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Treatment and outcome of nausea and vomiting of pregnancy
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Treatment and outcome of nausea and vomiting of pregnancy
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Dec 05, 2016.

INTRODUCTION — Nausea with or without vomiting is common in early pregnancy. Severe vomiting resulting in dehydration and weight loss is termed hyperemesis gravidarum and occurs infrequently. Symptoms usually resolve by midpregnancy regardless of severity and therapy.

Management of affected women depends upon symptom severity, the impact of her symptoms on her health and quality of life, and the safety of treatment for both her and the fetus. Treatment approaches include dietary/lifestyle changes, oral or rectal medication, and hospitalization for parenteral fluids and therapies in women who fail to respond to outpatient management and continue to lose weight. Enteral or parenteral nutrition may be required.

The treatment and outcome of nausea and vomiting of pregnancy will be reviewed here. The pathophysiology, clinical features, and evaluation of this disorder are discussed separately. (See "Clinical features and evaluation of nausea and vomiting of pregnancy".)

TREATMENT GOALS — When treating women with nausea and vomiting of pregnancy, the goals are to:

Reduce symptoms by changing her diet and environment and by treatment with medication

Correct acute consequences or complications of vomiting (eg, fluid depletion, hypokalemia, metabolic alkalosis)

Prevent serious complications of persistent vomiting, malnutrition, vitamin deficiency, and hypovolemia (eg, Wernicke encephalopathy, renal impairment, extreme weight loss)

Minimize the fetal effects of maternal nausea and vomiting and its treatment

NAUSEA WITH/WITHOUT OCCASIONAL VOMITING — For women with nausea alone and no or infrequent vomiting, the initial treatment approach involves counseling about dietary changes and trigger avoidance. Ginger and/or pyridoxine or doxylamine-pyridoxine is added if symptoms do not improve (algorithm 1).

Women with mild symptoms that do not respond to these interventions and desire additional treatment can be offered other oral medications if tolerable; otherwise, non-oral routes of administration are useful. (See 'Nausea with frequent vomiting' below.)

Diet

Meals and snacks — Women with nausea should eat before, or as soon as, they feel hungry to avoid an empty stomach, which can aggravate nausea [1]. A snack before getting out of bed in the morning can be helpful. In addition, snacks taken during the night (eg, crackers with peanut butter or cheese taken prior to bathroom trips) may be beneficial.

Meals and snacks should be eaten slowly and in small amounts every one to two hours to avoid a full stomach [2].

Women should determine what foods they tolerate best and try to eat those foods. Dietary manipulations that help some women include eliminating coffee and spicy, odorous, high-fat, acidic, and very sweet foods, and substituting snacks/meals that are protein-dominant, salty, low-fat, bland, and/or dry (eg, nuts, pretzels, crackers, cereal, toast) [1-3]. Drinking peppermint tea or sucking peppermint candies may reduce postprandial nausea [4]. High-quality evidence of the optimal dietary components to reduce nausea are sparse. Clinicians commonly recommend ingestion of frequent, small, carbohydrate-predominant meals/snacks, such as soda crackers or dry toast, based primarily on anecdotal evidence passed down over a century [5]. However, consumption of protein-predominant meals/snacks may be more helpful and was associated with quantifiable decreases in nausea in one study [6].

Women whose symptoms are related to delayed gastric emptying should improve with a diet consisting of low-fat solids and liquids since these foods are more readily emptied by the stomach; however, it is not known to what degree gastric emptying and dysfunction account for symptoms in women with nausea and vomiting of pregnancy.

Fluids — Fluids should be consumed at least 30 minutes before or after solid food to minimize the effect of a full stomach [2]. Fluids are better tolerated if cold, clear, and carbonated or sour (eg, ginger ale, lemonade, popsicles) and taken in small amounts; using a straw sometimes helps [7]. Some women find aromatic liquids, such as lemon or mint tea, more tolerable. Small volumes of electrolyte-replacement sports drinks can be used to replace both fluids and electrolytes, if tolerated.

Avoidance of triggers — Along with dietary changes, avoidance of environmental triggers is a key intervention for reducing nausea and vomiting of pregnancy [3]. Examples of some triggers include stuffy rooms, odors (eg, perfume, chemicals, food, smoke) [8], heat, humidity, noise, and visual or physical motion (eg, flickering lights, driving) [9]. Quickly changing position and not getting enough rest, particularly after eating, may also aggravate symptoms [10]. Lying down soon after eating and lying on the left side are additional potentially aggravating factors because these actions may delay gastric emptying [2]. Cold solid foods are tolerated better than hot solid foods because they have less odor and require less preparation time (ie, shorter exposure to the trigger if the woman is preparing her own meal) [2]. Brushing teeth after a meal [4], spitting out saliva, and frequently washing out the mouth can also be helpful.

Supplements containing iron should be avoided until symptoms resolve, as iron causes gastric irritation and can provoke nausea and vomiting [11]. Taking prenatal vitamins before bed with a snack, instead of in the morning or on an empty stomach, may also be helpful [12].

Ginger — We suggest use of ginger-containing foods (eg, ginger lollipops, ginger tea, foods made with ginger root or syrup) for women with mild nausea and vomiting. We do not prescribe powdered ginger because standard pharmacologic-grade ginger preparations are not readily available [13]; however, if prescribed, a common dose is 1 to 1.5 g orally divided over 24 hours (eg, 250 mg ginger capsules orally four times a day). In a 2014 systematic review and meta-analysis of 12 randomized trials (n = 1278 pregnant women), ginger improved nausea compared with placebo but did not significantly reduce vomiting [14].

Pyridoxine (vitamin B6) — Pyridoxine improves nausea and has a good safety profile with minimal side effects and is easy to obtain; therefore, we generally use pyridoxine as first-line drug treatment for mild nausea and infrequent vomiting of pregnancy [15].

