Abstract
Background: Ondansetron is a selective antagonist of the serotonin 5-HT3 receptor that is commonly used to treat morning sickness. It is estimated that 70%–80% of pregnant women suffer from morning sickness, a condition characterized by nausea and vomiting. However, it is still controversial regarding its safety during pregnancy, and continued research will be necessary to fully understand the risks and benefits associated with its use. Therefore, we aimed to identify and provide details of the efficacy and safety of ondansetron in clinical trials.
Methods: A search was conducted of the ClinicalTrials.gov database on 13 April 2023, using the search term “ondansetron and pregnancy.” Inclusion and exclusion criteria were defined to identify relevant clinical trials. The inclusion criteria encompassed clinical trials related to pregnancy that utilized ondansetron as a treatment, while other clinical trials were excluded from consideration. All data extractions such as study title, study status, study type, intervention details, and outcome were collected.
Results: A total of 18 clinical trials were identified, of which only 6 focused on studying the effects of ondansetron. Their respective study titles, statuses, conditions, interventions, outcome measures, and enrollment sizes have been written in detail. The information collected from these trials will contribute to our understanding of the potential benefits and risks of ondansetron in the context of pregnancy and its complications.
Conclusion: Ondansetron has been shown to be an effective treatment for nausea and vomiting, including pregnancy-related morning sickness. Further research is needed to better understand the potential risks and benefits associated with its use in pregnant women.
Systematic Review Registration:ClinicalTrials.gov, identifier
Introduction
Ondansetron is a selective serotonin receptor antagonist that prevents nausea and vomiting associated with chemotherapy, radiotherapy, and surgery and is commonly used to treat morning sickness (Wolf, 2000). It is estimated that 70%–80% of pregnant women suffer from morning sickness, a condition characterized by nausea and vomiting (Lee and Saha, 2011). Conditions such as malnutrition and dehydration can cause risks to the health of both the fetus and the mother (Maltepe, 2014). The hormonal changes that occur during pregnancy, such as elevated levels of chorionic gonadotropin (hCG), may result in increased levels of serotonin in the body, which, in turn, might be involved in causing maternal nausea and vomiting during pregnancy (Cengiz et al., 2015; Thibeault et al., 2019). Ondansetron works in the brain by selectively binding to specific serotonin (5-HT3) receptors (Simino et al., 2016). These are located on the terminals of the vagus nerve, which innervates the gastrointestinal tract (Griddine and Bush, 2022). Therefore, the serotonin receptors are blocked, inhibiting serotonin release. Serotonin, also known as 5-hydroxytryptamine (5-HT), is a neurotransmitter that regulates nausea and vomiting (Griddine and Bush, 2022). By preventing serotonin from binding to its receptors, ondansetron reduces nausea and vomiting (Yokoi et al., 2017). Even though the FDA initially approved ondansetron only for treating chemotherapy- and surgery-related nausea and vomiting (Hesketh et al., 2017), off-label prescribing of the drug for morning sickness has occurred in some cases (Griddine and Bush, 2022).
Ondansetron is, however, still controversial regarding its safety during pregnancy, and continued research is necessary to fully understand the risks and benefits associated with its use (Parker et al., 2018). Several reports have used different studies to determine ondansetron’s effectiveness in treating morning sickness in pregnant women (Colvin et al., 2013; Kennedy, 2016). The results of these studies have been promising, showing that ondansetron is an effective treatment for morning sickness. It is well tolerated, with few side effects, and can be taken in pill or injection form (Slattery et al., 2022). Even though ondansetron appears to be effective, safety concerns have been raised regarding its use during pregnancy (Michie and Hodson, 2020). Studies have found that it may increase the risk of cardiac arrhythmias and congenital disorders if prescribed in the first trimester of pregnancy (Kaplan et al., 2019). Some theories have been proposed that long-term exposure to ondansetron and continuous inhibition of serotonin can affect some physiological processes, including fetal development. However, the overall risk appears to be low, and other studies have reported conflicting results (Danielsson et al., 2014; Freedman et al., 2014).
It is important to remember that despite ondansetron’s apparent effectiveness at reducing nausea and vomiting caused by morning sickness during pregnancy, its safety is still under debate. For this reason, the severity of a patient’s symptoms and alternative treatment options should be considered before prescribing ondansetron during pregnancy (Ernst, 2019; Solihah et al., 2023). Regular monitoring of the patient’s condition is recommended to ensure the safety of the mother and baby. Finally, healthcare providers should provide support to the patient throughout the duration of the treatment. Using clinical trial results from ClinicalTrials.gov, this systematic review examines the efficacy and safety of ondansetron for morning sickness during pregnancy.
