Evidence-Based Approaches to Managing Nausea and Vomiting in Early Pregnancy

Tekoa L. King, CNM, MPH; Patricia Aikins Murphy, CNM, DrPH

J Midwifery Womens Health. 2009;54(6):430-444.

Pharmacologic Therapies

Several different categories of pharmaceuticals either singly or in combination are used to treat NVP. The drug categories, based on different mechanisms of action (Figure 3), include vitamins, antihistamines, anticholinergics, dopamine antagonists, phenothiazines (which antagonize the dopamine receptor in the CNS), butyrophenones, serotonin antagonists, and corticosteroids. Common doses and schedules are listed in Table 1. All drugs must be assessed for both safety and efficacy before being recommended for use in clinical practice and are presented here in the usual order of use in clinical practice. The US Food and Drug Administration (FDA) categorizes drugs according to the evidence for safety in pregnancy;^[72] these ratings are summarized in Table 2. Because vitamin B6 is often used alone or in addition to other pharmacologic therapies, it is reviewed first.

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Figure 3.

Mechanism of action of antiemetics used to treat nausea and vomiting in pregnancy.

Vitamin B6

Pyridoxine (vitamin B6), a water-soluble vitamin and essential coenzyme in the folate metabolism pathway, was first referenced for use in treating NVP in 1942.^[73] The mechanism of action for how pyridoxine affects nausea is unknown. No teratogenic risks have been associated with use of pyridoxine^[74] and it is considered FDA Pregnancy Category A. Two RCTs have found that regular use of pyridoxine is effective in decreasing the severity of nausea but has no effect on the frequency of vomiting episodes.^[75,76] Vutyvanich et al.^[75] compared the effects of a 25 mg per day dose of pyridoxine to placebo (N = 336) and found that after 5 days of therapy, the mean nausea scores were lower in the women in the intervention group (2.9 ± 2.2 versus 2.0 ± 2.7, respectively; P =.008), but there were no differences in the number of vomiting episodes. Sahakian et al.^[76] randomized 59 women to a dose of 75 mg pyridoxine daily versus placebo and compared the severity of nausea on a visual analog scale after 72 hours of therapy. The women in the intervention group who reported severe nausea pretreatment reported less intense nausea than those who took a placebo (mean difference in nausea score, 4.3 ± 2.1 versus 1.8 ± 2.2; P ≤.01), but there was no significant difference in the nausea scores for women who reported moderate or mild nausea at the onset of the trial. This trial also found a significant decrease in vomiting in the women who took the pyridoxine compared to those who took placebo (number of women still vomiting at 72 hours, 8 of 31 versus 15 of 28; P ≤.05). Pyridoxine as a single therapy is therefore useful for decreasing the severity of nausea and may have a mild effect on vomiting. The therapeutic benefit of pyridoxine is probably dose-related.

The effective dose of pyridoxine for treating NVP based on the doses used in the studies done to date is 30 to 75 mg per day, which is higher than the recommended daily allowance for pregnant or breastfeeding women (1.9 and 2.0 mg, respectively).^[77] Although there have been no large-scale directed investigations of the safety of pyridoxine alone, the vitamin was an ingredient in a drug called Bendectin, and extensive evaluations of that drug have shown no evidence of teratogenesis. Those studies indicated that pyridoxine doses up to 40 mg per day are safe.^[78,79] More recent studies of pyridoxine doses up to 75 mg have shown no evidence of teratogenesis, but the sample sizes were too small to definitively address the possibility of teratogenesis.^[76] Pyridoxine has been shown to cause neurologic problems in adults when taken in excessive doses.^[80] The determination of the optimal dose in pregnancy is still needed.

Antihistamines

Antihistamines block histamine receptors in both the vestibular system (H₁ receptors) and chemoreceptor trigger zone (H₂ receptors). These agents are the most widely used first-line medication therapy for women who have NVP. Diphenhydramine (Benadryl) and doxylamine (Unisom tablets) can be obtained without a prescription. There have been more than 20 controlled trials of various antihistamines, and interestingly, women who are exposed to antihistamines in the first trimester of pregnancy have a slightly lower risk for major and minor malformations when compared to women who have not been exposed to antihistamines during pregnancy (OR, 0.76; 95% CI, 0.60–0.94).^[81]

Pooled data from 7 RCTs that assessed the effectiveness of various antihistamines found that they significantly reduce vomiting (relative risk [RR] = 0.34; 95% CI, 0.27–0.43),^[82] but the trials used several different antihistamines with different doses so it is not clear what regimen is the most effective based on the studies. In summary, although antihistamines are both safe and efficacious, their usefulness is limited by an adverse side effect profile. Because antihistamines frequently cause drowsiness, many women are not able or willing to take these medications throughout the day. There are no studies to date that have assessed the safety or efficacy of nonsedating antihistamines (e.g., loratadine [Claritin], cetirizine [Zyrtec], or fexofenadine [Allegra]) for the treatment of NVP.

