Presently, 97.7% of prescriptions for the treatment of nausea and vomiting in pregnancy in the United States are with medications not labeled for use in pregnancy, not indicated for nausea and vomiting in pregnancy, and not classified as safe in pregnancy by the Food and Drug Administration. The use of ondansetron for nausea and vomiting in pregnancy has increased from 50,000 monthly prescriptions in 2008 to 110,000 at the end of 2013, despite unresolved issues regarding fetal safety and Food and Drug Administration warnings about serious dysrhythmias. In April 2013, the Food and Drug Administration approved the combination of doxylamine and pyridoxine, specifically for nausea and vomiting in pregnancy symptoms. Now that a safe and effective drug is available in the United States, there is no reason for women to be exposed to a drug of unproven maternal and fetal safety.
Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecting an estimated 80% of pregnant women. Because the withdrawal of Bendectin (delayed release doxylamine 10 mg-pyridoxine 10 mg; WMS Merrell Dow, Cincinnati, OH) from the US market in 1983, American women did not have access to a Food and Drug Administration (FDA)-approved drug for NVP for 30 years, until the same drug combination (under the trade name Diclegis; Duchesnay Inc., Blainville, Canada) was approved by the FDA in April 2013. The withdrawal of Bendectin from the US left American women without an FDA-approved drug for NVP and was associated with a 3-fold increased risk of hospitalization of women for the severe forms of this condition.
Presently, 97.7% of prescriptions for the treatment of NVP in the US are with medications not labeled for use in pregnancy, not indicated for NVP, and not classified as safe in pregnancy (FDA category A). The use of ondansetron for the treatment of NVP has steadily increased from 50,000 prescriptions per month in 2008 to 110,000 at the end of 2013 ( Figure ).
This means that around 1 million pregnant American women are exposed to ondansetron out of 4 million pregnancies a year. Ondansetron (GlaxoSmithKlein Inc, Philadelphia, PA) is a serotonin 5-HT 3 receptor antagonist, originally introduced to prevent nausea and vomiting induced by cancer chemotherapy, radiation therapy, and surgery. The fact that ondansetron became generic in 2007, and hence its price dropped, might have been an important cause for this increase, with easier access to Medicaid and health maintenance organizations. Prescribing ondansetron as a first line option is not consistent with American Professors in Gynecology and Obstetrics and American College of Obstetricians and Gynecologists evidence-based recommendations for the management of NVP.
It should be remembered that most drugs used in pregnancy, including steroids for the prevention of respiratory distress syndrome, all tocolytic agents, and magnesium sulfate for the prevention of cerebral palsy, to mention a few, have not been approved by the FDA. Yet, they are standard of care. In contrast, in the case of ondansetron there are unresolved issues surrounding the fetal and maternal safety, including recent warnings by the FDA on its potential to cause serious dysrhythmias.
Fetal safety concerns regarding ondansteron
The fetal safety of the ondansetron was first investigated in humans by Einarson et al in 2004 through a prospective controlled cohort study of 176 women, in whom we could not detect an increased teratogenic risk. However, this sample size had the statistical power to rule out only a 5-fold increased risk of major malformations, and not any specific malformation. In February 2013, Pasternak et al reported that ondansetron was not associated with increased malformation rates when used for morning sickness. This was based on retrospective analysis of data from the Danish Birth Registry, collected between 2004 and 2011 and linked to the National Prescription Register. Each of the 1970 women exposed to ondansetron was matched to 4 unexposed controls. Of note, the mean age at exposure was 10 gestational weeks, which means that half of the cases were exposed to ondansetron at later than 10 gestational weeks, when the morphologic malformations sought in this study could not be produced any more. This can cause a bias toward the null, diluting an existing risk because of inclusion of cases that were not exposed during embryogenesis.
However, in August of 2013, Andersen et al from Denmark presented a second study using the same Danish registries covering more years (1997-2010) and more pregnant women (897,018 vs 608, 835). In contrast to Pasternak et al, Andersen’s study detected a 2-fold increased risk of cardiac malformations with ondansetron (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.3–3.1), leading to an overall 30% increased risk of major congenital malformations. To rule out confounding by indication, Andersen et al also examined metoclopramide taken for morning sickness, detecting no increase in teratogenic risk.
The fact that the same large registry can be investigated to yield such opposing results is concerning. There is an exponential rise in use of prescription database linkage to birth registries. None of these were designed specifically to address fetal drug safety, and there may be flaws in the quality and completeness of the available data.