As a single agent, the recommended dose of pyridoxine is 10 to 25 mg orally every six to eight hours; the maximum treatment dose suggested for pregnant women is 200 mg/day. Sensory neuropathy has been reported with chronic intake of pyridoxine at doses >500 mg/day [16,17], but cumulative doses up to 500 mg/day appear to be safe for the mother [18]. Human data on fetal safety at this dose are limited. An observational study of 96 pregnant women in the first trimester with >50 mg/day pyridoxine intake (mean dose 132 mg/day, range 50 to 510 mg/day) and 96 control pregnant women found no associated major fetal malformations [19]. Pyridoxine 100 mg/kg was not teratogenic in animal studies [20].

Systematic reviews of randomized and/or controlled trials have shown that pyridoxine (vitamin B6) improves mild to moderate nausea but does not significantly reduce vomiting [21-23]. Thus, it is most useful for women with mild symptoms. The mechanism for the therapeutic effect is unknown. Hypotheses include prevention/treatment of vitamin B6 deficiency, intrinsic antinausea properties, and/or synergy with the antinausea properties of antihistamines [24]. Although vitamin B6 levels decrease as gestation advances, there is no proven correlation between maternal vitamin B6 levels and incidence or severity of nausea [25].

Doxylamine succinate and pyridoxine — We recommend the combination drug doxylamine-pyridoxine when pyridoxine treatment of mild nausea and vomiting of pregnancy fails to improve symptoms. Formulations of doxylamine-pyridoxine are available under various names worldwide (eg, Diclectin in Canada, Diclegis and Bonjesta in the United States).

Initially, we prescribe two extended-release tablets (each tablet contains doxylamine 10 mg and pyridoxine 10 mg) at bedtime [26,27]. The dose may be increased to four tablets over the course of the day as needed for more severe nausea (one tablet in the morning, one tablet in the afternoon, two tablets at bedtime). An extended-release tablet containing 20 mg of doxylamine succinate and 20 mg of pyridoxine is also available. A randomized placebo-controlled trial found that doxylamine succinate 10 mg and pyridoxine 10 mg combination preparation administered in doses of two to four tablets daily was safe and well tolerated by women with nausea and vomiting of pregnancy [28].

Combination tablets may be costly. In the United States, doxylamine is available in some over-the-counter sleeping pills (eg, Unisom Sleep Tabs) and as a prescription antihistamine chewable tablet (eg, Aldex AN): One-half of the 25 mg over-the-counter tablet or two chewable 5 mg tablets can be used off-label as an antiemetic. In addition, pyridoxine 25 mg, also available over-the-counter, is taken three or four times per day; the 10 mg dose of pyridoxine is not commercially available in the United States. This is a reasonable, less expensive substitute for combination tablets.

Doxylamine-pyridoxine was proven modestly effective for treatment of nausea and vomiting of pregnancy in a meta-analysis of placebo-controlled randomized trials [29] and appears to be more effective than either drug alone. It was the formulation for Bendectin, which was voluntarily withdrawn from the market in 1983 due to lawsuits alleging teratogenicity, although scientific evidence supports its safety [20,30,31] and efficacy [29,32-35]. A meta-analysis of controlled studies on outcome of pregnancies exposed to Bendectin reported no increase in the incidence of birth defects [31].

Other interventions

Acupuncture or acupressure – P6 acupressure wristbands (picture 1) do not require a prescription and have become a popular self-administered intervention [36]. In a 2015 systematic review of randomized trials of interventions for nausea and vomiting in early pregnancy, an acupressure wristband or P6 acupuncture was not significantly more effective than placebo [29]. One reason may be that a strong placebo effect has been observed in patients who receive sham therapy [37-40]. Acupressure and acupuncture have not been associated with any adverse effects on pregnancy outcome and may help some women, even if a placebo effect.

Self-administered nerve stimulation therapy over the volar aspect of the wrist at the P6 acupressure point using a commercial device also showed some promise in two randomized trials [41,42].

Hypnosis has been reported to be helpful in some patients [43].

Most other alternative medicine approaches have not been studied rigorously for efficacy or safety, and should be avoided for this reason. As an example, in 2009, the US Food and Drug Administration notified health care professionals and pregnant or breastfeeding women to avoid consuming Nzu, a traditional African remedy for morning sickness, because of potential health risks from high levels of lead and arsenic [44]. Nzu may be sold under such names as Calabash clay, Calabar stone, Mabele, Argile, or La Craie.

Psychotherapy can be a useful adjunctive therapy, particularly if psychological sources of anxiety are identified and can be ameliorated, and may reduce distress caused by nausea, the pregnancy, and other coincident events [45,46].

NAUSEA WITH FREQUENT VOMITING

General approach — For women who present with more than occasional vomiting but are not dehydrated, a reasonable approach is to discuss dietary changes and trigger avoidance as well as the initial interventions for mild symptoms described above (see 'Nausea with/without occasional vomiting' above). We also offer additional drugs that are reported to be effective and have a good maternal-fetal safety profile. If the initial drug is ineffective, then other drugs are added in a step-wise progression (algorithm 1) [15,47,48]. We typically continue a drug for several days to determine whether nausea and vomiting are improving. If symptoms persist, then we add another drug to the existing regimen; however, if the patient is experiencing side effects, we substitute another drug in its place.

Women with frequent vomiting require frequent assessment of their medical status and response to therapy. Those at the moderately severe end of this spectrum are evaluated daily, whereas those with severe disease (see 'Severe vomiting (dehydration, electrolyte abnormalities, and/or acid-base abnormalities)' below) are admitted and evaluated from hour to hour.

Historically, pregnant women have been excluded from most clinical drug trials. Thus, there are limited data from pregnant women to support the safety and efficacy of drugs used to treat nausea and vomiting. A number of reports have demonstrated that antiemetic drug therapy is more effective than placebo and does not increase the incidence of congenital anomalies [7,10,23,29,32,48,49]. However, there is little evidence from well-designed comparative trials upon which to base a treatment plan for women with nausea and vomiting of pregnancy.

