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.

Nonpharmacologic Treatments

Many women turn to nonpharmacologic therapies for NVP because of concerns about adverse effects of drugs during embryonic and early fetal development. In one survey report, 61% of callers to the Motherisk NVP HelpLine reported using complementary and alternative medicine (CAM) therapies, but only 8% had discussed these therapies with their health care providers.^[35] Herbal remedies were commonly mentioned as treatments for NVP and HG in a recent survey of midwives in Texas.^[36]

Use of Herbs

A review of 300 nonmedical sources of advice about herbal remedies in pregnancy (books, magazines, and Web sites) found that ginger, chamomile, peppermint, and red raspberry leaf tea were the most commonly cited herbal remedies for "morning sickness."^[37] Only the efficacy of ginger has been studied in appropriate trials.

Ginger Ginger (Zingiber officinale) has a long history as an antinausea remedy. Its effects are thought to be related to increasing tone and peristalsis in the gastrointestinal tract caused by anticholinergic and antiserotonin actions.^[38–40] Ginger acts directly on the digestive tract and is not associated with the central nervous system (CNS) side effects that are common to centrally acting antiemetic drugs.

Ginger is a thromboxane synthetase inhibitor,^[41] and a frequently cited comment by Backon^[42] cautions that ginger could affect testosterone receptor and sex steroid differentiation in the fetus. There is no clinical evidence to suggest that this is the case. In traditional medical systems and herbalist literature, ginger is often contraindicated for use by pregnant women because of its reputation for inducing menstruation or promoting bleeding, but there is no clinical evidence that it acts as an abortifacient.^[43] In the directed randomized clinical trials (RCTs) of ginger as a treatment for NVP,^[44–46] participants were followed to term in three of the studies and no adverse events were noted, but in none of these studies was the sample size large enough to make this determination with confidence. In two other studies,^[47,48] outcomes were compared to population estimates of adverse events; although the results were reassuring, the sample sizes were still not large enough to be statistically stable. Portnoi et al.^[49] matched 187 callers to the Motherisk Helpline who took ginger in early pregnancy to 187 women who took nonteratogenic drugs that were not antiemetics. They found no increase in rates of spontaneous abortions, stillbirths, birth weight, or gestational age at birth, and no increased risk of major malformations above the baseline rate of 1% to 3%.

Seven RCTs assessing the efficacy of ginger as a treatment for NVP have been published in the world literature, representing a variety of dosages and treatment durations. Fischer-Rasmussen et al.^[44] studied women hospitalized with HG in Denmark. In this randomized, double-blind, placebo-controlled, crossover trial, participants received either 250 mg of powdered ginger root or a placebo 4 times a day for 4 days and then switched groups after a 2-day washout. Both severity of nausea and number of episodes of vomiting were reduced during the treatment with ginger, and participants reported a preference for the ginger treatment.

The other trials were all conducted in ambulatory nonhospitalized populations. Three randomized blinded trials compared ginger treatment with a placebo. All studies used different measures to evaluate the effects on nausea, vomiting, and other outcomes. Dosages were 125 to 250 mg of ginger taken 4 times a day. Overall, ginger was associated with some improvement in nausea severity and vomiting.^[45–47]

Four studies compared the use of ginger to the use of pyridoxine (vitamin B6). In all of these studies, participants were ambulatory and <17 weeks pregnant. Dosages of ginger were 1 to 1.5 g per day, and dosages of pyridoxine ranged from 30 to 75 mg per day. Ginger was at least as effective as pyridoxine, and in some studies appeared to be more effective in alleviating symptoms of NVP.^[48,50–52]

In summary, RCTs suggest that ginger in doses equivalent to at least 1 g per day (in divided doses) can reduce symptoms of nausea and vomiting in both ambulatory and hospitalized pregnant women with NVP. It is not clear whether ginger is superior to pyridoxine, but studies indicate that it is at least equivalent. Ginger is available in a variety of forms, and an evaluation of products purchased in pharmacies and health food stores found a wide variation in the amount of active ingredients and suggested serving sizes.^[53] Exact dosing relies on use of standardized extracts. For women who have preferences for the form of ginger used, in general, 1 g of standardized extract is equivalent to 1 tsp of fresh grated rhizome, 2 droppers (2 mL) of liquid extract, four 8-oz cups of prepackaged ginger tea, four 8-oz cups of tea made with 0.5 tsp of grated ginger steeped for 5 to 10 minutes, 8 oz of ginger ale (made with real ginger), 2 pieces of crystallized ginger (1 inch square, 0.25 inches thick), or 2 teaspoons (10 mL) of ginger syrup.^[54] Capsules of ginger come in various dosages, ranging from 100 to 1000 mg, and chewable tablets contain 67.5 mg.