Anticholinergics

Although scopolamine has been used extensively to treat motion sickness in nonpregnant individuals and was recently found to be of benefit in reducing nausea after cesarean delivery,^[83] it has not been studied for efficacy or safety in the treatment of NVP. However, an epidemiologic study of teratogenic effects of drugs noted scopolamine exposure in the first trimester in 309 women without evidence of teratogenic effects.^[82] The only anticholinergic drug used to treat NVP has been dicyclomine (Bentyl), which is discussed next in the story of Bendectin.

Bendectin

Bendectin, a combination of dicyclomine, doxylamine succinate, and pyridoxine hydrochloride, was approved by the FDA for treating NVP and introduced to the US market in 1956. In 1976, dicyclomine was removed because studies found that it had no independent effect/efficacy, and Bendectin was reformulated to contain 10 mg of doxylamine and 10 mg of pyridoxine in a formulation that was taken three to four times per day.^[78] Bendectin was used by 25% to 30% of pregnant women in the United States through the 1970s. In the early 1980s, lawsuits alleging that Bendectin caused teratogenic effects occurred followed by extensive media coverage. The drug was voluntarily removed from the US market in June of 1983 by the manufacturer.^[84] Despite removal from the US market, the same formulation as in Bendectin is marketed under different brand names and continues to be used in Europe and Canada.

This is an unfortunate story, because Bendectin has been shown to be both safe and efficacious.^[85] In summary analyses, the pooled RR for fetal malformation is 0.98 (95% CI, 0.93–1.02),^[78] and the efficacy of Bendectin in treating NVP (summarizing 2 RCTs) has a RR of 0.53 (95% CI, 0.41–0.68).^[82] Kutcher et al.^[78] compared Bendectin sales prevalence with birth defects and hospitalization rates for HG over a 20-year period (1974–1994) and found that when Bendectin was withdrawn from the marketplace, birth defect rates remained unchanged but that hospitalization rates for HG drastically increased (Figure 4). In 1999, the FDA issued an advisory statement stating that Bendectin was not removed from the market because it was unsafe or ineffective and invited companies to resubmit applications for similar formulations.^[86] However, no pharmaceutical company has submitted a new drug application to date.

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Figure 4.

1974–1988 US temporal trends (as proportion of 1974) for limb reduction deformities, Bendectin sales, and hospitalizations for nausea and vomiting of pregnancy. Source: Lamm.^[120]

The ingredients that were in Bendectin are available over the counter in United States. Women can get doxylamine (Unisom SleepTabs) in 25 mg tablets and vitamin B6 in 25- or 50-mg tablets (note that Unisom SleepGels contain diphenhydramine, not doxylamine). There are various dose regimens possible, none of which have been studied in depth. The original Bendectin formulation was 10 mg of pyridoxine and 10 mg of doxylamine combined in a single tablet that could be taken up to 4 times per day. This dosing can be approximated by using half of a tablet of doxylamine twice during the day and 1 tablet of doxylamine at night, with a 25-mg tablet of pyridoxine (vitamin B6) 3 times per day. Because the studies on effectiveness of pyridoxine used 25 mg 3 times per day for a total of 75 mg per day, a 25-mg tablet or a 50-mg tablet broken in half can be used. One study of the Canadian formulation of Bendectin found that women who take suboptimal doses have higher levels of nausea. In this study, 40 mg of pyridoxine with 40 mg of doxylamine per day was the optimal dosing regimen for treating mild to moderate NVP.^[87]

Dopamine Antagonists

Phenothiazines, benzamides, and butyrophenones are the three classes of drugs that antagonize dopamine receptors. The primary drugs used for NVP are promethazine (Phenergan), prochlorpemazine (Compazine), metoclopramide (Reglan), and droperidol (Inapsine).

