Nausea and Vomiting in Pregnancy: Therapeutics

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The treatment of nausea and vomiting during pregnancy in the emergency department setting can be intimidating. Treating these patients is made even more challenging given the gaps of knowledge that inherently exist surrounding the safety and efficacy of many pharmacologic therapies used to treat expecting mothers. Notably, Matthews et al in their review of treatment in nausea and vomiting of pregnancy concluded in a recent Cochrane Review that “there is a lack of high‐quality evidence to support any particular intervention”.[1] In a more recent Cochrane Review, Boelig et al concluded, “on the basis of this review, there is little high‐quality and consistent evidence supporting any one intervention, which should be taken into account when making management decisions”.[2] In this post, we attempt to break-down some of the literature surrounding this largely discussed topic.

Nausea is a common symptom of pregnancy and is reported in up to 80% of pregnant women. Of this group, nearly 50% will experience some sort of vomiting or retching-like symptoms.[1] The most severe end of this spectrum is termed hyperemesis gravidarum, which is estimated to impact nearly 1% of all pregnancies.[1,3] Variably defined, the diagnosis incorporates the following: persistent vomiting unrelated to other underlying pathology, measure of starvation (I.e. ketonemia vs ketonuria), and often a loss of at least 5% of pre-pregnancy weight.[4]

The Pregnancy-Unique Quantification of Emesis and Nausea Index (PUQE Index ) has been developed to help clinicians assess the severity of a patient’s symptoms based on the patient’s own perception. Specifically, the index includes measures that discuss the symptom severity, desire for treatment, and potential effects of treatment on the fetus as they pertain to clinical decision making.  Based on three questions, expecting mothers can have a score up to 15, with scores ≤ 6 considered mild, 7-12 moderate, and ≥ 13 as severe. Overall, the clinician’s decision for treatment and disposition of this patient population should be based on the above factors.  The index and table above have been adapted from Koren et al 2002 and validated in Koren et al 2005.

As an emergency physician, hyperemesis gravidarum should be approached as a pathological state affecting both mother and fetus. For her fetus, one study by Gross et al (1989) compared fetal outcomes among 64 pregnant women suffering from hyperemesis. Those with weight loss >5% were compared to those without. Among women with significant weight loss, fetal outcomes were complicated by small birth weight and fetal growth restriction.[5] A systematic review and meta-analysis of literature surrounding the effect of hyperemesis gravidarum on fetal outcomes found babies born to mothers who suffered from hyperemesis gravidarum were also more likely to be born prematurely. However, there are not data supporting increased risk of congenital malformation among these individuals.[6]

For the mother, most harm caused is a result of the potential nutritional deficits of which they are at risk, specifically thiamine deficiency leading to Wernicke’s Encephalopathy or Wet Bari Bari. Mothers are also at risk of central pontine myelinolysis resulting from too rapid correction of hyponatremia. Cases of pneumomediastinum and esophageal rupture have been reported, as well as less common complications including rhabdomyolysis, vitamin K, B6, and B12 deficiency along with their associated symptomatology.[7] Acute tubular necrosis has been reported in association with severe volume depletion.[8]

Further, hyperemesis gravidarum the most common indication for hospitalization in the first trimester, and is the second most common indication for hospitalization throughout pregnancy, second only to preterm labor.[8-10] With such a profound impact on quality of life, the treatment of nausea and vomiting of pregnancy (NVP) is a necessary component of any emergency medicine providers’ toolbox.

Pathophysiology

The underlying pathophysiology of NVP is still under debate. One hypothesis suggests that the pathophysiology pertains to different human chorionic gonadotropin (hCG) isoforms versus one’s variable susceptibility to emetogenic stimuli. Such a hypothesis is evidenced by the fact that those who are multiparous or have a multi-gestational pregnancy are at increased risk of NVP.[8] Another hypothesis relates to the role of elevated estradiol as an emetogenic stimulus.[11-12] Others suggest that NVP is an evolutionary adaptation to protect an expecting mother from potentially dangerous foods.[13] Lastly, some have hypothesized there may be a psychologic predisposition to NVP.[8] However, given the threat such a condition as NVP can have on both mother and fetus, hyperemesis gravidarum should be treated as appropriately as a somatic process when presenting in the emergent setting.