Other Herbs There have been no directed investigations of other herbs for the treatment of NVP. However, there have been investigations of herbal treatments for the treatment of postoperative or chemotherapy-induced nausea and vomiting. In one study, peppermint oil was superior to placebo for postoperative nausea,^[55] but it is also considered an emmenagogue (i.e., a promoter of menstrual flow) in some herbal literature and therefore is not often recommended for use in pregnancy.^[43] Cannabis (marijuana) has been well studied as an antiemetic for patients undergoing chemotherapy;^[56] concerns have been identified about adverse effects on the fetus/child from prenatal use of marijuana, but it is not clear whether these concerns are pertinent to occasional recreational or medicinal use of the herb.^[57] Alcoholic extracts of cannabis, as opposed to the smoked herb, may have oxytocic properties and should not be used in pregnancy.^[43]

Acupressure and Acupuncture

Traditional Asian systems use a number of acupuncture points for antiemetic treatments, and the P6 or NeiGuan point is a major site for the relief of nausea and vomiting. It is located on the volar aspect of the wrist approximately 3 cm above the wrist crease, between 2 easily palpated tendons. It can be stimulated via the insertion of thin acupuncture needles, using transcutaneous electric nerve stimulation devices, or by applying pressure to the site. Pressure can be applied manually (using fingers or thumbs) or with wristband devices that provide steady pressure from a small button or disc on the site. The SeaBand is one commercial type of such devices. There are no concerns about the safety of properly applied acupressure and acupuncture. Points that are used to induce labor are different from the commonly used P6 point.

A number of studies of various acupuncture modalities have been conducted assessing the efficacy of acupuncture or acupressure for treating NVP with varying methodologies. Sham acupuncture is often used for comparison in studies of these remedies. Sham acupuncture consists of applying needles or pressure to sites that are considered to be nontherapeutic. Studies have suggested that there may be some benefits from sham acupuncture.^[58] Placebo acupuncture mimics the acupuncture process without actually applying pressure to any site.

A Cochrane review published in 2003^[4] summarized data from trials of adequate methodologic quality.^[59–65] Compared to no treatment, acupuncture remedies significantly reduced nausea (odds ratio [OR], 0.25; 95% confidence interval [CI], 0.14–0.43). Compared to sham acupuncture remedies, the effect was reduced and of marginal statistical significance (OR, 0.35; 95% CI, 0.12–1.09). The analysis of continuous outcomes showed no statistically significant beneficial effects. The authors concluded that the evidence for the benefits of P6 acupuncture or acupressure in treating NVP is mixed. The same conclusion was reached in a 2002 review.^[66]

Since the 2003 Cochrane review, several new trials have been published. Two involved participants who were hospitalized for HG and the intervention was either SeaBands^[67] or manual acupuncture^[68] in conjunction with routine care. Heazell et al.^[67] found no differences in median length of stay, antiemetic medication, or need for intravenous (IV) fluid comparing intervention to control groups. Shin et al.'s study^[68] was conducted in Korea and used researcher-applied manual acupressure; women up to 30 weeks' gestation were included in the trial. This study found some benefit to acupressure in both NVP scores and improvement of ketonuria. Jamigorn and Phupong^[69] compared acupressure using SeaBands to vitamin B6 (50 mg twice daily) and found no difference between the groups.

The summary evidence for benefits of acupressure or acupuncture in alleviating symptoms of NVP remains mixed. Certainly, manual acupressure or acupressure using products such as SeaBands is a low-cost intervention with no apparent adverse effects and could be suggested to women requesting intervention. Acupuncture using transcutaneous elective nerve stimulation devices would be more costly because of the cost of the device, and traditional acupuncture even more costly because of the need for visits to an acupuncturist.

Hypnosis, Behavior Modification, and Psychotherapy

Reports of benefits of hypnotherapy or other behavioral therapies in treating NVP are from case series describing women hospitalized with NVP and did not include control groups; therefore, it is not possible to differentiate true treatment benefits from normal recovery.^[70] However, Apfel et al.^[71] found that women with NVP are more hypnotizable than women in a control group, suggesting that they are more suggestible. It is possible that in some women, vomiting becomes a conditioned or anticipatory response^[19] and would be amenable to interventions such as hypnosis or other psychotherapeutic approaches.

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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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