Promethazine and Prochlorpemazine The phenothiazines promethazine and prochlorpemazine antagonize the dopamine (D₂) receptor in the CNS chemoreceptor trigger zone and also have a modest effect on H₁ receptors. There is no evidence of increased risk for teratogenic effects secondary to the use of these medications, and they are FDA Pregnancy Category C.^[82]

Phenothiazines are more effective than antihistamines in preventing or alleviating vomiting. Three RCTs have evaluated the effectiveness of phenothiazines for severe NVP (N ≈ 400). Various drugs were used, but when the results were pooled, the RR for NVP in women who took phenothiazines compared to women who took a placebo was 0.31 (95% CI, 0.24–0.42). The primary side effect of phenothiazines is sedation, which anecdotally may be the most common reason why women do not use these medications when prescribed.

Metoclopramide Metoclopramide (Reglan), a benzamide, has both a central and peripheral mechanism of action. This drug antagonizes both the dopamine (D₁) and serotonin receptors (5-HT₃) centrally and increases gastric emptying. Metoclopramide has not been found to have any association with congenital defects and is FDA Pregnancy Category B.^[82,88] No randomized studies of the effectiveness of oral metoclopramide have been conducted in pregnant women. Despite the lack of studies on effectiveness, this drug is widely used as a second step in treatment of NVP when phenothiazines or antihistamines are ineffective. Metoclopramide does not cause sedation, and many clinicians now prescribe metoclopramide orally for outpatient treatment without a previous trial of phenothiazines. In addition, metoclopramide is frequently used as a first-line treatment given intravenously or subcutaneously when women are admitted to an inpatient setting for treatment of HG, and has been shown to reduce the need for hospital visits and IV hydration.^[89,90]

Prochlorperazine, Promethazine, and Metoclopramide: Which Works Best? Bsat et al.^[91] prospectively randomized women with severe NVP (N = 156) to one of three groups: 1) 25-mg rectal suppositories of prochlorperazine (Compazine) to take every 12 hours as needed; 2) 25 mg of promethazine (Phenergan) to take orally every 6 hours as needed; or 3) one 50-mg intramuscular injection of pyridoxine (vitamin B6) with 10 mg metoclopramide (Reglan) taken orally every 6 hours as needed. After 3 days of treatment, the women in group 3 (pyridoxine/metoclopramide) had fewer number of emesis events when compared to the women in the other two groups. The RR for emesis when group 3 was compared to group 1 was 0.59 (95% CI, 0.39–0.88). The RR for emesis when group 3 was compared to group 2 was 0.62 (95% CI, 0.42–0.91). The subjective scores for how much better they felt after 3 days of treatment were also higher in group 1. Although this study did not specifically document or assess side effects, one woman in group 1 withdrew from the study secondary to a dystonic reaction; there were no reports of adverse side effects from the women in either of the two phenothiazine treatment regimens.^[91]

Droperidol: Pharmacologic Treatments for Severe Nausea and Vomiting in Pregnancy Droperidol (Inapsine) is the most recent dopamine antagonist to join the pharmacologic regimens used to treat severe NVP and/or HG. Droperidol belongs to the family of butyrophenones. It is more potent than phenothiazines and is commonly used by anesthesiologists intraoperatively to control postoperative nausea. There is no association between droperidol and congenital malformations, but there is a small risk of the mother developing prolonged QT syndrome which can lead to a potentially fatal arrhythmia.^[82] The American College of Obstetricians and Gynecologists (ACOG) recommends that this medication be used with caution.^[92]

Only one randomized trial has been conducted to date that has evaluated the effectiveness of droperidol. Nageotte et al.^[93] compared the outcomes of women hospitalized for HG who had a continuous infusion of droperidol with diphenhydramine (Benadryl) added to prevent extrapyramidal symptoms (see the next section on dystonic reactions to dopamine agonists) to the outcomes of women hospitalized in the same setting for HG but who did not receive this treatment regimen. The women who received the droperidol and diphenhydramine mixture had a decreased number of days hospitalized (3.1 ± 1.9 versus 3.8 ± 2.4 days; P =.028) and fewer readmissions (15.0% versus 31.5%; P =.015).^[93] Although this regimen was clearly effective, 15% of the women treated with droperidol and diphenhydramine had transient extrapyramidal or psychotropic symptoms despite the use of the diphenhydramine whereas none of the women in the placebo group had these side effects.

