INTRODUCTION — Nausea with or without vomiting is common in early pregnancy. Severe vomiting resulting in hypovolemia and weight loss is termed hyperemesis gravidarum and occurs infrequently. Symptoms usually resolve by midpregnancy regardless of severity and need for therapy.
Management of patients with nausea and vomiting of pregnancy (NVP) depends upon symptom severity, the impact of their symptoms on their health and quality of life, and the safety of treatment for both them and their fetus. Treatment approaches vary widely and include conservative measures (dietary/lifestyle changes), medication(s), and hospitalization for parenteral fluids and therapies in patients with hypovolemia or hyperemesis gravidarum who fail to respond to outpatient management. Enteral or parenteral nutrition may be required for those with persistent weight loss despite these interventions, although this is rare.
The treatment and outcomes of NVP will be reviewed here. Our approach is generally consistent with that of the American College of Obstetricians and Gynecologists [1]. The pathophysiology, clinical features, and evaluation of this disorder are discussed separately. (See "Nausea and vomiting of pregnancy: Clinical findings and evaluation".)
ASSESSMENT OF SEVERITY AND TREATMENT GOALS — When managing patients with NVP, the goals are to:
●Determine the severity of disease: nausea alone, vomiting without hypovolemia, or vomiting with hypovolemia. These designations refer to the patient's primary problem and are somewhat arbitrary as the frequency of vomiting typically varies from day to day.
●Correct hypovolemia, ketonuria and electrolyte abnormalities, if present.
●Reduce symptoms and improve quality of life through dietary and lifestyle changes followed by initiation of treatment with medications, if necessary.
●Prevent serious complications of persistent vomiting and hypovolemia, including vitamin deficiencies (eg, Wernicke encephalopathy) and extreme weight loss.
●Minimize the fetal effects of maternal pharmacologic treatment.
Early intervention and treatment of patients with mild and moderate symptoms may prevent progression to severe disease (eg, hyperemesis gravidarum [HG]) [1].
MANAGEMENT OF NAUSEA AS THE PRIMARY SYMPTOM — For patients whose primary symptom is nausea, the initial treatment approach involves counseling about dietary and lifestyle changes, such as trigger avoidance. Ginger and/or pyridoxine or the combination of doxylamine and pyridoxine are initial recommended therapies if symptoms do not improve (algorithm 1).
Dietary changes
Meals and snacks — Patients with nausea are advised to eat before, or as soon as, they feel hungry to avoid an empty stomach, which can aggravate nausea [2]. A snack before getting out of bed in the morning and snacks during the night may also be helpful (eg, crackers with peanut butter or cheese taken prior to getting up for nighttime bathroom trips).
Meals and snacks should be eaten slowly and in small amounts every one to two hours to avoid an overly full stomach, which can also aggravate nausea for some patients [3].
Patients should determine which foods they tolerate best and try to consume those foods. Dietary manipulations that help some patients include eliminating coffee and spicy, odorous, high-fat, acidic, or very sweet foods, and instead consuming snacks/meals that are protein-dominant, salty, low-fat, bland, and/or dry (eg, nuts, pretzels, crackers, cereal, toast) [2-4]. Sucking on peppermint candies may reduce postprandial nausea [5].
However, high-quality evidence of the optimal dietary components to reduce nausea are sparse. Although clinicians commonly recommend ingestion of frequent, small, carbohydrate-predominant meals/snacks (eg, soda crackers or dry toast) based primarily on anecdotal evidence passed down over a century [6], consumption of protein-predominant meals/snacks may be more helpful and was associated with quantifiable decreases in nausea in one study [7].
Patients 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 patients with NVP.
Fluids — Patients are advised to consume fluids at least 30 minutes before or after solid food to minimize the effect of a full stomach [3]. Fluids are better tolerated if cold, clear, and carbonated or sour (eg, ginger ale, lemonade, popsicles) and taken in small amounts; using a straw or very small cup sometimes helps [8]. Some patients find aromatic liquids, such as lemon, mint, or peppermint tea, more tolerable and helpful in reducing nausea.
Small volumes of electrolyte-replacement sports drinks, if tolerated, can be used to replace both fluids and electrolytes.
Trigger avoidance — Along with dietary changes, avoidance of environmental triggers is a key intervention for reducing NVP [4]. Examples of some triggers include stuffy rooms, odors (eg, perfume, chemicals, food, smoke) [9], heat, humidity, noise, and visual or physical motion (eg, flickering lights, driving) [10].
Lying down soon after eating and lying on the left side are additional potentially aggravating factors because these actions may delay gastric emptying [3]. Quickly changing position and not getting enough rest/sleep may also aggravate symptoms [11].
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 patients is preparing their own meal) [3].
Brushing teeth after a meal [5], spitting out saliva, and frequently rinsing the mouth can also be helpful. Switching to a different toothpaste may help those for whom strongly flavored toothpaste is a trigger.
Supplements containing iron should be avoided until symptoms resolve as iron causes gastric irritation and can provoke nausea and vomiting [12]. Taking prenatal vitamins before bed with a snack, instead of in the morning or on an empty stomach, may also be helpful [13]. Some patients may find chewable prenatal vitamins more tolerable than tablets or capsules. If prenatal vitamins are stopped, a supplement containing folic acid (400 to 800 mcg daily) is recommended, especially throughout the first trimester, until prenatal vitamins are again tolerated. (See "Folic acid supplementation in pregnancy".)
Ginger supplements — We suggest that patients with nausea try consuming ginger-containing foods (eg, ginger lollipops, ginger tea, foods or drinks containing ginger root or syrup). We do not prescribe powdered ginger because standard pharmacologic-grade ginger preparations are not readily available [14]; 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); doses of 0.5 to 2.5 g orally over 24 hours have been used and appear to be safe [15]. In meta-analyses of randomized trials (including over 1000 participants), ginger improved nausea compared with placebo but did not significantly reduce vomiting [16,17].
