From the Editor

Optimal pharmacologic treatment of nausea and vomiting of pregnancy

OBG Manag. 2015 February;27(2):8-10,12

References

1. Anderka M, Mitchell AA, Louik C, Werler MMA, Hernandez-Diaz S, Rasmussen SA; National Birth Defects Prevention Study. Medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects. Birth Defects Res A Clin Mol Teratol. 2012;94(1):22–30.

2. Matthews A, Haas Dm, O’Mathuna DP, Dowswell T, Doyle M. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev. 2014;(3):CD007575.

3. Borrelli F, Capasso R, Aviello G, Pittler MH, Izzo AA. Effectiveness and safety of ginger in the treatment of pregnancy-induced nausea and vomiting. Obstet Gynecol. 2005;105(4):849–856.

4. Koren G, Clark S, Hankins GD, et al. Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy: a randomized placebo controlled trial. Am J Obstet Gynecol. 2010;203(6):571.e1–7.

5. Einarson TR, Leeder JS, Koren G. A method for meta-analysis of epidemiologic studies. Drug Intell Clin Pharm. 1988;22(10):813–824.

6. McKeigue PM, Lamm SH, Linn S, Kutcher JS. Bendectin and birth defects. I. A meta-analysis of the epidemiologic studies. Teratology. 1994;50(1):27–37.

7. Mishriky BM, Habib AS. Metoclopramide for nausea and vomiting prophylaxis during and after cesarean delivery: a systematic review and meta-analysis. Br J Anaesth. 2012;108(3):374–383.

8. Abas MN, Tan PC, Azmi N, Omar SZ. Ondansetron compared with metoclopramide for hyperemesis gravidarum: a randomized controlled trial. Obstet Gynecol. 2014;123(6):1272–1279.

9. Tan PC, Khine PP, Vallikkannu N, Omar SZ. Promethazine compared with metoclopramide for hyperemesis gravidarum: a randomized controlled trial. Obstet Gynecol. 2010;115(5):975–981.

10. Matok I, Gorodischer R, Koren G, Sheiner E, Wiznitzer A, Levy A. The safety of metoclopramide use in the first trimester of pregnancy. N Engl J Med. 2009;360(24):2528–2535.

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14. Danielsson B, Wikner BN, Kallen B. Use of ondansetron during pregnancy and congenital malformations in the infant. Reprod Toxicol. 2014;50:134–137.

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16. US Food and Drug Administration. Ondansetron (Zofran) IV: drug safety communication - QT prolongation. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm310219.htm. Published June 29, 2012. Accessed December 26, 2014.

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18. Health Canada. Canadian Adverse Reaction Newsletter. 2003;13(3). http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/carn-bcei_v13n3-eng.php. Published June 24, 2003. Accessed December 26, 2014.

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Metoclopramide can cause tardive dyskinesia, a serious movement disorder that may be irreversible with discontinuation of the drug. This risk increases with dose and length of treatment. The FDA recommends that clinicians avoid the use of metoclopramide for more than 12 weeks.

Third-line pharmacologic treatment: Ondansetron
In the United States ondansetron is commonly used to treat NVP.¹² The drug is a selective 5-HT₃ antagonist that blocks serotonin action in the central nervous system chemoreceptor trigger zone. The elimination half-life of ondansetron is 3 to 6 hours (Lexicomp).

The frequent use of ondansetron may be due, in part, to the perception that it is a very effective antiemetic. For example, in one small clinical trial, ondansetron 4 mg every 8 hours was reported to be superior to a combination of pyridoxine 25 mg every 8 hours plus doxylamine 12.5 mg every 8 hours.¹³ (Note that the pyridoxine and doxylamine tablets used in this trial were not in a combination delayed-release formulation.) I am recommending ondansetron as a third-line treatment for NVP because, although it is effective, it may be associated with an increased risk of fetal cardiac anomalies.

Is ondansetron associated with cardiac malformations?
The FDA has assigned ondansetron to pregnancy category B; however, there is concern that it may be associated with congenital heart defects. In a recent study of 1,349 infants born to Swedish women who had filled a prescription for ondansetron in early pregnancy, a significantly increased risk of cardiovascular defect (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.04−2.14) and cardiac septum defect (OR, 2.05; 95% CI, 1.19−3.28) was reported.¹⁴ The cardiac anomalies were mostly atrial septal or ventricular septal defects.

In a second study, reported as an abstract, authors analyzed congenital malformations in 1,248 infants born to Danish women who filled a prescription for ondansetron in early pregnancy. These authors also found an increased risk of a congenital heart malformation (OR, 2.0; 95% CI, 1.3−3.1).¹⁵

A US case-control study showed an association between ondansetron use and cleft palate.¹ The Swedish¹⁴ and Danish¹⁵ studies reported above did not find an association between ondansetron use and cleft palate.

The FDA issued a warning in June 2012 that at a dose of 32 mg, administered intravenously, ondansetron may prolong the QT interval and result in a potentially fatal heart arrhythmia, torsades de pointes.¹⁶ In the announcement the FDA did not alter the recommendations for oral dosing because there is no strong evidence that oral dosing is associated with clinically significant arrhythmias. Authors of a recent systematic review concluded that IV administration of large doses of ondansetron may cause cardiac arrhythmias, especially in patients with cardiac disease and those taking other drugs that prolong the QT interval, but that a single oral dose of ondansetron does not have a significant risk of causing an arrhythmia.¹⁷

Health Canada¹⁸ has advised that many commonly prescribed medications increase serotonin activity. When multiple drugs that each increase serotonin activity are prescribed in combination, the risk of serotonin syndrome is increased. Serotonin syndrome results in hyperthermia, agitation, tachycardia, and muscle twitching and can be fatal. Ondansetron was specifically mentioned in the Health Canada warning, but a search of the literature revealed very few reported cases of ondansetron being implicated in the serotonin syndrome.¹⁹

My bottom-line recommendations
NVP is a common obstetric problem. When oral pharmacologic therapy is indicated, first-line treatment should be with the FDA-approved combination of doxylamine-pyridoxine because it is both effective and associated with no known increased risk of congenital malformations. An effective second-line agent is metoclopramide. Based on very limited data, metoclopramide appears effective and is not associated with an increased risk of congenital malformations. However, it is not FDA approved for treatment of NVP. Ondansetron appears to be effective but its use in early pregnancy may be associated with congenital anomalies. Consequently, ondansetron should not be used to treat NVP unless first- and second-line treatments have been ineffective to treat the patient’s symptoms.

INSTANT POLL
Which of the following pharmacologic treatments of nausea with or without vomiting during pregnancy is your first-line medication choice?
• Ondansetron
• Metoclopramide
• Doxylamine-pyridoxine
• Meclizine Promethazine
• Trimethobenzamide

Visit the Quick Poll on the homepage, give your answer, and then see how other ObGyns have answered.

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