Methods
Search strategy
A comprehensive investigation was carried out on ClinicalTrials.gov on 13 April 2023, to identify all pertinent studies about the utilization of ondansetron (commonly known as Zofran) as a therapeutic intervention for ailments or conditions associated with pregnancy. The search was conducted by inputting the term “pregnancy and ondansetron” into the search engine of the website to yield relevant results.
Systematic review search results
The process of identifying pertinent clinical trials relied on the specific criteria outlined in the research area of interest. The inclusion criteria encompassed clinical trials related to pregnancy that utilized ondansetron as a treatment, while other clinical trials were excluded from consideration.
Data extraction
Data such as study title, study status, study type, intervention details, and outcome.
Results
Analysis of the number of relevant clinical trials
As of 13 April 2023, a comprehensive search on ClinicalTrials.gov revealed 18 registered clinical trials specifically related to pregnancy and its complications. These trials focused on ondansetron as a potential treatment and were carefully identified and documented for further analysis. Among them, only 6 trials were dedicated to studying the effects of ondansetron, as highlighted in Table 1, thus aligning with our research objectives and meeting our study inclusion criteria. It is noteworthy that all 6 studies have been reported as completed clinical trials. Their respective study titles, statuses, conditions, interventions, outcome measures, and enrollment sizes have been detailed in Table 1.
TABLE 1
| # | Title | Status | Conditions | Interventions and dosing | Outcome measures | Study phase | Number of participants | Gestational weeks | Year |
|---|---|---|---|---|---|---|---|---|---|
| 1 | “Ondansetron VS. Doxylamine and Pyridoxine in Treating Nausea of Pregnancy” (The National Library of Medicine, 2013a) | Completed | Pregnancy with vomiting | *Ondansetron | Reduction of nausea on the VAS (Visual Analog Scale) | Not applicable | 36 | Less than 16 weeks pregnant by last menstrual period or ultrasound | 2013 |
| *Placebo (The dose is 4 mg ondansetron and a placebo capsule orally 3 times daily (TID) for 5 days) | Reduction in nausea and vomiting | ||||||||
| 2 | “Study of Drug Concentration of Ondansetron and Cefazolin in Mothers and Neonates” (The National Library of Medicine, 2016) | Completed | Pregnancy Complications | Phlebotomy (Post-delivery blood samples will be taken from the mother, umbilical artery and vein, and neonate along with other clinical labs) | Pharmacokinetics (PK) results for cefazolin and ondansetron in maternal blood specimens | Not applicable | 20 | Term pregnancy (37–42 weeks) | 2016 |
| Identification of placental transfer of studied meds (cefazolin and ondansetron) | |||||||||
| PK results of neonatal blood specimens | |||||||||
| 3 | “Validating the Effect of Ondansetron and Mirtazapine in Treating Hyperemesis Gravidarum” (The National Library of Medicine, 2022) | Terminated with an outcome for ondansetron | Hyperemesis gravidarum | Mirtazapine | A change in short-term vomiting and nausea from baseline to day 2 in the group treated with mirtazapine versus the placebo group | Phase 2 | 58 | Pregnant women with gestational age between 5 + 0 and 19 + 6 weeks | 2022 |
| Nausea gravidarum | Ondansetron | Change in short term vomiting and nausea from baseline to day 2 () in the group treated with ondansetron versus the placebo group | |||||||
| Vomiting during pregnancy | Placebo | Change in nausea and vomiting from baseline to Day 14 (+/-1) (long term) in the mirtazapine group versus the placebo group | |||||||
| Ondansetron dose is 8 mg oral tablet twice a day (BID) for 7 days | |||||||||
| 4 | “Intravenous Ondansetron to Attenuate the Hypotensive, Bradycardic Response to Spinal Anesthesia in Healthy Parturients” (The National Library of Medicine, 2011) | Completed | Hypotension pregnancy | Ondansetron | Number of participants who experienced adverse events as a measure of “safety and tolerability” dose of vasopressors administered | Phase 3 | 68 | ASA 2—Patients with mild systemic disease | 2011 |
| Placebo | Number of episodes of nausea | ||||||||
| Ondansetron 8 mg IV once daily (OD) | |||||||||
| Placebo will be administered prior to placement of the spinal anesthetic | |||||||||
| 5 | “How Pregnant Women and Their Babies Metabolize Ondansetron Compared to a Group of Non-pregnant Women” (The National Library of Medicine, 2013b) | Completed | Postoperative nausea | Ondansetron dose is 8 mg IV once if needed | Volume of distribution | Phase 2 | 100 | 2013 | |
| Estimated pharmacokinetic parameter | |||||||||
| Metabolic clearance of ondansetron | |||||||||
| 6 | “Can Ondansetron Prevent Neonatal Abstinence Syndrome (NAS) in Babies Born to Narcotic-dependent Women” (The National Library of Medicine, 2020) | Completed | Narcotic addiction | Ondansetron | Number of participants with neonatal abstinence syndrome | Phase 2 | 196 | Neonate gestation age between 37 weeks and 41 weeks and 6 days at birth | 2020 |
| Neonatal abstinence syndrome (NAS) | Placebo | Length of hospital stay | |||||||
| If pregnant women have not delivered within 4 h of receiving the IV study medication, they may be given a second dose of IV ondansetron | Total dose of narcotic needed to treat NAS symptoms | ||||||||
| Out of the 90 mother/baby pairs, 50% will receive ondansetron; the study medication will always be the same for mother and baby | Number of participants requiring adjunctive medication to treat NOWS |
Data from https://clinicaltrials.gov, updated on 13 April 2023.