Dystonic Reactions to Dopamine Antagonists Dystonic or extrapyramidal reactions are a side effect of all the drugs that antagonize dopamine (D₁) receptors. When dopamine (D₁) receptors in the CNS are antagonized, the normal impulses in the basal ganglia and extrapyramidal system that control involuntary motion, balance, posture, and coordination can be interrupted. The result is a side effect that mimics Parkinson disease, and the patient will present with dystonic, akathisia, akinesia, and/or tardive dyskinesia. Because metoclopramide (Reglan) crosses the blood–brain barrier, dystonic reactions are more likely with metoclopramide than with other dopamine antagonists. Dystonic reactions generally occur 1 to 3 days after the onset of therapy or after an increase in dosage.^[94] Fortunately, the treatment for dystonic reactions is simple and effective. A dose of 50 mg of diphenhydramine (Benadryl) administered intravenously restores the balance between acetylcholine and dopamine, and extrapyramidal symptoms usually resolve within 15 to 30 minutes after the administration of diphenhydramine.^[95,96]

Serotonin Antagonists

Ondansetron (Zofran), which has an antagonist effect on the serotonin receptor, is a very effective antiemetic for chemotherapy-induced nausea and vomiting but has not been extensively evaluated in pregnant women, although it is being used increasingly off-label for women with severe NVP and/or HG. There are no associations with malformations after the use of ondansetron in the first trimester of pregnancy, and it is FDA Pregnancy Category B.^[82,97]

Sullivan et al.^[98] conducted a double-blind randomized trial (N = 30) that compared 10 mg of ondansetron administered intravenously every 8 hours to 50 mg of promethazine (Phenergan) administered intravenously every 8 hours in women who were hospitalized for HG. The drugs were continued until the participants were able to eat a bland diet without emesis. There was no difference in length of hospitalization, decrease in nausea, or total doses of the medication. Eight women in the promethazine group reported sedation whereas none of the women in the ondansetron group reported uncomfortable sedation.^[98] Despite the negative finding of this RCT, case reports^[99,100] have reported remarkable success in treating women with HG with ondansetron who have failed other therapies, and ondansetron is increasingly used as a rescue antiemetic when women continue to have NVP despite treatment with antihistamines or dopamine antagonists.

Corticosteroids

Corticosteroids are primarily initiated when a woman is hospitalized with HG. There have been several studies evaluating the safety^[82,101,102] and effectiveness^{[82,103–106]} of corticosteroids for treating HG. Corticosteroids are associated with a small increase in the risk for oral clefts (RR, 3.4; 95% CI, 1.97–5.69),^[102] and at this time, ACOG recommends that they not be used before 10 weeks' gestation.^[92]

The studies conducted on efficacy of corticosteroids have been contradictory. Yost et al.^[106] found no difference in rehospitalization rates between women given methylprednisolone and women not treated with corticosteroids. These authors randomized 110 women who were hospitalized for HG to treatment with 125 mg methylprednisolone given intravenously followed by an oral prednisone taper (40 mg for 1 day, 20 mg for 3 days, 10 mg for 3 days, and 5 mg for 7 days) versus placebo administered with the same regimen. All women were treated with promethazine and metoclopramide for the first 24 hours of their hospitalization.^[106] Conversely, Safari et al.^[103] found no difference in rehospitalization rates between women treated with methylprednisolone and those treated with promethazine (Phenergan). Safari et al.^[103] randomized women (N = 40) hospitalized for HG to either methylprednisolone or promethazine given orally 3 times per day for 3 days. After 3 days of therapy, the women on 16 mg of methylprednisolone (n = 20) were tapered off the steroid over a 2-week period. Those on promethazine (n = 20) continued the 25-mg dose of promethazine 3 times per day. None of the women who took methylprednisolone required rehospitalization, whereas five of the women who used promethazine were rehospitalized within 2 weeks of the initial hospitalization. Other trials of prednisone or methylprednisolone have used different regimens and different doses. To date, it appears that these agents may affect a rapid resolution of symptoms in the short-term but the efficacy for long-term use is equivocal.^[107,108]

Intravenous Fluids

The use of IV fluids deserves particular attention. IV fluids are an essential treatment for women who are dehydrated, and anecdotally, women report significant improvement for several days after receiving IV fluids. Women who prefer to avoid all medications may choose to rely on intermittent IV hydration only. Dextrose-containing fluids should be avoided because Wernicke encephalopathy can occur in women who are given a large carbohydrate load when deficient in thiamine.^[109] Normal saline is the best choice for an IV infusion because it will resolve hyponatremia. Potassium chloride can be added as needed, as can either thiamine (vitamin B1) or a multivitamin solution. Thiamine is particularly important because the requirement for thiamine increases in pregnancy, deficiency can occur if vomiting is prolonged, and thiamine deficiency is the underlying etiology of Wernicke encephalopathy. The one study to date that has evaluated the effectiveness of IV fluids is the recent survey conducted by Goodwin et al.^[32] Of those who used IV fluids, 83.8% (603 of 1193) reported that IV fluids were either maybe effective or effective.