First-line drug therapy

Antihistamines (H1 antagonists) — We suggest the following antihistamines as first-line agents for women who have frequent vomiting or who desire additional treatment because their symptoms have not abated with the interventions described above. We begin with these drugs because they either have fewer maternal side effects or a more established fetal safety profile compared with other drugs.

Doxylamine-pyridoxine, meclizine, dimenhydrinate, and diphenhydramine are the antihistamines that have been most extensively studied for treatment of nausea and vomiting of pregnancy. There are no data on use of the scopolamine patch for nausea and vomiting of pregnancy.

The efficacy of antihistamines was illustrated in an analysis of pooled data from controlled trials that found use of these agents significantly reduced pregnancy-related nausea and vomiting (relative risk [RR] 0.34, 95% CI 0.27-0.43); however, these studies used a variety of antihistamines and measured different outcomes [32].

The safety of antihistamines (specifically histamine 1 [H1] receptor blockers) was affirmed in a meta-analysis that examined the association between antihistamine use and major malformations [50]. This review of 24 controlled studies, including over 200,000 first-trimester exposures, found that H1 receptor blockers appeared to have a protective effect on risk of malformations (odds ratio [OR] 0.76, 95% CI 0.60-0.94). Subsequent reviews have confirmed these findings [49,51-53].

The primary mechanism of antihistamines in treatment of nausea and vomiting of pregnancy is direct inhibition of histamine at the H1 receptor; the secondary mechanism is an indirect effect on the vestibular system by decreasing stimulation of the vomiting center. In addition, these agents inhibit the muscarinic receptor, which may mediate the emetic response.

Common side effects of this class of drugs include sedation, dry mouth, lightheadedness, and constipation.

Doxylamine and pyridoxine — This combination is a good initial antihistamine option for women who have not already had a trial of the drug. If ineffective, it should be discontinued before starting a different antihistamine. (See 'Doxylamine succinate and pyridoxine' above.).

Diphenhydramine — Diphenhydramine 25 to 50 mg orally every four to six hours, as needed. It can also be given intravenously 10 to 50 mg every four to six hours, as needed. Diphenhydramine is commonly used in pregnancy for treatment of nausea and vomiting as well as allergy symptoms (rhinitis, pruritus) and insomnia; available safety data are generally reassuring that it is not a teratogen [51-53].

Meclizine — Meclizine 25 mg orally every four to six hours, as needed. Meclizine has caused cleft palate in rats but at exposures far higher than those used therapeutically. Human data of an association between facial clefts and meclizine have been mixed, but three large studies did not show an increased risk of malformations [54-56].

Dimenhydrinate — Dimenhydrinate 25 to 50 mg orally every four to six hours, as needed. Otherwise, 50 mg dimenhydrinate is administered intravenously over 20 minutes or 50 to 100 mg is administered rectally (where available) every four to six hours, as needed; the total dose should not exceed 400 mg/day. If the woman has recently taken doxylamine, the total dose of dimenhydrinate should not exceed 200 mg/day. Available safety data are generally reassuring that it is not a teratogen [51-53,57].

Second-line drug therapy

Dopamine antagonists — Several types of dopamine receptor antagonists can be used for the treatment of nausea and vomiting of pregnancy. The three main classes are benzamides (metoclopramide), phenothiazines (promethazine and prochlorperazine), and butyrophenones (droperidol).

The use of these drugs is based on the observation that dopaminergic mechanisms are involved in the regulation of gastrointestinal motility. In the stomach, dopamine receptor agonists inhibit gastric motility, whereas dopamine receptor antagonists stimulate gastric motility and emptying and thus have antiemetic effects. Blockade of dopamine 2 receptors also appears to block emetic signaling.

Metoclopramide — Metoclopramide 10 mg orally, intravenously, or intramuscularly (ideally 30 minutes prior to meal and at bedtime) every six to eight hours is commonly prescribed for nausea and vomiting related to pregnancy [58]. In randomized trials evaluating this drug in women with hyperemesis, metoclopramide 10 mg was as effective as promethazine 25 mg [59] and ondansetron 4 mg [60].

A study of intravenous metoclopramide (1.2 to 1.8 mg/hour intravenously) plus diphenhydramine (50 mg every six hours) reported vomiting improved in 36 percent of patients and was more effective than the combination of droperidol (0.5 to 1 mg/hour) plus diphenhydramine, which had been used in previous patient cohorts [61]. In another series, combination therapy with metoclopramide and pyridoxine was superior to monotherapy with either prochlorperazine or promethazine in decreasing the number of vomiting episodes [62].

In large cohort studies, pregnancies exposed to metoclopramide during the first trimester of pregnancy did not have a significant increase in risk of major congenital malformations, miscarriage, or stillbirth compared with nonexposed pregnancies [63,64]. In the largest of these studies, over 45,000 fetuses were exposed to a median of 40 doses of metoclopramide in utero, beginning at a median of 57 gestational days [64].

Maternal side effects are a concern, especially with long-term use. Metoclopramide accounts for almost one-third of all drug-induced movement disorders, and female sex is a risk factor for development of these side effects [65]. However, in the randomized trial discussed above, dystonia was more common with promethazine than metoclopramide (14/73 [19.2 percent] versus 4/70 [5.7 percent]) [59].

Upon discontinuation of the drug, metoclopramide-induced tardive dyskinesia (involuntary and repetitive movements of the body) can be irreversible in some cases. Early detection and discontinuation of the metoclopramide are important for the prevention of permanent tardive dyskinesia. Use of metoclopramide with diphenhydramine or hydroxyzine may mask a dystonic reaction.

The use of subcutaneous pumps for timed release of medications, in particular metoclopramide, has been reported for outpatient management of nausea and vomiting in pregnancy with some benefit [66]. However, the experience is limited; we do not use them.