Initial pharmacotherapy
Pyridoxine (vitamin B6) monotherapy — Pyridoxine can improve nausea, has a good safety profile with minimal side effects, and is easy to obtain; therefore, we generally begin pyridoxine as the initial treatment.
As a single agent, the recommended dose of pyridoxine is 10 to 25 mg orally every six to eight hours with the maximum treatment dose suggested for pregnant individuals at 100 mg/day [18]. In settings where a 10 mg tablet is unavailable (eg, United States, Canada), half of a 25 mg pyridoxine tablet (ie, 12.5 mg) may be reasonably substituted with the understanding that the medication may not be evenly distributed throughout the oral tablet. Sensory neuropathy has been reported with chronic intake of pyridoxine at doses >500 mg/day [19,20], but cumulative doses up to 500 mg/day appear to be safe for the patient [21]. Human data on fetal safety at high doses are limited but reassuring. An observational study of 96 pregnant patients in the first trimester with >50 mg/day pyridoxine intake (mean dose 132 mg/day, range 50 to 510 mg/day) and 96 control pregnancies found no association with major fetal malformations [22]. Pyridoxine 100 mg/kg was not teratogenic in animal studies [23].
Systematic reviews of randomized and/or controlled trials have reported that pyridoxine (vitamin B6) improves mild to moderate nausea but does not significantly reduce vomiting [24-26]. 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 [27]. Although vitamin B6 levels decrease as gestation advances, there is no proven correlation between maternal vitamin B6 levels and incidence or severity of nausea [28].
Doxylamine-pyridoxine — We recommend the combination doxylamine-pyridoxine when pyridoxine treatment alone of nausea 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).
The recommended prescription starts with two extended-release tablets (each tablet contains doxylamine 10 mg and pyridoxine 10 mg) orally at bedtime [29,30]. The dose may be increased to four tablets orally over the course of the day, as needed, for more severe nausea (two tablets at bedtime and add one tablet midmorning and one tablet in midafternoon if needed). Thus, a patient will take two to four tablets per day depending on the regimen that controls their symptoms. 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 not associated with an increased risk of any adverse event and was well tolerated by patients with NVP [31].
A higher dose extended-release tablet containing 20 mg of doxylamine succinate and 20 mg of pyridoxine is also available. One of these tablets is taken at bedtime, and if symptoms persist into the next day, one additional tablet is taken in the morning. The patient may take one or two tablets per day depending on symptom severity.
The combination extended-release 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, can be taken three or four times per day along with 12.5 mg of doxylamine; the 10 mg dose of pyridoxine is not commercially available in the United States. This is a reasonable, less expensive substitute for combination extended-release tablets.
The combination of doxylamine-pyridoxine was proven modestly effective for treatment of NVP in a meta-analysis of placebo-controlled randomized trials [32] and appears to be more effective than either therapy 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 [23,33,34] and efficacy [32,35-38]. A meta-analysis of controlled studies on outcome of pregnancies exposed to Bendectin reported no increase in the incidence of congenital anomalies [34].
Other interventions
●Acupuncture, acupressure, or acustimulation – P6 acupressure wristbands (picture 1) do not require a prescription and have become a popular self-administered intervention [39]. In a 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 [32]. One reason may be that a strong placebo effect has been observed in patients who receive sham therapy [40-43]. Acupressure and acupuncture have not been associated with any adverse effects on pregnancy outcome and may help some patients, 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 has shown mixed results, with some promise in two randomized trials [44,45].
The available evidence on these measures is limited and studies have methodological flaws. Although data do not prove benefit, these measures are unlikely to be harmful. If a patient wants to try one or more of them, the provider should not discourage use.
●Hypnosis has been reported to be helpful in some patients [46].
●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 individuals to avoid consuming Nzu, a traditional African remedy for morning sickness, because of potential health risks from high levels of lead and arsenic, a problem that has been reported by others [47]. Nzu may be sold under such names as Calabash clay, Calabar stone, Mabele, Argile, or La Craie. In addition, there are no well-designed trials demonstrating safety and efficacy of essential oils, although low-quality studies have been published.
●Cannabis (also called marijuana) use during pregnancy has been increasing, and pregnant individuals increasingly self-report using it to alleviate the symptoms of NVP [48]. Although cannabis has been used to mitigate nausea and vomiting in nonpregnant individuals, the American College of Obstetricians and Gynecologists and public health authorities recommend advising pregnant individuals and those considering becoming pregnant to avoid using it or other cannabinoids to treat their nausea as concerns exist regarding fetal safety [49,50]. Individuals may not receive this information from cannabis dispensary employees, who have been found to endorse its use in pregnant people [51]. Potential adverse effects of prenatal cannabis use are reviewed separately. (See "Substance use during pregnancy: Overview of selected drugs", section on 'Cannabis (marijuana)'.)
●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 [52,53].
MANAGEMENT OF VOMITING WITHOUT HYPOVOLEMIA
Initial approach — For patients whose primary symptom is vomiting but who are not hypovolemic (no lassitude, postural dizziness, thirst, tachycardia, decreased urine volume and frequency; able to keep down some fluids), laboratory test results (eg, BUN, electrolytes, acid-base balance) are likely to be normal or near normal. A reasonable approach in these patients is to discuss dietary changes and trigger avoidance, as well as use of doxylamine-pyridoxine rather than pyridoxine alone. (See 'Management of nausea as the primary symptom' above and "Nausea and vomiting of pregnancy: Clinical findings and evaluation", section on 'Laboratory tests'.)
We also offer additional medications that are reported to be effective and have a good maternal-fetal safety profile. If doxylamine-pyridoxine is ineffective, then other medications are added in a stepwise progression because a combination of drugs may be effective (algorithm 1) [54,55]. We typically continue a medication for a week to determine whether nausea and vomiting are improving. If symptoms persist, then we add another class of medication to the existing regimen; however, if the patient is experiencing side effects, we substitute another medication in its place.