Treatments: Where to Start

Initially, preventative measures should be taken to reduce the occurrence of NVP. If feasible, patients with NVP should first consider dietary changes that incorporate avoidance of emetogenic stimuli or triggers. Small, intermittent snacks throughout the day as well as ensuring the patient is eating as soon as she feels hungry have been suggested to help alleviate NVP.[16]

Figure inspired by and adapted from the January 2018 ACOG Practice Bulletin published by the Committee on Obstetric Practice.[8] The above ultimately reflects practice guidelines as they have been adapted from the above clinical practice guidelines, specifically for those patients presenting with suspected hyperemesis gravidarum with volume depletion.

However, patients who present to the emergency department with continued NVP are often volume depleted and may be ketotic. Therefore, these patients should be treated with sodium-containing fluids including normal saline or lactated ringers, in addition to correcting underlying electrolyte derangements as needed, as well as considering dextrose to improve ketone clearance. [17-21] Careful consideration must be made in those with severe hyponatremia due to the risk of central pontine myelinolysis with rapid sodium correction. Further, though a rare complication, Wernicke’s Encephalopathy has been documented in multiple studies in association with hyperemesis graviderum and predisposition to vitamin deficiencies (alcoholism, chronic malnutrition) should be considered prior to starting dextrose-containing fluids.[17-20]

Regarding pharmacological therapy for NVP, many expecting mothers and clinicians are understandably concerned about the potential impact any treatment modalities may have on the developing fetus. As with many therapies during pregnancy, evidence from strong, randomized controlled trials (RCT) are lacking due to the ethical concerns surrounding research in pregnant patients. However, there have been a variety of cohort studies, large systematic reviews, and meta-analyses that provide insight into the safety and efficacy of many of these therapeutics on both mother and fetus. It is important to note that many of these studies have been conducted with the intention of outpatient use and have thus been extrapolated for use in the acute care setting.

Pyridoxine (Vitamin B6)

Pyridoxine, also known as vitamin B6, is a water-soluble vitamin derived from plant products. Pyridoxine is a vital component to many processes, including immune function, heme synthesis, and a variety of other vital biochemical processes.[22] The mechanism of action of vitamin B6 as it pertains to nausea and vomiting in pregnancy is largely unknown, however studies have demonstrated some efficacy in NVP symptom management.  

Efficacy

Sahakian et al. conducted a double-blinded, RCT evaluating the use of vitamin B6 25 mg every eight hours in 31 women versus placebo in 28 women over a 72-hour period. Their results demonstrated statistically significant improvement in the mean difference of nausea scores in those with severe nausea treated with B6 compared with placebo (P value < 0.01), and no improvement in those with mild to moderate nausea.[23] Another RCT conducted by Vutyavanich et al compared pyridoxine 30 mg per day versus placebo among 342 randomized women and found a statistically significant decrease in the severity of nausea using a visual analog scale (p value of 0.0008), though there was no noted improvement in vomiting.[24] Further, a recent systematic review conducted by McParlin and colleagues (2016) reviewed a total of 78 studies, 67 of which were RCTs. Fourteen of these reviewed the efficacy of vitamin B6 in reducing nausea and vomiting of pregnancy, concluding that vitamin B6 an effective treatment for mild to moderate nausea, however did not find evidence to support reduction in vomiting.[25] Thus, doses of 10-25 mg orally every 6 hours has been shown to be effective in limiting nausea symptoms, but limited efficacy in vomiting, without teratogenic effects.[23-24,26-28]

Safety

As for safety, Shrim et al (2009) conducted a study among 192 pregnant women, 96 of which reported taking higher than standard doses of vitamin B6 and were compared to a group of 96 women who did not report vitamin B6 use. After their analysis, they concluded that there was no statistical difference between vitamin B6 use and adverse fetal outcomes, including fetal birth weight, gestational age, live births, and congenital malformations. The authors note that, despite promising results, their study was limited by power.[28]  

Doxylamine

Doxylamine is a first-generation histamine H1 antagonist, acting at H1 receptors in the central nervous system, blocking its stimulatory effect at the tuberomammillary nucleus which results in drowsiness. It is oftentimes used in combination with pyridoxine, and combination tablets containing pyridoxine 10 mg and doxylamine 10 mg are available. Doses of up to 20 mg each have been shown to be both safe and effective for the mother,[29] and tablets may be taken two to four times per day.