Domperidone is another promotility agent, but there is no information on its safety or efficacy for treatment of nausea and vomiting of pregnancy.

Promethazine — Promethazine is primarily an H1 receptor-blocking agent, but is also a weak dopamine antagonist. Promethazine 12.5 to 25 mg can be given orally, per rectum, or intramuscularly every four hours. Oral or rectal administration is preferred. Intra-arterial, intravenous, and subcutaneous administration are contraindicated, as inadvertent intra-arterial injection can result in gangrene of the affected extremity, and subcutaneous injection may result in tissue necrosis. (See "Characteristics of antiemetic drugs".)

Fetal safety [67] and maternal efficacy in relief of both nausea and vomiting have been demonstrated in large groups of patients [32,50,59,68-70]. Disadvantages include prominent sedation and risk of dystonic reactions. These risks are elevated under conditions of prolonged use and high dosing. Use of promethazine appears to lower the seizure threshold, which may be important in women with seizure disorders or late in pregnancy in women with preeclampsia.

There are conflicting reports regarding a potential risk of neonatal respiratory depression following the administration of promethazine during labor [67]. Neonatal platelet aggregation also may be impaired when the drug is given intrapartum, but this does not appear to increase the need for intervention in the newborn. These observations are unlikely to be relevant for women who take promethazine in early pregnancy for nausea and vomiting.

Prochlorperazine — Prochlorperazine 5 to 10 mg orally, intravenously, or intramuscularly every six hours or 25 mg per rectum twice per day, as needed, appears to benefit some patients [62]. Safety information is limited: Although case reports of malformations in exposed infants have been published, larger series have not reported an increased risk of birth defects. Results from animal studies vary depending on the animal exposed [67]. Overall, prochlorperazine is well tolerated with rare serious side effects. Common mild side effects include drowsiness, dizziness, headaches, and urinary retention. Some patients experience extrapyramidal symptoms, but this is uncommon.

In a randomized trial involving 84 male and female emergency department patients with uncomplicated nausea and vomiting due to gastritis/gastroenteritis, prochlorperazine 10 mg intravenously relieved symptoms of nausea and vomiting more quickly and completely than promethazine 25 mg intravenously, with no difference in incidence of extrapyramidal effects [71].

Third-line drug therapy

Serotonin antagonists — Ondansetron, granisetron, and dolasetron are selective antagonists at the 5-hydroxytryptamine-3 (5-HT3) serotonin receptor. This class of drug has a favorable efficacy-safety profile in non-pregnant individuals with nausea and vomiting of various etiologies and severities.

The use of ondansetron in pregnant women is controversial. We individualize its use weighing the risks and benefits during pregnancy. We counsel pregnant women regarding the available data and the possible associated small risk of cardiovascular anomalies (see 'Ondansetron' below). There are no human data on the safety of granisetron, dolasetron, or other 5-HT3 antagonists in pregnancy; animal studies did not show adverse pregnancy effects [67].

Ondansetron — Hyperemesis is a common unlabeled indication for use of ondansetron. In a small randomized trial, use of ondansetron resulted in clinically significant reductions in both nausea and vomiting compared with the combination of doxylamine and pyridoxine [72]. In another randomized trial, it was more effective than metoclopramide for reduction of vomiting, but not nausea [73].

Ondansetron 4 mg can be taken orally every eight hours, as needed, or administered intravenously by bolus injection every eight hours, as needed. The dose is increased if necessary, and limited to ≤16 mg/dose. A single report described use of subcutaneous ondansetron via a microinfusion pump in 521 women with severe nausea and vomiting, with improvement of symptoms to mild to moderate in 50 percent of women within three days of therapy [74]. Based on this report and data in other populations, administration of ondansetron via a microinfusion pump appears to be a reasonable alternative route for treating severe nausea and vomiting of pregnancy.

Headache, fatigue, constipation, and drowsiness are the most common drug-related side effects. Ondansetron can cause QT prolongation, particularly in patients with underlying arrhythmia risk factors, such as a personal or family history of long QT syndrome, hypokalemia or hypomagnesemia, heart failure, administration of concomitant medications that lead to QT prolongation, and use of multiple doses or intravenous ondansetron. Electrocardiographic and electrolyte monitoring is recommended in these patients [75]. Serotonin syndrome is a potentially life-threatening condition associated with use of serotonergic agents and manifested by increased serotonergic activity in the central nervous system. (See "Serotonin syndrome (serotonin toxicity)".)

Available data suggest that use of ondansetron in early pregnancy is not associated with a high risk of congenital malformations, but a small increased risk of cardiovascular malformations, especially septum defects, may exist. A 2016 systematic review including the following studies and two smaller studies came to the same conclusion [76]. Animal data on ondansetron are reassuring as to its safety in pregnancy.

A Danish study based on the Danish prescription register with 1233 presumed first-trimester exposures reported ondansetron was not associated with an increased risk of major congenital anomalies (OR 1.2, 95% CI 0.69-1.82), miscarriage, low birth weight, or small for gestational age when used for treatment of nausea and vomiting of pregnancy [77].

Analysis of data from the National Birth Defects Prevention Study (NBDPS) in the United States showed a possible association between ondansetron and isolated cleft palate (adjusted OR 2.37, 95% CI 1.18-4.76), but data were limited to only 55 first-trimester exposures [78].

A Swedish study using data obtained by midwife interview or from the Swedish prescription register reported ondansetron was associated with an increased risk for cardiovascular defects (OR 1.62, 95% CI 1.04-2.14), particularly a cardiac septum defect (OR 2.05, 95% CI 1.19-3.28) [79]. There were 1349 presumed first-trimester exposures in this study.

An Australian study that linked data from multiple registries did not find a significant increase in major malformations (OR 1.2, 95% CI 0.6-2.2) [80]. An increase in obstructive renal defects was noted, but there were only five cases, suggesting this was due to chance.