Patients who are vomiting most food and liquids require frequent, even daily, assessment of their medical status and response to therapy. Ambulatory management may be appropriate for patients with severe symptoms who have a strong preference to avoid admission, provided intensive follow-up and daily treatment with intravenous fluid and injectable medication are available, if needed [56]. Those who are becoming hypovolemic or have electrolyte abnormalities or vital sign or neurologic changes are admitted for hour-to-hour evaluation and more intensive therapy. (See 'Management of vomiting with hypovolemia' below.)
Historically, pregnant individuals have been excluded from most clinical drug trials. Thus, there are only limited data on pregnant people to support the safety and efficacy of medications used to treat nausea and vomiting. A number of reports have demonstrated that antiemetic therapy is more effective than placebo and does not increase the incidence of congenital anomalies [8,11,26,32,35,55,57]. However, there is little evidence from well-designed comparative trials that show clear superiority of one medication over another. It is therefore recommended that safety profiles, patient tolerance, and cost all be considered in the choice of pharmacotherapeutic management [58].
Add an antihistamine (H1 antagonists) — If doxylamine-pyridoxine (see 'Doxylamine-pyridoxine' above) has been ineffective, we would discontinue it before starting a different antihistamine. We suggest the following antihistamines as second-line agents for patients who are vomiting. We begin with these agents because they either have fewer maternal side effects or a more established fetal safety profile compared with other medications. However, antihistamines should be avoided in patients taking ondansetron or other medications that prolong the QT interval.
Dimenhydrinate, meclizine, and diphenhydramine are the antihistamines that have been most extensively studied for treatment of NVP. There are no data on use of the scopolamine patch for NVP. Scopolamine should be avoided in patients with preeclampsia with severe features as eclamptic seizures have been reported after parenteral administration [59].
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 [35].
The safety of antihistamines was affirmed in a meta-analysis that examined the association between histamine 1 [H1] antihistamine use and major malformations [60]. This review of 37 controlled studies, including nearly 50,000 first-trimester exposures, found that the risk of major malformations was similar in exposed and nonexposed pregnancies (cohort studies: odds ratio [OR] 1.07, 95% CI 0.98-1.16; case-control studies: OR 1.05, 95% CI 0.90-1.23).
The primary mechanism of antihistamines in treatment of NVP 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 antihistamines include sedation, dry mouth, lightheadedness, and constipation.
Diphenhydramine — Diphenhydramine can be given 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 [61-63].
Dimenhydrinate — Dimenhydrinate can be given 25 to 50 mg orally every four to six hours, as needed. Otherwise, 50 mg dimenhydrinate is administered intravenously over 20 minutes or 50 mg is administered rectally (where available [64]) every four to six hours, as needed; the total dose should not exceed 300 mg/day. If the patient is taking doxylamine, the total dose of dimenhydrinate should not exceed 200 mg/day. Available safety data are generally reassuring that it is not a teratogen [61-63,65].
Meclizine — Meclizine is used primarily for managing motion sickness and vertigo. In the United States, it is not the H1 antagonist chosen for treatment of NVP, but it is one of the options used for this indication in some countries [66]. Meclizine can be given 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 [67-69].
Add a dopamine antagonist — Several types of dopamine receptor antagonists can be used for the treatment of NVP. The three main classes are benzamides (metoclopramide), phenothiazines (promethazine and prochlorperazine), and butyrophenones (droperidol). Metoclopramide, promethazine, and prochlorperazine are discussed here; droperidol is discussed below. (See 'Droperidol' below.)
The use of these medications 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 5 to 10 mg orally, intravenously, or intramuscularly (ideally 30 minutes prior to meal and at bedtime) every six to eight hours is commonly prescribed for NVP [70]. In randomized trials evaluating it in patients with hyperemesis, metoclopramide 10 mg was as effective as promethazine 25 mg [71] and ondansetron 4 mg [72].
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 [73]. 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 [74].
In a meta-analysis of six cohort studies including a total of over 33,000 first-trimester metoclopramide exposures and over 373,000 unexposed controls, the risk for major congenital anomalies was not significantly increased in exposed infants (OR 1.14, 95% CI 0.93-1.38) [75]. These data are reassuring, but subject to several limitations, including inability to confirm actual metoclopramide exposure (as opposed to dispensed prescriptions) and outcomes limited to liveborn infants.
Maternal side effects are a concern, especially with long-term use. Metoclopramide accounts for almost one-third of all drug-induced movement disorders; 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]) [71]. Older age, higher dose, and female sex are risk factors for development of these side effects [76]. Tardive dyskinesia is rare in young patients. More information on side effects is available separately. (See "Characteristics of antiemetic drugs", section on 'Benzamides'.)
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. Tapering rather than abrupt discontinuation is unnecessary. Upon discontinuation, metoclopramide-induced tardive dyskinesia (involuntary and repetitive movements of the body) can be irreversible in some cases.
The use of subcutaneous pumps for timed release of medications, in particular metoclopramide, has been reported for outpatient management of NVP with some benefit [77]. Experience is limited, and we do not use them.
Metoclopramide can be effective in the setting of diabetic gastroparesis; however, the degree to which delayed gastric emptying is involved in NVP independent of gastroparesis is unknown.
Domperidone is another promotility agent, but there is no information on its safety or efficacy for treatment of NVP.
Promethazine — Promethazine is primarily an H1 receptor-blocking agent, but it is also a weak dopamine antagonist. The safest and preferred route of administration is orally or rectally, 12.5 to 25 mg every four hours. If administered parenterally, intramuscular administration is the preferred route. The intravenous route of administration should only be used as a last resort because inadvertent intraarterial injection can result in gangrene of the affected extremity and is also associated with severe extravasation reactions. Subcutaneous injection is contraindicated as it may cause severe tissue necrosis. (See "Characteristics of antiemetic drugs".)
Fetal safety [78] and maternal efficacy in relief of both nausea and vomiting have been reported in studies including large numbers of patients [35,71,79,80]. 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 patients with seizure disorders or late in pregnancy in patients with preeclampsia.