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Table 1. Doses of Antiemetics Used to Treat Nausea and Vomiting in Pregnancy
Drug Name (Trade Name)	Dose	Major SEs (Recommendations)	FDA Pregnancy Category
Antihistamines (H₁ antagonists)
Diphenhydramine (Benadryl)	50–100 mg q 4–6 h PO/IM/IV	May cause drowsiness (can be used to offset anxiety caused by metoclopramide or phenothiazines)	B
Dimenhydrinate (Dramamine)	50–100 mg q 4–6 h PO/PR^a; 50 mg (in 50 mL of saline over 20 min) q 4–6 h IV	May cause drowsiness (can be used to offset anxiety caused by metoclopramide or phenothiazines)	B
Doxylamine (Unisom)	12.5 mg twice a day PO or 12.5 mg in morning and 25 mg at night PO		A
Phenothiazines (central D₂ antagonists)
Prochlorperazine (Compazine)	5–10 mg q 4–6 h PO/IM/IV; 25 mg rectal suppository bid; maximum dose is 40 mg/day	Sedation, anticholinergic effects, mouth, EPS, hypotension if given IV too quickly	C
Promethazine (Phenergan)	12.5–25 mg q 4–6 h PO/IM/IV/PR	Sedation, anticholinergic effects, mouth, EPS, hypotension if given IV too quickly	C
Benzamides (central and peripheral D₂ antagonists)
Metoclopramide (Reglan)	5–10 mg PO q 8 h PO/IM; 1–2 mg/kg IV; continuous SQ dose regimens available^b	EPS, agitation, anxiety, acute dystonic reactions (give 50 mg diphenhydramine before dose to prevent EPS)	B
Serotonin antagonists
Ondansetron (Zofran)	4–8 mg PO 3–4 times per day 4–8 mg over 15 min IV q 12 h; may be given 1 mg/h continuously for 24 h	Headache	B
Butyrophenones
Droperidol^c (Inapsine)	0.625–2.5 mg IV over 15 min then 1.25 mg or 2.5 mg IM as needed; can be given IV continuously at 1–1.25 mg/h	EPS, prolonged QT syndrome (give 50 mg diphenhydramine before dose to prevent EPS; reserve for persons who have failed other regimens)	C

bid = Two times daily; EPS = extrapyramidal effects; FDA = US Food and Drug Administration; IM = intramuscular; IV = intravenous; PO = per os (orally); PR = per rectum (rectally); SE = side effect; SQ = subcutaneous.
^aMaximum dose is 200 mg/day if taken concomitantly with doxylamine, 400 mg/day if taken as a single agent.
^bContinuous dose regimens can be found in Buttino Jr et al.^[89]
^cTo be used only after medical consultation and if other medications have failed to resolve symptoms, secondary to risk for prolonged QT syndrome.

Table 2. US Food and Drug Administration Ratings for Drug Use in Pregnancy ^a
Category	Interpretation
A	Adequate, well controlled studies in pregnant women have not shown an increased risk of fetal abnormalities to the fetus in any trimester of pregnancy.
B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate and well controlled studies in pregnant women. OR Animal studies have shown an adverse effect, but adequate and well controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester.
C	Animal studies have shown an adverse effect and there are no adequate and well controlled studies in pregnant women. ORNo animal studies have been conducted and there are no adequate and well controlled studies in pregnant women.
D	Adequate well controlled or observational studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective.
X	Adequate well controlled or observational studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities or risks. The use of the product is contraindicated in women who are or may become pregnant.

Source: US Food and Drug Administration (21 CFR §201.57).^[72]
^aNote that the US Food and Drug Administration has proposed changes to prescription drug labeling for use in pregnancy and lactation. (See www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093311.htm for additional information.)

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