Granisetron — Like ondansetron, granisetron is a 5-HT3 antagonist used primarily for prevention of nausea and vomiting associated with chemotherapy, radiation therapy, and surgery (including cesarean delivery). It is available in oral, intravenous, and transdermal formulations. Its only advantage over ondansetron is transdermal availability. A single small observational study reported a significant reduction in Pregnancy-Unique Quantification of Emesis/Nausea (PUQE) score (table 1) in pregnant women treated with intravenous or transdermal granisetron [81]. The transdermal formulation was convenient for women who could not tolerate an oral drug and effective (mean PUQE score 7.6 before application and approximately 4 during the week of application), but it is very expensive.

Human data on reproductive effects are sparse. Adverse effects have not been reported in animal reproduction studies. A study that compared the effects of two doses of granisetron (3 ng/mL and 30 ng/mL) in primary cells isolated from human fetal organs did not identify any toxicity [82].

Adjunctive therapy

Acid-reducing agents — Acid-reducing medications can be used as adjunctive therapy. In women with heartburn/acid reflux and nausea/vomiting of pregnancy, an observational study found that acid-reducing pharmacotherapy (eg, antacids, H2 blockers, proton pump inhibitors) combined with anti-emetic therapy resulted in significant improvement in symptoms and well-being three to four days after beginning therapy [83].

Antacids containing aluminum or calcium are safe for pregnant women and preferable to those containing bismuth or bicarbonate, which may have adverse fetal/neonatal effects [84].

The greatest experience with pharmacologic acid-suppressive therapy in pregnant women has been with the H2 receptor antagonists ranitidine and cimetidine, which appear to have a good maternal-fetal safety profile. The efficacy of ranitidine 150 mg orally twice daily for treatment of acid reflux was demonstrated in a placebo-controlled, double-blind trial of 20 pregnant women whose heartburn was refractory to conservative measures; heartburn severity was reduced 44 percent compared to placebo [85].

There is less experience using proton pump inhibitors (eg, lansoprazole or esomeprazole 30 or 40 mg intravenously or orally every 24 hours) during pregnancy, but they probably have a good maternal-fetal safety profile [86,87].

Safety data for acid-reducing agents are reviewed in more detail separately. (See "Medical management of gastroesophageal reflux disease in adults", section on 'Pregnancy and lactation'.)

SEVERE VOMITING (DEHYDRATION, ELECTROLYTE ABNORMALITIES, AND/OR ACID-BASE ABNORMALITIES)

General approach — Women with persistent nausea and vomiting should be evaluated by their clinician and/or in the emergency department to determine the severity of disease, assess the woman's volume and metabolic status, exclude other diagnoses that could account for her symptoms, and guide replacement therapy. We instruct women with nausea and vomiting of pregnancy to report to the emergency department for symptoms of lightheadedness, dizziness, faintness, tachycardia, or if they are unable to keep food/fluids down for more than 12 hours. A trial of rehydration and intravenous antiemetic therapy in the emergency medicine department before admission is reasonable for women with mild dehydration, normal electrolyte levels, and normal acid-base balance. Hospital admission is appropriate for those with persistent vomiting after rehydration and intravenous antiemetic therapy, as well as women who present with severe dehydration, abnormal electrolyte levels, and abnormal acid-base balance. The decision to admit versus discharge to home needs to be individualized based on the patient's severity of disease, resources, patient compliance, and her ability to obtain and have access to outpatient resources, ie, home health care, infusion pump for administration of intravenous ondansetron at home, etc.

These patients and their families often need emotional support to help deal with stress and anxiety about the maternal illness and its effect on the fetus, and the disruption to their home- and work-related activities [88]. In some cases, psychiatric consultation and psycho-social counseling can be helpful to teach the patient relaxation and coping techniques and address underlying psychopathology, if present [89].

For women with persistent vomiting after inpatient therapy, it is important to exclude underlying diseases that can cause hyperemesis. (See "Clinical features and evaluation of nausea and vomiting of pregnancy", section on 'Differential diagnosis'.)

Fluids and nutrition — Most patients respond to intravenous hydration and a short period of gut rest, followed by reintroduction of oral intake and pharmacologic therapy.

Fluids — Dehydration occurs when fluid losses exceed fluid intake and is often associated with electrolyte abnormalities, fatigue, dizziness, and weakness. We correct dehydration with up to 2 L intravenous Ringer's lactate infused over three to five hours, supplemented with appropriate electrolytes and vitamins. Isotonic saline is used to treat hyponatremia in hypovolemic patients with minimal or no symptoms and serum sodium levels >120 mEq/L who are at low risk of complications from untreated hyponatremia or from excessive rapid correction of hyponatremia such as osmotic demyelination syndrome (cerebral edema and neurologic symptoms). (See "Osmotic demyelination syndrome (ODS) and overly rapid correction of hyponatremia" and "Overview of the treatment of hyponatremia in adults".)

Subsequently, the infusion rate is adjusted to maintain a urine output of at least 100 mL/hour and the solution is changed to dextrose 5 percent in 0.45 percent saline. The optimum replacement fluid regimen has not been studied. It is prudent to avoid use of dextrose in the initial rehydration fluid because of the theoretical concern of inducing Wernicke's encephalopathy from dextrose infusion in a thiamine-deficient state [90]. We delay dextrose infusion until after the patient has received thiamine in her initial rehydration fluid (see 'Vitamins and minerals' below). A single small randomized trial of intravenous rehydration with 5 percent dextrose-0.9 percent saline versus 0.9 percent saline solution in women hospitalized for hyperemesis gravidarum did not report significant differences in important clinical outcomes (vomiting, resolution of electrolyte abnormalities, length of hospitalization, duration of intravenous antiemetic), but nausea improved faster in the 5 percent dextrose group; all participants also received thiamine and an antiemetic intravenously [91]. A limitation of this trial is that only 60 percent of the women had severe disease (ie, weight loss ≥5 percent body weight, ketonuria 4+).