Participants
A total of 508 adult female participants from a search of ClinicalTrials.gov were included in the systematic review.
Interventions
Along with ondansetron, some studies have used mirtazapine and metoclopramide for different purposes.
Discussion
In recent years, ondansetron has received increasing attention for its efficacy and safety in treating morning sickness in pregnancy (Kennedy, 2016). Approximately 80% of pregnant women experience morning sickness, or nausea and vomiting, during pregnancy, particularly during the first trimester (Koren, 2014). Such symptoms often negatively impact their quality of life (Clark et al., 2013). There has been significant interest in ondansetron as several studies over the past few years have shown it to be an effective treatment for morning sickness (Quinlan and Hill, 2003; Kennedy, 2016; Fejzo et al., 2019). Various studies have shown that ondansetron works by blocking serotonin receptors in the brain, alleviating nausea and vomiting symptoms in pregnant women (Heckroth et al., 2021). However, despite the evidence suggesting its efficacy, there is still some concern about its use during pregnancy and it is important to conduct further research to better understand the potential risks and benefits associated with its use in pregnant women (Carstairs, 2016; Kaplan et al., 2019).
Ondansetron’s pharmacokinetics are characterized by rapid absorption, extensive distribution, and hepatic metabolism (Simpson and Hicks, 1996). The drug exhibits swift absorption following oral administration, resulting in peak plasma concentrations manifesting within a span of 1–2 h. Oral ondansetron bioavailability is approximately 60% due to first-pass metabolism in the liver. The drug is extensively distributed throughout the body, with a volume of distribution (Vd) of approximately 140 L. Ondansetron is highly protein-bound, with more than 70% of the drug bound to plasma proteins. The drug is metabolized in the liver by several cytochrome P450 enzymes, primarily CYP3A4 and CYP2D6, and eliminated mainly via feces (Roila and Del Favero, 1995; Christofaki and Papaioannou, 2014).
Ondansetron’s pharmacodynamics are dose-dependent and exhibit a ceiling effect. The drug has a half-life of approximately 4 h and a duration of action of 8–12 h (Lozano, 2013). Ondansetron’s therapeutic dose range is 4–8 mg, and higher doses do not provide additional benefits (Meiri et al., 2007). The drug is generally well-tolerated; the most common adverse effects are headaches, constipation, and diarrhea. Ondansetron may also prolong the QT interval and increase the risk of cardiac arrhythmias (Charbit et al., 2005; Freedman et al., 2014).
Conclusion
Ondansetron has been shown to be an effective treatment for nausea and vomiting, including pregnancy-related morning sickness. The drug works by blocking serotonin receptors in the brain, reducing vomiting reflex activation. Despite evidence suggesting its efficacy, there are still concerns about its use during pregnancy, particularly during the first trimester. This is due to potential risks to fetal development, including congenital malformations. While some studies have reported a statistically significant association between ondansetron exposure and an increased risk of cardiac malformations, conflicting evidence has also been reported. Further research is warranted to assess the potential risks and benefits associated with the use of ondansetron in pregnant women to ensure that it can be used safely with minimal risk to both the mother and unborn baby.
Statements
Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Author contributions
AA: Data collection, Investigation, Methodology, Software, Writing–original draft, Writing–review and editing.
Funding
The author declare that no financial support was received for the research, authorship, and/or publication of this article.
