDA issued a safety warning (accessible on http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm310219.htm) regarding the 32-mg dose of ondansetron because it may prolong the Q-T interval and predispose to Torsades de Pointes arrhythmia, and it recommended that no single intravenous ondansetron dose should exceed 16 mg. A 2012 report linked ondansetron to cleft palate, but it concluded that the association “could be chance findings, warrant further investigation.”24 Reassuringly, a major study published in 2013 showed that major birth defects were not increased after ondansetron exposure during early pregnancy.13

Ondansetron has recently lost its patent, and the FDA first approved a generic ondansetron intravenous formulation in November 2006 (accessible on http://www.fda.gov/newsevents/newsroom/pressannouncements/2006/ucm108791.htm). Generic ondansetron was available in our setting but at the time of the trial, the cost of a 4-mg intravenous ondansetron dose was more than an order of magnitude higher than that for a 10-mg intravenous metoclopramide dose. The cost disadvantage of ondansetron compared with metoclopramide should decline in time as generic exclusivity is lost and with competition between generic manufacturers.

Our trial has strengths and limitations. Our double-blind trial design minimized systematic bias. We analyzed according to intention to treat with minimal incomplete datasets. Given that the actual standard deviations in the well-being visual numeric rating scale scores were narrower than assumed, the power of the trial to detect a one-unit difference was 99.6%. As for limitations, the primary outcomes were over the course of a 24-hour time scale only. However, 84% of our participants needed only the four doses of trial intravenous antiemetic before conversion to an oral antiemetic and 17% were discharged the next day, indicating that 24 hours can be appropriate to gauge antiemetic effectiveness in our hyperemesis gravidarum patients. We evaluated a broad range of adverse symptoms that could lead to false-positive results attributable to multiple analyses, but the broad range of our side effects finding was consistent with the published data.9,22 However, our trial was probably underpowered to evaluate some of the other less common side effects listed in Table 2, possibly resulting in false-negative findings. We did not control oral intake or collect data regarding oral calorie intake; participants resumed oral intake as they felt able. All participants were administered the same regimen of 3 L intravenous rehydration over the 24-hour study period. Because vomiting and nausea were no different and because the trial was blinded in our view, it is unlikely that the reporting of an excess of dry mouth in the metoclopramide arm was attributable to confounding from intravenous or oral rehydration differences across the intervention arms.

A Cochrane review has indicated that no trial of treatments for hyperemesis gravidarum showed any evidence of benefit,25 suggesting that comparison with placebo can still be appropriate. Hyperemesis gravidarum patients admitted to our center26 have metabolic and biochemical profiles similar to those of women with hyperemesis gravidarum reported in other studies of hyperemesis gravidarum,27,28 indicating that our findings should be generalizable to other hyperemesis gravidarum populations.

Metoclopramide is effective and economical, has a long history of widespread use, has an excellent fetal safety record,6,7 and remains a reasonable first-line short-term antiemetic choice in hyperemesis gravidarum despite the better tolerability of ondansetron.

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