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TDM JOURNAL CLUB

Scary Science: OndansetronSafety in PregnancyTwoOpposing Results From the

Same Danish Registry

A critical review of several recentpapers published on ondansetron usein pregnancy

Abstract: While perceived safe in preg-nancy, several recent studies raise concernsabout both fetal and maternal safety ofondansetron. Until more data are available,it should not be a rst-line medication formorning sickness.

In February 2013, theNew England

Journal of Medicine published an articleby Pasternak et al reporting that ondanse-tron is not associated with increased mal-formation rates when used for morningsickness.1 This was based on retrospec-tive analysis of data from the DanishBirth Registry collected between 2004and 2011, and linked to the National Pre-scription Register to identify prescriptionsof the drug. Each woman exposed toondansetron (n = 1970) was matched to4 unexposed control cases.

Of note, the mean age of exposurewas 10 gestational weeks, which means

that half of the cases were exposed toondansetron at later than 10 gestationalweeks, when malformations could not be

produced any more. This can cause a biastoward the null, that is, dilute an existingrisk because of inclusion of cases thatwere not exposed during embryogenesis.

On August 27, 2013, this study byPasternak was presented again at theInternational Society of Pharmacoepi-demiology in Montreal. Back-to-backwith this study, Andersen et al2 fromDenmark presented a study using the same

registries. This study covered more years(19972010) and more pregnant women(897,018 versus 608,835) using the samenational registries as in Pasternaks study.Of major concern, Andersens study

detected a 2-fold increased risk of cardiacmalformations with ondansetron {oddsratio = 2.0 (95% condence interval[CI], 1.33.1)} leading to an overallincreased risk of major malformations of30%. To rule out confounding by indica-tion, Andersen et al also examined meto-clopramide taken for morning sickness,nding no increased teratogenic risk.

The fact that the same large regis-try can be manipulated to yield suchopposing results is very concerning. Weare witnessing exponential rise in use of

prescription database linkage to birthregistries. None of these were designedspecically to address fetal drug safety,and there may be aws in the quality andcompleteness of the data. The example

of the Danish data shows that in additionto these potential aws, human decisionscan shape the results in any direction.This is scary.

Ondansetron, a potent antiemeticagent, is a 5-HT3 receptor antagonist

blocking the effect of serotonin, whichwas designed originally for cancerchemotherapy-induced nausea and vomit-ing. The drug is labeled also for use fornausea and vomiting associated withradiation therapy, anesthesia, and surgery.However, because of 30 years without an

FDA-approved drug for morning sicknessin the United States, increasing numbersof American women suffering from nau-sea and vomiting of pregnancy (NVP)have been managed with ondansetron. Asof April 2013, the doxylaminepyridoxinecombination (Diclegis) has been approved

by the regulatory agency.

FETAL SAFETY

The fetal safety of the drug has beenrst addressed by Einarson et al

3 in 2004through a prospective controlled cohortstudy of 176 women, mostly American,in whom we could not detect an increasedteratogenic risk. However, this sample sizecould rule out only a 5-fold increased riskof major malformations and not any spe-cic malformation. In February 2013, Pas-ternak et al1 published the article citedabove, further suggesting that the drugmay be safe. However, the opposing re-sults of analysis of the same Danish data-

base by a different group of researcherscall for caution.

Of potential importance, a recentlarge control study by the Sloan epide-miology unit and the Centers of DiseaseControl and Prevention has detected a 2-fold increased risk for cleft palate asso-ciated with ondansetron taken for NVPin the rst trimester of pregnancy [oddsratio = 2.37 (95% CI, 1.284.76)].4

MATERNAL SAFETY

In June 2012, the FDA issueda warning of possible serious QT pro-longation andTorsade the Pointe among

people receiving ondansetron.5 As a result,the FDA requires strict follow-up of

patients receiving ondansetron, to ruleout long QT, electrolyte imbalance, con-

gestive heart failure, or taking concomitantmedications that prolong the QT interval.5

In the context of NVP, quite a few womenwith severe NVP may have electrolyteabnormalities (hypokalemia or hypomag-nesemia). Presently, counseling of womenwho receive ondansetron for morningsickness reveals that these FDA precau-tions are not being followed.