Conflict of interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1
CarstairsS. D. (2016). Ondansetron use in pregnancy and birth defects: a systematic review. Obstetrics Gynecol.127 (5), 878–883. 10.1097/AOG.0000000000001388
2
CengizH.DagdevirenH.CaypinarS. S.KanawatiA.YildizS.EkinM. (2015). Plasma serotonin levels are elevated in pregnant women with hyperemesis gravidarum. Archives Gynecol. obstetrics291, 1271–1276. 10.1007/s00404-014-3572-2
3
CharbitB.AlbaladejoP.Funck-BrentanoC.LegrandM.SamainE.MartyJ. (2005). Prolongation of QTc interval after postoperative nausea and vomiting treatment by droperidol or ondansetron. J. Am. Soc. Anesthesiol.102 (6), 1094–1100. 10.1097/00000542-200506000-00006
4
ChristofakiM.PapaioannouA. (2014). Ondansetron: a review of pharmacokinetics and clinical experience in postoperative nausea and vomiting. Expert Opin. Drug Metabolism Toxicol.10 (3), 437–444. 10.1517/17425255.2014.882317
5
ClarkS.HughesB.McDonaldS. S. (2013). The impact of nausea and vomiting of pregnancy on quality of life: report of a national consumer survey and recommendations for improving care. Obstetrical Gynecol. Surv.68 (9), S1–S10. 10.1097/ogx.0b013e3182a8784d
6
ColvinL.GillA. W.Slack-SmithL.StanleyF. J.BowerC. (2013). Off-label use of ondansetron in pregnancy in Western Australia. BioMed Res. Int.2013, 909860. 10.1155/2013/909860
7
DanielssonB.WiknerB. N.KällénB. (2014). Use of ondansetron during pregnancy and congenital malformations in the infant. Reprod. Toxicol.50, 134–137. 10.1016/j.reprotox.2014.10.017
8
ErnstE. (2019). “Complementary/alternative medicine during pregnancy,” in Therapeutics in pregnancy and lactation (England, UK: Routledge), 207–213.
9
FejzoM. S.TrovikJ.GrootenI. J.SridharanK.RoseboomT. J.VikanesÅ.et al (2019). Nausea and vomiting of pregnancy and hyperemesis gravidarum. Nat. Rev. Dis. Prim.5 (1), 62. 10.1038/s41572-019-0110-3
10
FreedmanS. B.UlerykE.RumantirM.FinkelsteinY. (2014). Ondansetron and the risk of cardiac arrhythmias: a systematic review and postmarketing analysis. Ann. Emerg. Med.64 (1), 19–25. 10.1016/j.annemergmed.2013.10.026
11
GriddineA.BushJ. S. (2022). “Ondansetron,” in StatPearls (Petersburg, Florida: StatPearls Publishing).
12
HeckrothM.LuckettR. T.MoserC.ParajuliD.AbellT. L. (2021). Nausea and vomiting in 2021: a comprehensive update. J. Clin. gastroenterology55 (4), 279–299. 10.1097/MCG.0000000000001485
13
HeskethP. J.KrisM. G.BaschE.BohlkeK.BarbourS. Y.Clark-SnowR. A.et al (2017). Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J. Clin. Oncol.35 (28), 3240–3261. 10.1200/JCO.2017.74.4789
14
KaplanY. C.RichardsonJ. L.Keskin-ArslanE.Erol-CoskunH.KennedyD. (2019). Use of ondansetron during pregnancy and the risk of major congenital malformations: a systematic review and meta-analysis. Reprod. Toxicol.86, 1–13. 10.1016/j.reprotox.2019.03.001
15
KennedyD. (2016). Ondansetron and pregnancy: understanding the data. Obstet. Med.9 (1), 28–33. 10.1177/1753495X15621154
16
KorenG. (2014). Treating morning sickness in the United States: changes in prescribing are needed. Am. J. Obstetrics Gynecol.211 (6), 602–606. 10.1016/j.ajog.2014.08.017
17
LeeN. M.SahaS. (2011). Nausea and vomiting of pregnancy. Gastroenterol. Clin.40 (2), 309–334. 10.1016/j.gtc.2011.03.009
18
LozanoR. (2013). Mirtazapine and ondansetron: a dual pharmacodynamic and pharmacokinetic interaction. Afr. J. Psychiatry16 (1), 56.
19
MaltepeC. (2014). Surviving morning sickness successfully: from patient’s perception to rational management. J. Popul. Ther. Clin. Pharmacol.21 (3), e555–e564.
