Efficacy and safety of ondansetron for morning sickness in pregnancy: a systematic review of clinical trials

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.

Search strategy
A comprehensive investigation was carried out on ClinicalTrials.govon 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.

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.

Participants
A total of 508 adult female participants from a search of ClinicalTrials.govwere 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.