Relief of symptoms is common within one to two days of rehydration [7]. Relocation from the home environment, as well as replenishment of fluids and electrolytes, may contribute to palliation of symptoms.

Vitamins and minerals — If the patient is experiencing persistent vomiting, it is important to replenish low levels of vitamins (especially thiamine), electrolytes, and minerals [92].

Thiamine – We provide thiamine (vitamin B1) supplementation by giving 100 mg intravenously with the initial rehydration fluids and another 100 mg daily for the next two or three days. Early administration of thiamine is important to prevent a rare maternal complication, Wernicke's encephalopathy [7,93,94]. (See "Wernicke encephalopathy".)

Other vitamins – We administer a multivitamin (MVI) intravenously daily: MVI (10 mL) plus 0.6 mg folic acid (to bring the folic acid total to 1 mg) in one liter and vitamin B6 25 mg in every liter. Intravenous MVI has 150 mcg of vitamin K. Additional vitamin K replacement is not necessary unless clinically indicated to treat a coagulopathy.

Electrolytes – After initial rehydration with Ringer's lactate (see 'Fluids' above), we administer dextrose 5 percent in 0.45 percent saline with 20 mEq potassium chloride at 150 mL/hour.

Magnesium and calcium – Hypomagnesemia is a common cause of hypocalcemia. We first correct the low magnesium level by giving 2 g (16 mEq) magnesium sulfate infused as a 10 percent solution over 10 to 20 minutes, followed by 1 g (8 mEq) in 100 mL of fluid per hour. The repletion of magnesium is continued if the serum magnesium level is less than 0.8 mEq/L (1 mg/dL or 0.4 mmol/L). Once serum magnesium levels are restored, we reassess the calcium level. If serum calcium is still low, we administer 1 to 2 g calcium gluconate in 50 mL of 5 percent dextrose solution over 10 to 20 minutes.

Phosphorus – If phosphorus levels are low, phosphorus can be replaced in intravenous hydration with sodium phosphate or potassium phosphate at 20 to 40 mmol/day. If the patient can tolerate oral replacement, phosphorus can be replaced with oral sodium phosphate/potassium phosphate one to two tablets by mouth four times a day with a full glass of water.

Diet — A diet that attempts to minimize nausea and vomiting can be resumed after a short period of gut rest. We usually begin women on a diet consisting of bananas, rice, applesauce, and toast (BRAT diet) and then advance their diet as tolerated. Consistent protein intake is key in helping prevent nausea. Additional dietary manipulations are described above. (See 'Diet' above.)

Patients who have not eaten for several days may develop edema when resuming feeding with carbohydrates [95]. This results from the retention of sodium during fasting combined with enhanced sodium resorption due to the actions of insulin once carbohydrates are reintroduced [96]. No intervention is required; the edema will gradually resolve.

Drug therapy — Non-oral routes of administration are necessary for women with persistent vomiting. We begin ondansetron intravenously upon hospitalization for intravenous fluid therapy. After the woman has stabilized, ondansetron is discontinued. If symptoms recur, antiemetic medications are the same as those used to treat women with frequent vomiting without dehydration or other serious sequelae (algorithm 1). Oral medications are initiated in women who can tolerate them. These oral medications can be then be used at home when the patient is discharged from the hospital. (See 'Nausea with frequent vomiting' above.)

REFRACTORY SEVERE VOMITING — We consider vomiting refractory and severe when patients are unable to tolerate the first-, second-, and third-line medications described above.

Drug therapy — We generally treat refractory severe vomiting with glucocorticoids but may begin with chlorpromazine in selected patients, such as those in whom the side effects of steroids may be more serious. We rarely use droperidol.

Glucocorticoids — Glucocorticoids are reserved for treatment of severe and refractory vomiting, given the risk of maternal side effects and uncertain efficacy [15]. (See "Major side effects of systemic glucocorticoids".)

The mechanism of action is not well understood [97-100] and there is a paucity of evidence that glucocorticoids are effective [23,32,101]. The largest placebo controlled trial included 110 women with severe hyperemesis and reported that women who received glucocorticoid therapy had a similar clinical course and need for rehospitalization as those given placebo [102]. However, a systematic review that included three randomized clinical trials comparing glucocorticoids with placebo or promethazine or metoclopramide found that women with severe nausea and vomiting may benefit with corticosteroids [49]. We have also observed improvement in symptoms with glucocorticoid use in some patients with refractory severe vomiting.

Glucocorticoid use has been associated with a slightly increased risk of oral clefts when the drug is administered before 10 weeks of gestation; therefore, ideally, use of glucocorticoids should be avoided in the first trimester [103-107]. If administered after 10 weeks, the palate has formed and is not at risk for developing defects.

An effective dose is methylprednisolone (16 mg) intravenously every 8 hours for 48 to 72 hours [97]. An alternative regimen is hydrocortisone 100 mg intravenously twice daily [49]. Glucocorticoids can be stopped abruptly if there is no response, and tapered over two weeks in women who experience relief of symptoms. Glucocorticoid use may lead to hyperglycemia; blood glucose levels should be monitored in women with pregestational and gestational diabetes.

After intravenous therapy, we use an oral prednisone taper regimen of 40 mg oral prednisone per day for one day, followed by 20 mg per day for three days, followed by 10 mg per day for three days, and then 5 mg per day for seven days. This regimen may be repeated up to three times over a six-week period.

Chlorpromazine — Chlorpromazine is a dopamine antagonist; maternal side effects are more frequent and/or severe compared with the other dopamine antagonists discussed above (see 'Dopamine antagonists' above), so this drug is reserved for refractory cases. Adverse effects include extrapyramidal reactions, orthostatic hypotension, anticholinergic effects, and altered cardiac conduction.

Chlorpromazine 25 to 50 mg intravenously or intramuscularly or 10 to 25 mg orally every four to six hours is the usual dose; a rectal suppository is available in some countries.