There are conflicting reports regarding a potential risk of neonatal respiratory depression following the administration of promethazine during labor [78]. Neonatal platelet aggregation also may be impaired when it 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 patients 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 [74]. Safety information is limited: Although case reports of malformations in exposed infants have been published, larger series have not reported an increased risk of congenital anomalies. Results from animal studies vary depending on the animal exposed [78]. Overall, prochlorperazine is well tolerated with rare serious side effects, although QT prolongation is a potential side effect.
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 [81].
Add a serotonin antagonist — Ondansetron, granisetron, and dolasetron are selective antagonists at the 5-hydroxytryptamine-3 (5-HT3) serotonin receptor. This class of medications has a favorable efficacy-safety profile in nonpregnant individuals with nausea and vomiting of various etiologies and severities.
The use of ondansetron in pregnancy is controversial. We individualize its use, weighing the risks and benefits during pregnancy. We counsel pregnant patients regarding the available data and the possible associated small risk of cardiovascular anomalies (see 'Ondansetron' below). There are limited human data on the safety of granisetron, dolasetron, or other 5-HT3 antagonists in pregnancy; animal studies did not show adverse pregnancy effects.
Ondansetron
●Candidates – We believe, ideally, a combination of two oral agents should be tried and found to be unsuccessful before initiating oral ondansetron in pregnancies less than 10 weeks of gestation. The American College of Obstetricians and Gynecologists recommends discussing the available data (see below) with patients and weighing the potential risks against the effectiveness of ondansetron in treating nausea and vomiting on a case-by-case basis in patients less than 10 weeks of gestation whose symptoms are refractory to the medications discussed above [1]. Some other organizations have recommended avoidance in the first trimester or use as a second-line agent because of a possible small increase in risk of oral clefts and possibly ventricular septal defects (see below) [82,83].
NVP and hyperemesis gravidarum are common off-label uses 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 [84]. In another randomized trial, it was more effective than metoclopramide for reduction of vomiting but not nausea [85].
●Dose – Ondansetron 4 mg can be taken orally or intravenously by bolus injection every eight hours, as needed. The dose is increased if necessary, but limited to ≤8 mg/dose. A single report described use of subcutaneous ondansetron via a microinfusion pump in 521 pregnant patients with severe nausea and vomiting, with improvement of symptoms to mild to moderate in 50 percent of patients within three days of therapy [86]. 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 NVP. However, adverse side effects are common, and it has not proven to be cost effective, even when compared with hospitalization.
●Side effects – Headache, fatigue, constipation, and drowsiness are the most common drug-related side effects. A stool softener and mild laxative can be helpful for patients experiencing constipation. At least 10 patients have had signs or symptoms of myocardial ischemia (most commonly during intravenous administration) that resolved with prompt treatment and where a causal role of ondansetron could not be ruled out, prompting the manufacturer to recommend patient monitoring during and after administration [87]. 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 [88]. More detailed information on side effects is available separately. (See "Characteristics of antiemetic drugs", section on '5-HT3 receptor antagonists'.)
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)".)
●Risk of congenital anomalies – Available data suggest that use of ondansetron in early pregnancy is not associated with a high risk of congenital malformations, but a small absolute increase in risk of cardiovascular malformations (especially septum defects) and cleft palate may exist [89-92]. One review of available data through 2020 estimated that the absolute increase in risk above baseline for orofacial defects may be only 0.03 percent, and for ventricular septal defects it may be 0.3 percent [93].
A retrospective cohort study including over 1.8 million pregnancies among individuals enrolled in Medicaid concluded that first-trimester oral ondansetron exposure was not associated with an increased risk of cardiac malformations or congenital malformations overall after adjustment for known confounders [89]. There was an increased risk of oral clefts (RR 1.24, 95% CI 1.03-1.48), but the absolute risk difference was low (risk difference 2.7 per 10,000 births, 95% CI 0.2-5.2). This study, which included almost 90,000 first-trimester ondansetron exposures, is the largest study of this issue and provides the most reassuring data. The same authors repeated the analysis for intravenous exposures and found that intravenously administered ondansetron was not associated with an increase in the risk of oral clefts (RR 0.95, 95% CI 0.63-1.43), cardiac malformations, or congenital malformations overall [94]. Although the point estimate was lower for intravenous ondansetron compared with oral ondansetron, the 95% CI was wide and the upper limit was similar to that for oral ondansetron; thus, the authors concluded that the observed risks are not clearly different for intravenous versus oral ondansetron [95].
Meta-analyses have not found increased risks for major congenital malformations associated with ondansetron use in pregnancy [96,97]. A meta-analysis that included the studies discussed above was limited by inclusion of many other studies that did not adjust for known confounders, as well as moderate to high risk of bias of all included studies [96]. In this analysis, first-trimester exposure to ondansetron was associated with a trend toward an increase in risk for oral clefts (OR 1.22, 95% CI 1.00-1.49) and ventricular septal defects (OR 1.11, 95% CI 1.00-1.23), but not for major congenital malformations overall, cardiac malformations overall, atrial septal defects, or cleft lip with or without cleft palate.
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 birth). 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 symptoms in pregnant patients treated with intravenous or transdermal granisetron [98]. The transdermal formulation was convenient for patients who could not tolerate an oral pharmacotherapy and effective, but it is very expensive.
Human data on reproductive effects are sparse [99-101]. 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 [99]. A study of 100 granisetron-exposed pregnancies (88 with first-trimester exposure) reported no increase in major or minor congenital anomalies compared with unexposed pregnancies [100].
Side effects are similar to those for other 5-HT3 antagonists, such as ondansetron. (See 'Ondansetron' above and "Characteristics of antiemetic drugs", section on '5-HT3 receptor antagonists'.)
Adjunctive therapy
Acid-reducing agents — Acid-reducing medications can be used as adjunctive therapy. In patients with heartburn/acid reflux and NVP, an observational study found that acid-reducing pharmacotherapy (eg, antacids, H2 blockers, proton pump inhibitors) combined with antiemetic therapy resulted in significant improvement in symptoms and well-being three to four days after beginning therapy [102]. In many patients with significant NVP, the ability to ascertain whether or not acid reflux is a contributing factor may be difficult. As a result, we often start prophylactic therapy with an acid-reducing agent in these patients.