Of potential importance, a recent large case control study by the Sloan epidemiology unit and the Centers of Disease Control and Prevention, has reported a 2-fold increased risk for cleft palate associated with ondansetron taken for NVP in the first trimester of pregnancy (OR, 2.37; 95% CI, 1.28–4.76).
Maternal safety concerns regarding ondansetron
The maternal safety of ondansetron has been challenged in June 2012, when the FDA issued a warning of possible serious cardiac output (QT) prolongation and Torsade the Pointe among people receiving ondansetron. As a result, the FDA requires strict workup of patients receiving ondansetron, to rule out long QT, electrolyte imbalance, congestive heart failure or taking concomitant medications that prolong the QT interval. Because this drug is not approved by the FDA for pregnant women, the FDA did not specifically address precautions in pregnancy. However, in the context of NVP, women with severe NVP often exhibit electrolyte abnormalities (hypokalenia or hypomagnesemia). Presently, counseling of women who receive ondansetron for morning sickness suggests that these FDA precautions are not being followed.
Serotonin syndrome is a life-threatening disorder of excessive serotonergic activity, typically occurring when 2 or more serotonin-modifying agents are used simultaneously, although it may also occur with a single agent. From Jan. 1, 1998, to Dec. 30, 2002, Health Canada received 53 reports of suspected serotonin syndrome, most often reported with the use of selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors and selective serotonin- norepinephrine reuptake inhibitors.
The clinical presentation of seretonergic syndrome is characterized by the triad of cognitive or behavioral changes (confusion, agitation, lethargy, coma), autonomic instability (hyperthermia, tachycardia, diaphoresis, nausea and vomiting, diarrhea and dilated pupils) and neuromuscular changes (myoclonus, hyperreflexia and tremor).
Critically, serotonin syndrome has also been reported with the concomitant use of 5-HT 3 receptor antagonists (eg, ondansetron, dolasetron, granisetron). Because large numbers of pregnant women suffering from depression are prescribed SSRIs, and up to 80% experience morning sickness a possible interaction between SSRIs and ondansetron, leading to serotonin syndrome, must be considered.
Because the paramount challenge of treating pregnant women with medications surrounds fetal and maternal safety, ondansetron should be used cautiously only after drugs with a better safety record, which have been labeled to use in pregnancy (eg, doxylamine-pyridoxine) have been tried.
Maternal safety concerns regarding ondansetron
The maternal safety of ondansetron has been challenged in June 2012, when the FDA issued a warning of possible serious cardiac output (QT) prolongation and Torsade the Pointe among people receiving ondansetron. As a result, the FDA requires strict workup of patients receiving ondansetron, to rule out long QT, electrolyte imbalance, congestive heart failure or taking concomitant medications that prolong the QT interval. Because this drug is not approved by the FDA for pregnant women, the FDA did not specifically address precautions in pregnancy. However, in the context of NVP, women with severe NVP often exhibit electrolyte abnormalities (hypokalenia or hypomagnesemia). Presently, counseling of women who receive ondansetron for morning sickness suggests that these FDA precautions are not being followed.
Serotonin syndrome is a life-threatening disorder of excessive serotonergic activity, typically occurring when 2 or more serotonin-modifying agents are used simultaneously, although it may also occur with a single agent. From Jan. 1, 1998, to Dec. 30, 2002, Health Canada received 53 reports of suspected serotonin syndrome, most often reported with the use of selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors and selective serotonin- norepinephrine reuptake inhibitors.
The clinical presentation of seretonergic syndrome is characterized by the triad of cognitive or behavioral changes (confusion, agitation, lethargy, coma), autonomic instability (hyperthermia, tachycardia, diaphoresis, nausea and vomiting, diarrhea and dilated pupils) and neuromuscular changes (myoclonus, hyperreflexia and tremor).
Critically, serotonin syndrome has also been reported with the concomitant use of 5-HT 3 receptor antagonists (eg, ondansetron, dolasetron, granisetron). Because large numbers of pregnant women suffering from depression are prescribed SSRIs, and up to 80% experience morning sickness a possible interaction between SSRIs and ondansetron, leading to serotonin syndrome, must be considered.
Because the paramount challenge of treating pregnant women with medications surrounds fetal and maternal safety, ondansetron should be used cautiously only after drugs with a better safety record, which have been labeled to use in pregnancy (eg, doxylamine-pyridoxine) have been tried.
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