SEROTONIN SYNDROME

Serotonin syndrome is life-threaten-

ing disorder of excessive serotonergicactivity typically occurring when 2 ormore serotonin-modifying agents are usedsimultaneously, although it may also occurwith a single agent.6 From January 1, 1998to December 30, 2002, Health Canadareceived 53 reports of suspected serotoninsyndrome. Serotonin syndrome was mostoften reported with the use of selectiveserotonin reuptake inhibitors, monoamineoxidase inhibitors, and venlafaxine.

The clinical presentation is charac-terized by the triad of cognitive or

behavioral changes (confusion, agitation,lethargy, coma), autonomic instability(hyperthermia, tachycardia, diaphoresis,nausea, vomiting, diarrhea, dilated pu-

pils), and neuromuscular changes (myoc-lonus, hyperreexia, tremor).

6

Critically, serotonin syndromehas also been reported with the con-comitant use of 5-HT3 receptor antag-onists (eg, ondansetron, dolasetron,granisetron).7,8 Because a large num-

ber of pregnant women are on selec tiveserotonin reuptake inhibitors and up to

The author was the PI on the US doxylaminepyridoxine study and is consultant for Duch-esnay Inc, Quebec.

Correspondence: Gideon Koren, MD, Universityof Toronto, Department of Pediatrics, Toronto,Ontario, Canada (e-mail: gkoren@sickkids.ca).

Copyright 2014 by Lippincott Williams & Wilkins

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90% experience morning sickness,a possible interaction with ondansetronleading to serotonin syndrome must beconsidered. Because the paramountchallenge of treating pregnant womenwith medications is fetal, and maternalsafety ondansetron should be used cau-tiously only after drugs with bettersafety record, which have been labeledto use in pregnancy (eg doxylamine

pyri doxine) have been tried.

Gideon Koren, MDUniversity of Toronto, Department of

Pediatrics, Toronto, Ontario, Canada.

REFERENCES

1. Pasternak B, Svanstrm H, Hviid A. Ondanse-tron in pregnancy and risk of adverse fetal out-comes. N Engl J Med. 2013;368:814823.

2. Andersen JT, Jimenez-Solem E, Andersen NL,et al. Ondansetron Use in Early Pregnancy

and the Risk of Congenital MalformationsA Regis ter Based Natio nwide Contr ol Study.

International Society of Pharmaco-epidemiology.Montreal, Canada; 2013. Abstract 25, Pregnancysession 1.

3. Einarson A, Maltepe C, Navioz Y, et al. Thesafety of ondansetron for nausea and vomitingof pregnancy: a prospective comparative study.BJOG. 2004;111:940943.

4. Anderka M, Mitchell AA, Louik C, et al. Med-ications used to treat nausea and vomiting ofpregnancy and the risk of selected birth defects.

Birth Defects Res A Clin Mol Teratol.2012;94:

2230.5. FDA Drug Safety communication: Abnormal

heart rhythms may be associated with use of

Zofran (ondansetron). Available at: http://www.

fda.gov/Drugs/DrugSafety/ucm271913.htm.6. Mason PJ, Morris VA, Balcezak TJ. Serotonin

syndrome presentation of 2 cases and review of

the literature. Medicine (Baltimore). 2000;79:201209.

7. Turkel SB, Nadala JG, Wincor MZ. Possible

serotonin syndrome in association with 5-HT3antagonist agents. Psychosomatics. 2001;42:

258260.

8. Sorscher SM. Probable serotonin syndrome var-

iant in a patient receiving a selective serotonin

reuptake inhibitor and a 5-HT3 receptor antag-

onist.J Psychopharmacol. 2002;16:191.

TDM Journal Club Ther Drug Monit Volume 36, Number 1, February 2014

2 2014 Lippincott Williams & Wilkins