Droperidol — We rarely use this drug to treat nausea and vomiting of pregnancy because of maternal safety concerns, although it is an effective antiemetic. In one study, patients with hyperemesis gravidarum treated with droperidol-diphenhydramine had significantly shorter hospitalizations (3.1 versus 3.8 days), fewer days per pregnancy hospitalized for hyperemesis (3.5 versus 4.8 days), and fewer readmissions with this diagnosis (15.0 versus 31.5 percent) than women treated with other parenteral therapies [108]. No congenital anomalies were reported in 108 pregnancies [67]. However, maternal side effects are a concern, especially with long-term use. Droperidol has been associated with QT prolongation and/or torsades de pointes when used in doses higher than those typically used for treatment of nausea and vomiting [109]. The US Food and Drug Administration issued a black box warning in 2001 [110], and the drug was removed from the European market in March 2001.

Enteral and parenteral nutrition — Women who are refractory to all pharmacologic and nonpharmacologic interventions should be supported with enteral (tube feedings [111]) or parenteral nutrition and intravenous fluids as long as necessary. Enteral support during early pregnancy can reduce perinatal morbidity [112]. We continue such women on pharmacologic interventions that provide some relief of their nausea and vomiting.

Nutritional status and methods of alimentation (eg, tube feedings, parenteral nutrition) should be assessed in conjunction with a nutritionist or nutrition service. The optimal timing for initiating enteral or parenteral nutrition has not been established; the decision is based upon clinical judgment. In general, enteral nutrition is begun in women who cannot maintain their weight because of vomiting and despite a trial of the interventions described above. Enteral nutrition via gastric or duodenal intubation is preferable to the parenteral route and may relieve nausea and vomiting [113]. Adequate protein-caloric parenteral nutrition requires a central venous access device, which may lead to catheter-related infection or thrombosis [114,115]. (See "Nutrition support in critically ill patients: Parenteral nutrition".)

The American Gastroenterological Association has published a technical review and position statement on parenteral nutrition [116,117].

MANAGEMENT OF STABLE AND IMPROVING PATIENTS — We continue the drug regimen that has been effective until the patient has been completely asymptomatic (no nausea or vomiting) for at least a week. At that time, we discontinue the medications and see how she responds. If nausea and vomiting recurs, we resume therapy. The majority of women will have resolution of nausea and vomiting by 16 to 20 weeks of gestation and will be able to discontinue their medications. Rare patients require therapy beyond 20 weeks.

OUTCOME AND PROGNOSIS

Short-term outcomes

Nausea and vomiting of pregnancy — Although the maternal course can be long and tedious [118], nausea and vomiting of pregnancy is typically not associated with adverse pregnancy outcomes in the absence of severe malnutrition. There is strong evidence that women with nausea and vomiting in early pregnancy have a lower rate of miscarriage than women without these symptoms. In one meta-analysis, the odds of miscarriage in women with nausea and vomiting in the first 20 weeks of pregnancy was odds ratio (OR) 0.36 (95% CI 0.2-0.42) [119]. The analysis did not correlate outcome with respect to the severity of the disorder, most of the women in the studies had mild symptoms rather than hyperemesis, most data were collected retrospectively, and women with pregnancy losses before recognition of pregnancy were not included.

These limitations were address in a subsequent prospective study of 797 women with a history of one or two pregnancy losses in whom early pregnancy was identified by daily periconceptional human chorionic gonadotrophin testing and nausea and vomiting were recorded in preconception and pregnancy diaries [120]. In this population, nausea alone was associated with a 50 percent reduction in clinical pregnancy loss (hazard ratio [HR] 0.50, 95% CI 0.32-0.80), and nausea with vomiting was associated with a 75 percent reduction in clinical pregnancy loss (HR 0.25, 95% CI 0.12-0.51), after adjustment for covariates (eg, age, smoking, number of prior losses and live births, karyotype). Symptomatic women had a similar reduction in peri-implantation pregnancy loss, which was not statistically significant.

The frequency of congenital anomalies is not increased among offspring of gravidas with nausea and vomiting in pregnancy [121], whether or not they take antiemetic medications [68,122-126].

Hyperemesis — Despite the potential severity of hyperemesis gravidarum and its attendant early weight loss, most studies have reported no difference in birth weight or gestational age at birth between affected pregnancies and those unaffected by severe vomiting, as long as prepregnancy weight was normal and there was "catch-up" weight gain later in pregnancy [123,124,127]. In contrast, women with severe vomiting who require multiple hospitalizations may not have "catch up" weight gain; an adverse effect on birth weight is more likely in these women, and rarely the fetus is growth-restricted [122,128-131]. Women who have less than 7 kg weight gain are more likely to have preterm birth/low birth weight/small for gestational age infants [111,131,132]. When studies of women with hyperemesis gravidarum were pooled without regard to prepregnancy weight or catch-up weight gain, the risks of preterm delivery, low birth weight (LBW), and birth of a small for gestational age (SGA) infant were slightly but significantly increased (preterm delivery OR 1.32, 95% CI 1.04-1.68; LBW OR 1.42, 95% CI 1.27-1.58; SGA OR 1.28, 95% CI 1.02-1.60; 17.9 versus 12.7 percent) [121].

The availability of parenteral and enteral nutrition has reduced maternal morbidity, and mortality is virtually nonexistent in women who are treated. If left untreated, there have been reports of sequelae of micronutrient deficiency (eg, most commonly Wernicke encephalopathy from deficiency of vitamin B1, possibly very rare bleeding diathesis or embryopathy from vitamin K deficiency) and adverse effects of malnutrition (immunosuppression, poor wound healing, muscle wasting) [93,128,133-137]. Esophageal tears (Mallory-Weiss), esophageal rupture, pneumothoraces, pneumomediastinum, rhabdomyolysis, osmotic demyelination syndrome (formerly known as central pontine myelinolysis), hepatic insufficiency, diaphragmatic tear, venous thrombosis, and acute tubular necrosis are other rare complications in women with persistent severe vomiting [138-144]. An association between second-trimester hyperemesis gravidarum and placental dysfunction (eg, preeclampsia, abruption, SGA) was reported in a population-based cohort study [145]. It is unclear whether there is a small increase in risk of perinatal death [121,146].