Antacids containing aluminum or calcium are safe for pregnant patients and preferable to those containing bismuth or bicarbonate, which may have adverse fetal/neonatal effects [103].
The largest experience with pharmacologic acid-suppressive therapy in pregnant patients has been with the H2 receptor antagonists cimetidine and ranitidine, which appeared to have a good maternal-fetal safety profile; however, in 2020, the US Food and Drug Administration requested manufacturers withdraw all ranitidine products from the market immediately because some ranitidine products contained the contaminant N-Nitrosodimethylamine (NDMA), a probable human carcinogen. Cimetidine dosing ranges from 200 mg orally twice daily for symptomatic relief of dyspepsia to up to 400 mg orally twice daily for gastroesophageal reflux disease. In 2005, the European Network of Tetralogy Information Network Services reported 553 cases in which pregnant patients were exposed to H2 blockers, of whom 113 were exposed to cimetidine [104]. Rates of malformations, low birth weight, and preterm birth were similar for exposed and non-exposed fetuses. (See "Medical management of gastroesophageal reflux disease in adults", section on 'Pregnancy and lactation'.)
There is less experience using proton pump inhibitors (eg, lansoprazole or esomeprazole 30 or 40 mg intravenously or orally every 24 hours) during pregnancy. Overall, they probably have a good maternal-fetal safety profile [105,106]. However, use of alternative agents may be prudent in patients with renal disease, as some studies have linked chronic use of proton pump inhibitors with an increased risk of acute kidney injury and end stage renal disease [107].
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'.)
Gabapentin — In a randomized double-blinded trial comparing a seven-day course of oral gabapentin (1800 to 2400 mg/d) with an active comparator (either oral ondansetron 24 to 32 mg/d or oral metoclopramide 45 to 60 mg/d) in 21 patients with medically refractory hyperemesis gravidarum requiring intravenous hydration, treatment with gabapentin resulted in a 52 percent greater decrease in baseline adjusted Motherisk-pregnancy-unique quantification of nausea and emesis total scores [108]. Further study of the safety and efficacy of gabapentin are warranted before it can be recommended.
MANAGEMENT OF VOMITING WITH HYPOVOLEMIA
General approach — Patients with persistent nausea and vomiting should be evaluated by their clinician and/or in the emergency department to assess their volume and metabolic status, exclude other diagnoses that could account for their symptoms, and guide replacement and pharmacologic therapy. (See "Nausea and vomiting of pregnancy: Clinical findings and evaluation", section on 'Evaluation'.)
We instruct patients with NVP to report to the emergency department or labor and delivery unit if they have symptoms of hypovolemia (eg, lassitude, postural dizziness, thirst, tachycardia, decreased urine volume and frequency) or if they are unable to keep food/fluids down for more than 12 hours. A trial of replacement fluid and intravenous antiemetic therapy before admission is reasonable for patients with normal electrolyte levels and normal acid-base balance. Hospital admission is appropriate for those with persistent symptoms after replacement fluid and intravenous antiemetic therapy, as well as patients who present with abnormal electrolyte levels and acid-base balance. The decision to admit versus discharge to home needs to be individualized based on the patient's severity of disease, resources, and ability to access outpatient resources (eg, home health care, infusion pump for administration of intravenous ondansetron at home) and comply with recommendations.
These patients and their families/close contacts 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 [109]. 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 [110].
It should also be noted that a single episode of inpatient treatment is often not durable; in a literature review, approximately 25 percent of patients who were admitted to the hospital for treatment of hyperemesis required readmission for persistent or recurrent symptoms [111]. As a result, prior to discharge, patients should be given a clear explanation of which medications to take, how to take them, and how long to continue them. For patients with persistent vomiting after inpatient therapy, it is important to exclude underlying diseases that can cause hyperemesis. (See "Nausea and vomiting of pregnancy: Clinical findings and evaluation", section on 'Differential diagnosis'.)
Replacement fluid therapy 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 and electrolytes — Hypovolemia occurs when fluid losses exceed fluid intake and is often associated with electrolyte abnormalities, fatigue, dizziness, and weakness. We correct hypovolemia 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".)
After initial replacement fluid therapy with Ringer's lactate, we administer dextrose 5 percent in 0.45 percent saline with 20 mEq potassium chloride at 150 mL/hour to patients with normal potassium levels (hypokalemia is discussed below). The infusion rate is adjusted to maintain a urine output of at least 100 mL/hour.
The optimum replacement fluid regimen has not been studied. It is prudent to avoid use of dextrose in the initial replacement fluid because of the theoretical concern of inducing Wernicke's encephalopathy from dextrose infusion in a thiamine-deficient state [112]. We delay dextrose infusion until after the patient has received thiamine in their initial replacement fluid (see 'Vitamins and minerals' below). A single small randomized trial of intravenous replacement fluid therapy with 5 percent dextrose-0.9 percent saline versus 0.9 percent saline solution in patients 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 [113]. A limitation of this trial is that only 60 percent of the patients had severe disease (eg, weight loss ≥5 percent body weight).
Most hypokalemic patients have a serum potassium concentration of 3.0 to 3.4 mEq/L. This degree of potassium depletion usually produces no symptoms. Treatment is usually started with 10 to 20 mEq of potassium given two to four times per day (20 to 80 mEq/day), depending upon the severity of the hypokalemia. Potassium must be given more rapidly to patients with hypokalemia that is severe (serum potassium less than 2.5 to 3.0 mEq/L) or symptomatic. A saline rather than a dextrose solution should be used for initial therapy of hypokalemia since the administration of dextrose stimulates the release of insulin which drives extracellular potassium into the cells, which can lead to a transient 0.2 to 1.4 mEq/L reduction in the serum potassium concentration, particularly if the solution contains only 20 mEq/L of potassium. Sequential monitoring of the serum potassium is essential to determine the response. (See "Clinical manifestations and treatment of hypokalemia in adults", section on 'Treatment'.)
