The American College of Obstetrics and Gynecology (ACOG) discussed antiemetic options for pregnancy in a 2018 practice bulletin. Overall, no single therapeutic approach has proven most effective for pregnancy or each of the three stages, and risk and benefits should be weighed on a case-by-case basis. The recommended algorithm for general pregnancy-related nausea and vomiting recommends a stepwise approach. Vitamin B6 (pyridoxine) with/without doxylamine is initially recommended. If symptoms persist, the addition of dimenhydrinate PRN/scheduled dosing, prochlorperazine, or promethazine is recommended. The continuation of symptoms leads to the addition of other agents depending on the hydration status of patients (no dehydration: oral ondansetron; dehydration: intravenous ondansetron; see Table 1). [1]
A 2022 systematic review and meta-analysis evaluated abnormal pregnancy outcomes after using ondansetron during pregnancy. In total, 20 articles were analyzed, which consisted of 11 cohort studies, 5 case-control studies, 2 case reports, and 1 case series. Compared with patients who did not use ondansetron, patients who were exposed reported higher incidence of cardiac defects (odds ratio [OR] 1.06; 9% confidence interval [CI] 1.01 to 1.10), neural tube defects (OR 1.12; 95% CI 1.05 to 1.18), and chest cleft (OR 1.21; 95% CI 1.07 to 1.37), although a later sensitivity analysis showed no difference between groups regarding incidence of cardiac defects or neural tube defects, and elimination of controversial studies resulted in no association found between ondansetron and cardiac defects altogether. An association between ondansetron and reduced incidence of miscarriage was observed (OR 0.53; 95% CI 0.31 to 0.89). No difference between groups was found in incidence of orofacial clefts, spinal limb defects, urinary tract deformities, any congenital malformations, stillbirth, preterm birth, neonatal asphyxia, or neonatal development. Notably, duration of treatment and dosage varied between cases, and ondansetron was often reserved for patients with more severe symptoms per societal guidelines, thus introducing confounding within the results. [2]
A 2020 network meta-analysis (NMA) of 18 randomized controlled trials (RCTs) compared different treatment options including promethazine in pregnant individuals with hyperemesis gravidarum (HG). The primary outcome of control of HG symptoms did not include promethazine in the analysis (n= 400 participants), demonstrating methylprednisolone (OR 6.7; 95% CI 1.1 to 38.8) as the only pharmacological intervention to be associated with significantly better control of HG symptoms compared to standard of care. For secondary outcomes, ondansetron was associated with reduced hospital stay (weighted mean difference [WMD] -0.2; 95% CI -0.31 to -0.01) and diazepam with reduced risk of hospital admission (OR 0.11; 95% CI 0.01 to 0.95). Compared to metoclopramide, promethazine did not exhibit significantly better improvements in emetic episodes, nausea scores, hospital stay, and quality of life. Similarly, no significant differences were noted between promethazine and the standard of care in the use of rescue antiemetics and hospital admission. Subgroup analysis of patients with severe nausea/vomiting associated with dehydration and metabolic disturbances in the form of ketonuria and weight loss found no differences in the primary outcomes between methylprednisolone and ondansetron compared to metoclopramide. The overall quality of evidence appeared to be very low, and findings need to be confirmed in head-to-head clinical trials in the future. [3]
A 2017 book chapter from the Emergency Department Management of Obstetric Complications provided a stepwise treatment approach to managing pregnancy-associated nausea and vomiting. Similar to the guideline recommendations, pyridoxine plus doxylamine is recommended as the first-line pharmacological intervention in addition to supportive care. Second-line options for relieving moderate to severe vomiting included diphenhydramine, dimenhydrinate, or metoclopramide. In patients with refractory symptoms not responding to aforementioned second-line agents, ondansetron, prochlorperazine, promethazine, or methylprednisolone may be administered. Additionally, promethazine suppository is another option for patients unable to tolerate oral medications. Though not directly compared with each other, higher quality evidence existed within medical literature for ondansetron compared to promethazine or prochlorperazine. It should be noted that steroids in general should be considered last resort therapy due to the risks of fetal oral clefts and low birth weight. [4]
A 2014 review on the outpatient management and special considerations of nausea and vomiting in pregnancy (NVP) assessed the conservative measures and available pharmacotherapy for the treatment of the symptoms of nausea and vomiting despite changes in lifestyle and nutrition. The combination of oral pyridoxine and doxylamine for the treatment of NVP has the most data on safety and efficacy and has been utilized by healthcare providers in the U.S. Dimenhydrinate and promethazine were considered second-line agents for NVP that can be administered orally or rectally. Human and animal studies did not demonstrate an association between the use of promethazine during pregnancy (including the first trimester) and an increased risk of malformation. If none of the previously mentioned medications control symptoms, the third-line therapy for NVP would be changing the route of delivery of promethazine to intramuscular. Metoclopramide is another medication that can be given orally or intramuscularly. Metoclopramide works as an antiemetic and prokinetic agent by decreasing gastrointestinal emptying time and acting on the chemoreceptor trigger zone. Therefore, it can be useful in patients with diabetes and gastroesophageal reflux disease. If symptoms are still not adequately controlled, a serotonin 5-hydroxytryptamine 3-receptor (5-HT3) antagonist such as ondansetron can be introduced. While ACOG guidelines reserve the use of ondansetron as a last-line therapy for NVP in the presence of dehydration, it is often prescribed in the outpatient setting due to less sedating effects when compared to promethazine and antihistamine. As every woman has her perception of disease severity and desire for treatment, it is essential to track symptoms in order to assess for a decrease or resolution of symptoms as well as escalations in symptoms that might require additional therapy. [5]
A 2022 study on birth defects using data from the case-control National Birth Defects Prevention Study (1997-2011) to examine whether first-trimester NVP or its specific treatments were associated with 37 major birth defects. Overall, mothers of 66.6% of 28,628 cases and 69.9% of 11,083 controls reported first-trimester NVP. Pooled analysis demonstrated increased risks for promethazine and tetralogy of Fallot (adjusted OR [aOR] 1.49; 95% CI 1.05 to 2.10), promethazine and craniosynostosis (aOR 1.44; 95% CI 1.08 to 1.92), ondansetron and cleft palate (aOR 1.66; 95% CI 1.18 to 2.31), pyridoxine and heterotaxy (aOR 3.91; 95% CI 1.49 to 10.27), and pyridoxine and cataracts (aOR 2.57; 95% CI 1.12 to 5.88). Notably, findings do not necessitate causation, as data were derived from reports of first-trimester NVP. [6]