There can be significant psychosocial morbidity, including substantial effects on ability to work outside the home, household duties, parenting activities, and social interaction [147-150]. In a study of 808 women who completed a survey on a hyperemesis gravidarum website, 15 percent reported at least one termination due to the disease [151]. The burdens of caregiver time and use of health care resources also need to be considered.

Long-term outcomes — Although long-term follow-up data are limited, nausea and vomiting of pregnancy and hyperemesis do not appear to adversely affect cognitive development of offspring [152,153]. Hyperemesis has been associated with reduced insulin sensitivity in prepubertal children [154], and poor in utero nutrition has been associated with some cancers in adulthood [155]. Larger follow-up studies are needed to determine whether nausea and vomiting of pregnancy and/or hyperemesis gravidarum have long-term effects on offspring. These studies need to use well-defined criteria for the severity of the disease, and adjust for key maternal characteristics, such as prepregnancy weight and weight gain during pregnancy. Metabolic and cardiovascular outcomes should be evaluated since SGA birth has been linked to chronic disease in adult life [156]. A study of offspring of women with early pregnancy weight loss >5 kg did not show an adverse effect on glucose or lipid levels or body mass index at 5 to 6 years of age, but diastolic blood pressure was 1.4 mmHg higher in this group [157].

There are no high-quality data on long-term maternal outcomes. Associations between hyperemesis and cancer have been observed, but study results are inconsistent [158].

Recurrence — The disorder is likely to recur in subsequent pregnancies [131,159-161]. Two population-based series reported the risk of recurrent hyperemesis in a second pregnancy was 15 [159] and 20 [131] percent in women with previous hyperemesis, but only 0.7 percent in women with no such history [159]. Another study contacted women who had one pregnancy complicated by hyperemesis gravidarum and registered on an internet site sponsored by the Hyperemesis Education and Research Foundation [160]. Of 100 respondents, 57 had become pregnant again, of whom 46 experienced recurrent severe nausea and vomiting; 37 women reported that they did not want to get pregnant a second time because of the recurrence risk of hyperemesis gravidarum.

PREVENTION — Ideally, all women of child-bearing age should be advised to take a daily multivitamin with folic acid beginning in the preconception period; this reduces the risk of congenital anomalies, particularly neural tube defects, and may help to decrease the frequency and severity of nausea and vomiting during pregnancy [162-164]. The positive effects of multivitamins are likely due to the general optimization of nutritional status and metabolism. (See "Folic acid supplementation in pregnancy".)

In addition, heartburn and acid reflux have been associated with increased severity of nausea and vomiting of pregnancy, which suggests that managing these disorders prior to pregnancy might prevent or reduce the severity of symptoms [165]. (See "Medical management of gastroesophageal reflux disease in adults", section on 'Pregnancy and lactation'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Morning sickness (The Basics)" and "Patient education: Taking over-the-counter medicines during pregnancy (The Basics)" and "Patient education: Hyperemesis gravidarum (The Basics)")

Beyond the Basics topic (see "Patient education: Nausea and vomiting of pregnancy (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS — A step-wise approach to treatment of nausea and vomiting of pregnancy is provided in the algorithm (algorithm 1). The steps are based on evidence of efficacy and safety profiles. The goal is to reduce symptoms through changes in diet/environment and by medication, correct consequences or complications of nausea and vomiting, and minimize the fetal effects of maternal nausea and vomiting and its treatment.

Women should try to become aware of, and avoid, environmental triggers and foods which might provoke their nausea and vomiting. (See 'Nausea with/without occasional vomiting' above.)

Acupuncture and acupressure have not been proven to significantly reduce nausea and vomiting. However, given the absence of harm and the strong placebo effect, some patients may benefit from a trial of acupressure wrist bands. Patient preferences should guide therapy. (See 'Other interventions' above.)

Where available, we suggest pyridoxine-doxylamine succinate combination therapy for initial pharmacologic treatment of nausea of pregnancy (Grade 2B). If this drug is not available, we suggest pyridoxine, adding doxylamine succinate if pyridoxine alone is not effective. (See 'Doxylamine succinate and pyridoxine' above and 'Pyridoxine (vitamin B6)' above.)

If nausea and vomiting persists, we suggest adding diphenhydramine 25 to 50 mg orally every four to six hours or meclizine 25 mg orally every six hours (Grade 2C). If symptoms do not improve, we suggest adding a dopamine antagonist (prochlorperazine, metoclopramide) (Grade 2C). (See 'Dopamine antagonists' above.)

For patients who require hospitalization because of dehydration, we suggest a serotonin antagonist (ondansetron) (Grade 2C). (See 'Serotonin antagonists' above.)

Women who are dehydrated or have electrolyte abnormalities or acid-base disturbances should receive intravenous fluids. Thiamine supplements should be added to the intravenous solution to prevent Wernicke's encephalopathy. We suggest a short period of gut rest during hydration, followed by reintroduction of oral intake with liquids and bland, low-fat foods. (See 'Fluids and nutrition' above and 'Diet' above.)

We reserve use of glucocorticoids for treatment of refractory cases after the first trimester. (See 'Glucocorticoids' above.)

The optimal timing for initiating enteral or parenteral nutrition has not been established; the decision is based upon clinical judgment. In general, enteral nutrition is begun in women who cannot maintain their weight because of vomiting and despite a step-wise trial of pharmacologic interventions. (See 'Enteral and parenteral nutrition' above.)

We suggest that women of child-bearing age take a multivitamin with folic acid to help prevent nausea and vomiting during pregnancy (Grade 2C), as well as for reducing the risk of neural tube defects. (See 'Prevention' above.)

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