Relief of symptoms is common within one to two days of replacement fluid therapy [8]. 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) and minerals, which may be depleted. In addition, nutritional rehabilitation of malnourished or undernourished individuals can cause fluid and electrolyte shifts resulting in hypophosphatemia, hypokalemia, and other complications (refeeding syndrome) [114-116]. (See "Anorexia nervosa in adults and adolescents: The refeeding syndrome", section on 'Refeeding syndrome'.)
●Thiamine – We provide thiamine (vitamin B1) supplementation by giving 100 mg intravenously with the initial replacement 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 [8,117,118]. (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.
●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 with a diet consisting of bananas, rice, applesauce, and toast (BRAT diet) and then advance the diet as tolerated. Consistent protein intake is key in helping prevent nausea. Additional dietary manipulations are described above. Referral to a nutritionist may be helpful for those patients with underlying medical conditions, like diabetes, or who would benefit from more education on the ideal diet to manage the symptoms of NVP. (See 'Dietary changes' above.)
Patients who have not eaten for several days may develop edema when resuming feeding with carbohydrates [119]. This results from the retention of sodium during fasting combined with enhanced sodium resorption due to the actions of insulin once carbohydrates are reintroduced [120]. No intervention is required; the edema will gradually resolve.
Pharmacotherapy — Non-oral routes of administration are necessary for patients with persistent vomiting. We begin ondansetron 4 to 8 mg intravenously (IV push) once every eight hours upon hospitalization for intravenous fluid therapy. After the patient has stabilized, ondansetron is discontinued. Per American College of Obstetricians and Gynecologists' guidelines, the risk:benefit should be considered for those patients under 10 weeks of gestation, given controversy regarding a potential risk of a small increase in congenital anomalies (see 'Ondansetron' above). Intravenous dimenhydrinate 50 mg every four to six hours, metoclopramide 5 to 10 mg every eight hours, or promethazine 12.5 to 25 mg every four to six hours is an alternative to ondansetron [1].
If symptoms recur, antiemetic medications are the same as those used to treat patients with frequent vomiting without hypovolemia or other serious sequelae (algorithm 1). Oral medications are initiated in patients who can tolerate them. These oral medications can then be used at home when the patient is discharged from the hospital. Rectally administered medications are an alternative. (See 'Management of vomiting without hypovolemia' above.)
Ideally, a patient who has been admitted for treatment should be sent home when they have been stabilized on a scheduled antiemetic. In addition, they should have a second agent that has been effective for breakthrough symptoms. They should continue this prescribed regimen for at least a week, at which time they can be reevaluated to see if medications can be tapered or discontinued. The goal is to prevent relapse and an additional hospitalization. However, discharge medications are often not prescribed. In a population-based study, 50 percent of patients discharged from the hospital after treatment of NVP were not offered prescriptions for antiemetics [121].
REFRACTORY SYMPTOMS
Additional laboratory evaluation in patients with refractory symptoms — Case reports and small series have reported improvement in symptoms in patients with severe disease after treatment of Helicobacter pylori [122]. Although these observations support the hypothesis of H. pylori as an etiologic factor, confirmatory evidence from controlled trials is needed. The American College of Obstetricians and Gynecologists suggests considering testing for H. pylori infection in patients who are unresponsive to standard therapy [1]. It can also be considered in patients whose symptoms have not subsided by 16 to 20 weeks of gestation. Indications for diagnostic testing for H. pylori in the general population, appropriate choice of test, and consideration of treatment of patients who test positive are reviewed separately. (See "Indications and diagnostic tests for Helicobacter pylori infection in adults" and "Treatment regimens for Helicobacter pylori in adults", section on 'Treatment during pregnancy and lactation'.)
Pharmacotherapy — We generally treat patients with refractory symptoms 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 — A short course of glucocorticoids is added to the patient’s current regimen for treatment of refractory symptoms, given the risk of maternal side effects and uncertain efficacy. (See "Major side effects of systemic glucocorticoids".)
The mechanism of action is not well understood [123-126], and there is a paucity of evidence that glucocorticoids are effective [26,35,127]. The largest placebo-controlled trial included 110 patients with severe hyperemesis and reported that patients who received glucocorticoid therapy had a similar clinical course and need for rehospitalization as those given placebo [128]. However, a systematic review that included three randomized clinical trials comparing glucocorticoids with placebo or promethazine or metoclopramide found that patients with severe nausea and vomiting may benefit with corticosteroids [57]. 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 administered before 10 weeks of gestation; although this association remains controversial and has not been confirmed in recent studies (see "Etiology, prenatal diagnosis, obstetric management, and recurrence of cleft lip and/or palate", section on 'Environmental factors'), ideally, use of glucocorticoids should be avoided in the first trimester [129-133]. 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 [123]. An alternative regimen is hydrocortisone 100 mg intravenously twice daily [57]. Glucocorticoids can be stopped abruptly if there is no response and tapered over two weeks in patients who experience relief of symptoms. Glucocorticoid use may lead to hyperglycemia; therefore, blood glucose levels should be monitored in patients 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 'Add a dopamine antagonist' above). Adverse effects include extrapyramidal reactions, orthostatic hypotension, anticholinergic effects, and altered cardiac conduction. Therefore, we reserve the addition of this medication for selected patients with refractory symptoms, such as those in whom the side effects of steroids may be more serious (eg, diabetes mellitus).
Chlorpromazine 25 to 50 mg intravenously or intramuscularly or 10 to 25 mg orally every four to six hours is the usual dose.
Droperidol — We rarely use droperidol to treat NVP 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 patients treated with other parenteral therapies [134]. No congenital anomalies were reported in 108 pregnancies [78]. 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 [135]. The US Food and Drug Administration issued a boxed warning in 2001 [136], and the medication was removed from the European market in March 2001.
Tube feeding and parenteral nutrition — Patients whose symptoms are refractory to all pharmacologic and nonpharmacologic interventions should be supported with tube feeding or parenteral nutrition (and intravenous fluids) for as long as necessary [137,138]. Nutritional support during early pregnancy can reduce the frequency of late pregnancy morbidities associated with hyperemesis gravidarum. We also administer pharmacologic interventions if they provide some relief of nausea and vomiting.