20
MeiriE.JhangianiH.VredenburghJ. J.BarbatoL. M.CarterF. J.YangH. M.et al (2007). Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting. Curr. Med. Res. Opin.23 (3), 533–543. 10.1185/030079907x167525
21
MichieL. A.HodsonK. K. (2020). Ondansetron for nausea and vomiting in pregnancy: re-evaluating the teratogenic risk. London, England: SAGE Publications Sage UK, 3–4.
22
ParkerS. E.Van BennekomC.AnderkaM.MitchellA. A.National Birth Defects Prevention Study (2018). Ondansetron for treatment of nausea and vomiting of pregnancy and the risk of specific birth defects. Obstetrics Gynecol.132 (2), 385–394. 10.1097/AOG.0000000000002679
23
QuinlanJ. D.HillD. A. (2003). Nausea and vomiting of pregnancy. Am. Fam. physician68 (1), 121–128.
24
RoilaF.Del FaveroA. (1995). Ondansetron clinical pharmacokinetics. Clin. Pharmacokinet.29 (2), 95–109. 10.2165/00003088-199529020-00004
25
SiminoG. P. R.MarraL. P.AndradeE. I. G. d.AcúrcioF. d. A.ReisI. A.De AraújoV. E.et al (2016). Efficacy, safety and effectiveness of ondansetron compared to other serotonin-3 receptor antagonists (5-HT3RAs) used to control chemotherapy-induced nausea and vomiting: systematic review and meta-analysis. Expert Rev. Clin. Pharmacol.9 (9), 1183–1194. 10.1080/17512433.2016.1190271
26
SimpsonK. H.HicksF. M. (1996). Clinical pharmacokinetics of ondansetron. A review. J. Pharm. Pharmacol.48 (8), 774–781. 10.1111/j.2042-7158.1996.tb03973.x
27
SlatteryJ.QuintenC.CandoreG.PinheiroL.FlynnR.KurzX.et al (2022). Ondansetron use in nausea and vomiting during pregnancy: a descriptive analysis of prescription patterns and patient characteristics in UK general practice. Br. J. Clin. Pharmacol.88 (10), 4526–4539. 10.1111/bcp.15370
28
SolihahR.PurwatiA. E.SandrianiS.MiraN. (2023). Literature Review: herbs to prevent nausea and vomiting in pregnant women. Nurul Ilmi J. Health Sci. Midwifery1 (1), 37–44. 10.52221/nuri.v1i1.209
29
The National Library of Medicine (2016). NCT01357369. Available at: https://clinicaltrials.gov/study/NCT01357369.
30
The National Library of Medicine (2011). NCT01414777. Available at: https://clinicaltrials.gov/study/NCT01414777.
31
The National Library of Medicine (2013a). NCT01668069. Available at: https://clinicaltrials.gov/study/NCT01668069.
32
The National Library of Medicine (2013b). NCT01801475. Available at: https://clinicaltrials.gov/study/NCT01801475.
33
The National Library of Medicine (2020). NCT01965704. Available at: https://clinicaltrials.gov/study/NCT01965704.
34
The National Library of Medicine (2022). NCT03785691. Available at: https://clinicaltrials.gov/study/NCT03785691.
35
ThibeaultA.-A. H.SandersonJ. T.VaillancourtC. (2019). Serotonin-estrogen interactions: what can we learn from pregnancy?Biochimie161, 88–108. 10.1016/j.biochi.2019.03.023
36
WolfH. (2000). Preclinical and clinical pharmacology of the 5-HT3 receptor antagonists. Scand. J. Rheumatology29 (113), 37–45. 10.1080/030097400446625
37
YokoiA.MiharaT.KaK.GotoT. (2017). Comparative efficacy of ramosetron and ondansetron in preventing postoperative nausea and vomiting: an updated systematic review and meta-analysis with trial sequential analysis. PLOS ONE12 (10), e0186006. 10.1371/journal.pone.0186006
Summary
Keywords
ondansetron, pregnancy, clinical trials, serotonin, vomiting, morning sickness
Citation
Ashour AM (2023) Efficacy and safety of ondansetron for morning sickness in pregnancy: a systematic review of clinical trials. Front. Pharmacol. 14:1291235. doi: 10.3389/fphar.2023.1291235
Received
08 September 2023
Accepted
11 October 2023
Published
23 October 2023
Volume
14 - 2023
Edited by
Hanan Farouk Aly, National Research Centre, Egypt
Reviewed by
Khalid Ibrahim, University of Zakho, Iraq
Gehad Subaiea, University of Hail, Saudi Arabia
Updates
Copyright
© 2023 Ashour.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ahmed M. Ashour, amashour@uqu.edu.sa
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.