Efficacy

One RCT conducted by Koren et al compared a combination vitamin B6-doxylamine therapy (Diclectin) with placebo and evaluated daily individual PUQE scores over fourteen days. At study conclusion, researchers found a statistically significant improvement in PUQE scores in the pyridoxine-doxylamine group compared to placebo (-4.8 2.7 vs –3.9  2.6, P = 0.006).[30]

Safety

From the mid-1900s to early 1980s, vitamin B6 therapy was used in combination with doxylamine in the treatment of NVP. In the early 1980s, however, Diclectin was taken off the market due to concerns of its teratogenic effects as outlined by multiple cohort and case-control studies.[8] A 1994 meta-analysis of these studies ultimately revealed a statistically insignificant pooled relative risk for birth malformations associated with Diclectin during the first trimester, 0.95 (95% Confidence interval of 0.88 - 1.04).[31] It has since been re-approved by the FDA in 2013, and the combination of pyridoxine and doxylamine has been recommended as first line therapy per the Clinical Management Guidelines for Obstetrician-Gynecologists.[8]

Dimenhydrinate

Briefly, dimenhydrinate (Dramamine) is another H1-antagonist. Like doxylamine, dimenhydrinate acts at centrally acting H1 receptors. Dimenhydrinate can be administered at doses of 25-50 mg orally every four to six hours, or intravenously at 50 mg every four to six hours. Given dimenhydrinate and doxylamine share the same mechanism of action, it is recommended that no more than 200 mg dimenhydrinate be given to a patient concurrently taking doxylamine.[16] Multiple studies have been conducted that have failed to find any association between dimenhydrinate and congenital anomalies.[32-34]

Ondansetron (Zofran)

Ondansetron is a commonly used anti-emetic that works by antagonizing serotonin at the 5-HT3 receptor peripherally at the vagus nerve terminal as well as centrally at the chemoreceptor trigger zone. Ondansetron has been recommended to aid in the treatment of NVP, especially in those hospitalized with hypovolemia secondary to NVP;[16] however, due to an overall lack of evidence regarding its safety profile, ACOG recommends ondansetron be used as a second-line agent, and recommend a risk-benefit discussion especially in those <10 weeks pregnant.[8]

Efficacy

The evidence behind the efficacy and use of ondansetron in NVP is limited to a couple of small RCTs. One study conducted by Oliveira et al (2014) compared ondansetron to the combination of vitamin B6 and doxylamine, with outcomes assessed including patient-reported scores on the visual analog scale (VAS) and symptoms of vomiting. 36 women were randomized to either group with results showing statistically significant improvement in both VAS and vomiting among the ondansetron group compared with the B6-doxylamine group.[35] Another RCT including 83 women compared ondansetron to metoclopramide and found statistically significant improvement in vomiting symptoms among the ondansetron group, however, there was no difference in nausea.[36]

Safety

It is important to note that there is insufficient data surrounding ondansetron and other 5-HT3 antagonists and their safety profile in pregnancy. One systematic review concluded that there was no overall increase in risk associated with ondansetron and congenital birth defects.[37] In a large retrospective cohort study including 1.8 million pregnancies found no association with cardiac malformations when exposed to ondansetron in the first trimester. However, there was an increased risk of oral clefts.[38] A similar study investigated the association between IV administration of ondansetron and found no statistically significant risk of oral cleft, cardiac, or congenital malformations.[39] Another more recent systematic review suggests there may be an association with cleft palate as well as ventricular septal defects, though some studies included are considered to have poor quality data and failed to control for confounding variables.[40] Despite the above, ondansetron is commonly used in the emergency department in treating patients presenting with persistent symptoms.

Metoclopramide

Metoclopramide is a dopamine antagonist, as well as a serotonin 5-HT4 agonist, that blocks dopamine effects in the chemoreceptor trigger zone of the medulla oblongata which is responsible for inducing nausea and vomiting. Metoclopramide is prescribed at 5-10 mg orally, intravenously, or intramuscularly every six to eight hours.