Nutritional status and methods of alimentation (eg, tube feeding, parenteral nutrition) should be assessed in conjunction with a nutritionist or nutrition service. The optimal timing for initiating tube feeding or parenteral nutrition has not been established; the decision is based upon clinical judgment.
In general, tube feeding or parenteral nutrition is begun in patients 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 [139]. In patients hospitalized for hyperemesis, routine initiation of enteral tube feeding in addition to standard care (replacement fluid therapy, antiemetic therapy) upon hospital admission did not appear to improve any maternal or newborn outcome compared with standard care alone in a randomized trial [140]. In particular, nausea and vomiting symptoms and duration of hospital stay were similar in both groups. Tube feeding was supposed to be continued for at least seven days or until the patient was able to maintain an oral intake of 1000 kcal/day; however, 53 percent went off protocol, primarily because the tube was poorly tolerated. Although the trial has several limitations such as a high drop-out rate, missing data, and outcomes based on survey of participants, it is the first randomized trial examining the value of early enteral tube feeding. (See "Enteral feeding: Gastric versus post-pyloric" and "Nutrition support in critically ill patients: Enteral nutrition".)
Adequate protein-caloric parenteral nutrition requires a central venous access device, which may lead to catheter-related infection or thrombosis [141,142] (see "Nutrition support in critically ill patients: Parenteral nutrition"). The American Gastroenterological Association has published a technical review and position statement on parenteral nutrition [143,144].
Other — We do not routinely administer thromboprophylaxis. Hyperemesis may be a risk factor for venous thromboembolism [145,146], and at least one guideline [147] recommends offering low molecular weight heparin thromboprophylaxis to patients hospitalized with hyperemesis (unless there is a specific contraindication [particularly an increased risk for bleeding]); however, this recommendation is based on low-quality evidence, including expert opinion and case reports. Thromboprophylaxis may be appropriate in selected patients at high risk for venous thromboembolism. (See "Deep vein thrombosis and pulmonary embolism in pregnancy: Prevention".)
SPECIAL POPULATIONS
Nausea and vomiting in patients with diabetes — Special care should be taken for patients with preexisting diabetes and nausea and vomiting to avoid a hypoglycemic crisis, especially after taking insulin. Such patients should have glucose tablets, juice, or other glucose-containing liquids available to help increase blood glucose when needed and should be able to adjust insulin dosing, as necessary. Clear instructions about how to appropriately self-adjust insulin dosing based on food intake and when to seek additional medical care (eg, hypoglycemia that does not resolve with oral glucose intake, intractable vomiting) are essential. (See "Management of type 1 diabetes mellitus in children during illness, procedures, school, or travel", section on 'Sick-day management'.)
MANAGEMENT OF STABLE AND IMPROVING PATIENTS — We continue the medication 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 they respond. If nausea and vomiting recurs, we resume therapy. The majority of patients 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 [148], NVP is typically not associated with adverse pregnancy outcomes in the absence of severe malnutrition [149]. The frequency of congenital anomalies is not increased among offspring of patients with NVP or hyperemesis [150], whether or not they take antiemetic medications [79,151-155].
There is strong evidence that patients with nausea and vomiting in early pregnancy have a lower rate of miscarriage than patients without these symptoms. In one meta-analysis, the odds of pregnancy loss in patients with nausea and vomiting in the first 20 weeks of pregnancy was odds ratio (OR) 0.36 (95% CI 0.2-0.42) [156]. The analysis did not correlate outcome with respect to the severity of the disorder, most of the patients in the studies had mild symptoms rather than hyperemesis, most data were collected retrospectively, and patients with pregnancy losses before recognition of pregnancy were not included.
These limitations were addressed in a subsequent prospective study of 797 patients 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 [157]. 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 patients had a similar reduction in peri-implantation pregnancy loss, which was not statistically significant.
●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 in the normal range and there was "catch up" weight gain later in pregnancy [152,153,158]. In contrast, patients 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 pregnancies, and rarely the fetus is growth-restricted [151,159-162]. Patients who have less than 7 kg weight gain are more likely to have preterm birth/low birth weight/small for gestational age newborns [137,162,163]. When studies of patients with hyperemesis gravidarum were pooled without regard to prepregnancy weight or catch-up weight gain, the risks of preterm birth, low birth weight (LBW), and birth of a small for gestational age (SGA) newborn were slightly but significantly increased (preterm birth 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) [150].
The availability of parenteral and enteral nutrition has reduced maternal morbidity, and mortality is virtually nonexistent in patients 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) [117,159,164-168]. Esophageal tears (Mallory-Weiss), esophageal rupture, splenic avulsion, 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 patients with persistent severe vomiting [169-176]. An association between second-trimester hyperemesis gravidarum and placental dysfunction (eg, preeclampsia, abruption, SGA) was reported in a population-based cohort study [177]. It is unclear whether there is a small increase in risk of perinatal death [150,178].
There can be significant psychosocial morbidity, including substantial effects on ability to work outside the home, household duties, parenting activities, and social interaction [179-182]. The risk for developing postpartum depression also appears to be increased [149,183]. In a study of 808 individuals who completed a survey on a hyperemesis gravidarum website, 15 percent reported at least one termination due to the disease [184]. The burdens of caregiver time and use of health care resources also need to be considered.
In a retrospective study, patients with hyperemesis gravidarum who delivered by cesarean appeared to be at increased risk for postoperative nausea and vomiting, which tended to be more severe compared with those with no history of hyperemesis, even after adjustment for clinically significant confounding factors [185]. These findings should be confirmed in a prospective study. Prophylaxis for postoperative nausea and vomiting is routinely administered before or during cesarean birth, but a specific approach for patients with hyperemesis has not been studied. Patients with a history of hyperemesis gravidarum may need higher doses of antiemetic prophylaxis (eg, ondansetron 8 mg every 8 hours scheduled for 24 hours or metoclopramide 10 mg every 8 hours then as needed to prevent nausea/vomiting). It is important to remind patients that loss of appetite is the first sign of nausea/vomiting, and they should take the ondansetron before it worsens. They need to stay ahead of nausea because it is easier to prevent than to relieve after it occurs. (See "Anesthesia for cesarean delivery", section on 'Preventing nausea and vomiting' and "Postoperative nausea and vomiting".)
Long-term outcomes
●Offspring – Although long-term follow-up data are limited, NVP and hyperemesis do not appear to adversely affect cognitive development of offspring [186,187]. Hyperemesis has been associated with reduced insulin sensitivity in prepubertal children [188], and poor in utero nutrition has been associated with some cancers in adulthood [189]. Larger follow-up studies are needed to determine whether NVP 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 [190]. A study of offspring of individuals 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 [191]. Meta-analysis has not been useful in defining the long-term risks because of few studies are available and they are generally of low quality, with high heterogeneity and inconsistent findings [192].
●Maternal – There are no high-quality data on long-term maternal outcomes. An association between hyperemesis and a decreased risk of cancer has been observed [193,194]. Patients with hyperemesis appear to have a similar risk of cardiovascular death as those without this disorder [194].
Recurrence — The disorder is likely to recur in subsequent pregnancies [162,195-197], usually with similar severity. Population-based series reported the risk of recurrent hyperemesis in a second pregnancy was 15, 20, 24, and 89 percent in patients with previous hyperemesis [162,195,198,199], but only 0.7 percent in those with no such history [195]. Another study contacted individuals who had one pregnancy complicated by hyperemesis gravidarum and registered on an internet site sponsored by the Hyperemesis Education and Research Foundation [196]. Of 100 respondents, 57 had become pregnant again, of whom 46 experienced recurrent severe nausea and vomiting; 37 individuals reported that they did not want to get pregnant a second time because of the recurrence risk of hyperemesis gravidarum.
PREVENTION — Ideally, all females of child-bearing age should be advised to take a daily multivitamin with folic acid beginning at least one month prior to conception; 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 [200-202]. 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 NVP, which suggests that managing these disorders prior to pregnancy might prevent or reduce the severity of symptoms [203]. (See "Medical management of gastroesophageal reflux disease in adults", section on 'Pregnancy and lactation'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nausea and vomiting of pregnancy".)
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
●Treatment algorithm – A stepwise approach to treatment of nausea and vomiting of pregnancy (NVP) is provided in the algorithm (algorithm 1). The steps are based on quality of 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.
●Behavioral interventions – Patients with nausea and vomiting should try to become aware of, and avoid, environmental triggers and foods which might provoke their symptoms. (See 'Management of nausea as the primary symptom' above.)
●Management of mild nausea and vomiting
•Acupuncture and acupressure – 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.)
•Initial therapy – Where available, we suggest doxylamine-pyridoxine combination therapy for initial pharmacologic treatment of nausea of pregnancy (Grade 2B). If not available, we suggest pyridoxine, adding doxylamine succinate if pyridoxine alone is not effective. (See 'Doxylamine-pyridoxine' above and 'Pyridoxine (vitamin B6) monotherapy' above.)
•Second-line therapy – If nausea is accompanied by vomiting but without hypovolemia, we suggest adding diphenhydramine 25 to 50 mg orally every four to six hours (Grade 2C). If symptoms do not improve, we suggest adding a dopamine antagonist (prochlorperazine, metoclopramide) (Grade 2C). (See 'Add a dopamine antagonist' above.)
•Third-line therapy – If vomiting persists but without hypovolemia, we discuss the potential risks and effectiveness of oral or intravenous ondansetron in treating nausea and vomiting on a case-by-case basis in patients less than 10 weeks of gestation, given controversies about a potential small increase in risk of congenital anomalies. Ideally, a combination of two agents should be tried and found to be unsuccessful before initiating ondansetron in pregnancies less than 10 weeks. (See 'Ondansetron' above.)
●Management of vomiting resulting in hypovolemia
•Trial of outpatient therapy – For patients with vomiting, hypovolemia, and normal electrolyte levels and acid-base balance, a trial of replacement fluid and intravenous antiemetic therapy in the emergency medicine department is reasonable.
•Candidates for hospitalization – Hospital admission is appropriate for those with persistent vomiting after replacement fluid and intravenous antiemetic therapy, as well as patients who present with 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, ability to comply with the management plan, and ability to obtain and have access to outpatient resources (ie, home health care, infusion pump for administration of intravenous ondansetron, etc). (See 'Management of vomiting without hypovolemia' above.)
•Pharmacotherapy
-Ondansetron – For patients who are hospitalized because of hypovolemia, we suggest intravenous ondansetron (Grade 2C). Before 10 weeks of gestation, controversies about a potential small increase in risk of congenital anomalies should be discussed. (See 'Pharmacotherapy' above and 'Ondansetron' above.)
-Thiamine supplements – Thiamine supplements should be added to the intravenous replacement fluid solution to prevent Wernicke's encephalopathy. (See 'Vitamins and minerals' above.)
-Role of glucocorticoids – We reserve use of a short course of glucocorticoids, in addition to the patient's current antiemetic medications, for treatment of refractory symptoms after the first trimester. (See 'Glucocorticoids' above.)
•Alimentation
-Oral – We suggest a short period of gut rest during volume replacement, followed by reintroduction of oral intake with liquids and bland, low-fat foods. (See 'Replacement fluid therapy and nutrition' above and 'Dietary changes' above.)
-Enteral and parenteral – 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 patients who cannot maintain their weight because of vomiting and despite a step-wise trial of pharmacologic interventions. (See 'Tube feeding and parenteral nutrition' above.)
●Prevention – We suggest that females of child-bearing potential take a multivitamin with folic acid to help prevent NVP (Grade 2C), as well as for reducing the risk of neural tube defects. (See 'Prevention' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Susan Ramin, MD, and Jerrie S Refuerzo, MD, who contributed to an earlier version of this topic review.