Safety

Two large cohort studies have been conducted to evaluate the relationship between metoclopramide and congenital malformations in the first trimester, both of which found no increased risk of congenital defects.[41-42] However, there is a concern for maternal side effects including dystonia and tardive dyskinesia with long-term use. Thus, frequent patient monitoring is necessary to avoid the sometimes-irreversible side effects of tardive dyskinesia if used on a long term basis.  One RCT compared metoclopramide with ondansetron, finding they were equally efficacious though there were increased adverse side effects associated with metoclopramide administration, particularly xerostomia, drowsiness, and ketonuria at 24 hours.[46]

Chlorpromazine

Chlorpromazine is a dopamine antagonist that can be prescribed at 25 to 50 mg IV or IM or 10 to 25 mg orally every 4-6 hours.

Safety

Unlike the dopamine antagonists noted above, chlorpromazine has been found to have increased risk of maternal side effects, including extrapyramidal reactions, anticholinergic effects, cardiovascular conduction abnormalities.[16] As a result, experts only recommend the addition of chlorpromazine in those patients who have such refractory NVP that they are a candidate for last-ditch steroids and have underlying risk factors that may make steroid use unfavorable.

Promethazine

Promethazine can be administered orally, intramuscularly, or per rectum – intravascular, intraarterial, and subcutaneous administration is contraindicated.

Efficacy

When compared to metoclopramide, promethazine has been shown to carry increased risk of maternal side effects, including drowsiness, dystonia, and tardive dyskinesia.[45] Given the above evidence, metoclopramide has been shown to be both safe and effective with fewer side effects, and therefore metoclopramide is often used over other dopamine antagonists.

Safety

Multiple studies have failed to support a relationship between promethazine and congenital abnormalities.[44]

Refractory symptoms: Steroids and Droperidol

Steroids

Short courses of glucocorticoids have been suggested as a last-ditch effort for symptom alleviation in refractory cases of NVP. The mechanism of action is not well understood at this time, however methylprednisolone 16 mg IV every 8 hours [47] up to three days or hydrocortisone 100 mg IV twice daily [25] followed by a prednisone taper have been suggested to have some benefit in these cases.[16]

As adapted from Hoes et al 2007. EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases.43

Efficacy

One systemic review from 2016 including three RCTs compared glucocorticoids to placebo or other anti-emetics and found some possible benefit in severe cases.[25] Another RCT comparing prednisolone with placebo found no difference in nausea and vomiting scores.[48]

Safety

Glucocorticoid use prior to 10 weeks of pregnancy has been associated with increased risk of oral cleft and therefore administration should be avoided in the first trimester.[49-53]

Droperidol

Droperidol has been making a recent comeback in the treatment of refractory cases of nausea and vomiting of all etiologies, and has been found to be quite effective in the alleviation of NVP in limited studies.

Efficacy

One study compared a droperidol-diphenhydramine combination with other antiemetic therapies and found that those treated with droperidol-diphenhydramine had statistically significant decrease in hospital length of stay as well as fewer readmissions.[54]

Safety

Given the risk of QT prolongation and progression to torsades de pointes,[55] maternal caution should be used when using this drug for prolonged periods of time or at large doses. Congenital anomalies have yet to be reported. Thus, droperidol may be a drug more readily reached for in patients presenting with NVP, though further epidemiologic studies should be encouraged evaluating its efficacy as well as maternal and congenital safety profile before it be adopted into routine clinical practice. 

Summary

Nausea and vomiting of pregnancy is a frequent cause of morbidity and reduced quality of life in those who are pregnant. NVP can have deleterious effects on both mother as well as fetus. One can attempt the avoidance of medical management through various dietary and preventative changes. However, many will have nausea and vomiting significant enough to push some to seek acute medical management. In those presenting with suspected hyperemesis gravidarum, volume and nutrient repletion should be considered first line. The data surrounding further medical therapies are scarce. However, it is largely agreed upon that the use of vitamin B6 with or without doxylamine is an effective and safe first line therapy. However, patients presenting to the emergency department are often those that have symptoms refractory to common outpatient therapies and require the use of other anti-emetics. Ondansetron is commonly reached for first in the emergent setting. However, given its lack of evidence regarding teratogenicity, metoclopramide may be considered in the acute management of NVP.

article by Josh Ferreri, MD

Dr. Ferreri is a PGY-1 Emergency Medicine Resident at the University of Cincinnati

Peer Editing and Post by Sim Mand, MD and Ryan LaFollette, MD

Dr. Mand is a Chief Resident and soon-to-be Ultrasound Fellow at the University of Cincinnati and Dr. LaFollette is an Assistant Residency Director and Co-Editor of TamingtheSRU

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