Nausea and vomiting of pregnancy: Treatment and outcome

INTRODUCTION — 

Management of patients with nausea and vomiting of pregnancy (NVP) depends upon symptom severity, the impact of symptoms on health and quality of life, and the safety of treatment for both mother and fetus. NVP is typically a self-limited condition and not associated with adverse pregnancy outcomes.

Treatment approaches commonly include conservative measures (dietary and lifestyle modifications) and/or medication(s). Patients who fail to respond to outpatient medical management may require hospitalization for parenteral fluids and medications. Early intervention and treatment of these patients may prevent progression to hyperemesis gravidarum, which, although rare, may require enteral or parenteral nutrition, a trial of psychiatric medications if the patient has psychiatric comorbidities, or corticosteroids or gabapentin in refractory cases [1,2].

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 NVP are discussed separately. (See "Nausea and vomiting of pregnancy: Clinical findings and evaluation".)

ASSESSMENT OF SEVERITY AND TREATMENT GOALS — 

NVP severity should be assessed at each patient encounter as the severity of symptoms, such as the frequency of vomiting, can vary from day to day. Although there is no standard definition of, or criteria for, diagnosis of hyperemesis gravidarum, these patients typically present with weight loss (more than 5 percent prepregnancy weight); clinical signs of dehydration and volume depletion (eg, tachycardia, orthostatic hypotension); laboratory abnormalities (eg, electrolyte, thyroid, and liver abnormalities; ketonuria); and nutritional deficiencies. (See "Nausea and vomiting of pregnancy: Clinical findings and evaluation", section on 'Evaluation' and "Nausea and vomiting of pregnancy: Clinical findings and evaluation", section on 'Scoring systems'.)

The goals of treatment are to:

●Reduce severity of symptoms and improve quality of life.

●Correct hypovolemia, ketonuria and electrolyte abnormalities, if present.

●Prevent serious complications of persistent vomiting, including, but not limited to, vitamin deficiencies, electrolyte abnormalities, or weight loss.

●Minimize the potential fetal effects of maternal pharmacotherapy.

MANAGEMENT OF NAUSEA AS THE PRIMARY SYMPTOM — 

For patients whose primary symptom is nausea, the initial treatment approach involves counseling on conservative measures, such as dietary and lifestyle changes, and trigger avoidance. If conservative measures fail, initiating pharmacotherapy may avoid progression of symptoms (algorithm 1 and table 1).

Conservative interventions

Dietary changes

Meals and snacks — Advise patients to:

●Eat before, or as soon as, they feel hungry to avoid an empty stomach, which can aggravate nausea [3]. 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). Foods with protein are more likely to prevent nausea compared with carbohydrates alone [4,5]. Don't skip meals.

●Consume meals and snacks slowly and in small amounts every one to two hours to avoid gastric distention, which can aggravate nausea in some patients [6]. Rinsing the mouth with water, brushing teeth, or sucking on peppermint candies may reduce postprandial nausea [7].

●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, bland, low-fat, dry, and/or salty (eg, nuts, pretzels, crackers, cereal, toast, rice) [3,6,8]. (See 'Diet' below.)

In the general population, nausea related to delayed gastric emptying (gastroparesis) improves with a diet consisting of low-fat foods, soluble fiber, and liquids (including pureed food) since they are more readily emptied by the stomach [9]. However, it is not known to what degree gastric emptying and dysfunction account for symptoms experienced by patients with NVP.

Fluids — Advise patients to:

●Consume fluids at least 30 minutes before or after solid food to minimize the sensation of stomach fullness [6].

●Choose fluids that are cold (or partially frozen), clear, and carbonated or sour. Popsicles and ginger ale are often well tolerated. However, some patients do not tolerate carbonated beverages because release of carbon dioxide can cause gastric distention and aggravate symptoms. Some patients find aromatic liquids, such as lemon, mint, or peppermint tea, more tolerable and helpful in reducing nausea.

●Consume fluids in small amounts; using a straw or very small cup sometimes helps. Small volumes of electrolyte-replacement sports drinks, if tolerated, can be used to replace both fluids and electrolytes.

Trigger avoidance — Avoiding environmental triggers is a key intervention for reducing the symptoms of NVP, along with dietary changes [8].

●Examples of some triggers include stuffy rooms, odors (eg, perfume, chemicals, food, smoke) [10], heat, humidity, noise, and visual or physical motion (eg, flickering lights, driving) [11]. Lying down soon after eating and lying on the left side are potentially aggravating factors because these actions may delay gastric emptying [6]. Quickly changing position and not getting enough rest/sleep may also aggravate symptoms [12].

●Cold solid foods tend to be more tolerable than hot solid foods because they have less odor and require less preparation time (ie, shorter exposure to the trigger if patients are preparing their own meals) [6].

●Brushing teeth after a meal [7], spitting out saliva, and frequently rinsing the mouth can be helpful. Switching to a different toothpaste may help those for whom strongly flavored toothpaste is a trigger.

●Taking prenatal vitamins with/after food, and specifically with a snack before going to bed, or in the morning after breakfast, may be helpful [13]. Some patients find chewable prenatal vitamins more tolerable than tablets or capsules. Prenatal vitamins/supplements containing iron should be avoided until symptoms resolve, as iron causes gastric irritation and can provoke nausea and vomiting [14]. 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 "Preconception and prenatal folic acid supplementation".)

Ginger supplements — Patients can try ginger-containing foods (eg, ginger lollipops, ginger tea, foods or drinks containing ginger root or syrup). Powdered ginger is not available as a standard pharmacologic-grade ginger preparation [15]; 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 [16]. In meta-analyses of randomized trials, ginger improved nausea compared with placebo but did not significantly reduce vomiting [17,18].

Acupuncture, acupressure, or acustimulation — The available evidence on these measures is limited and available studies have methodological weaknesses. Although data do not prove a definitive benefit, we would not discourage use if a patient wants to try one or more of these measures since they may be helpful (even if by a placebo effect) and are unlikely to be harmful.

P6 acupressure wristbands (picture 1) have become a popular self-administered intervention [19]; however, 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 [20]. One reason may be that a strong placebo effect has been observed in patients who receive sham therapy [21-24]. A randomized trial noted modest statistically significant improvements in Pregnancy-Unique Quantification of Emesis (PUQE) scores (table 2) with acupuncture, doxylamine-pyridoxine, and the combination of both over the 14-day treatment course compared with sham acupuncture, placebo, and sham acupuncture plus placebo (mean difference -0.7, -1.0, and -1.6 points, respectively) [25]. Limitations of the trial were that the placebo effects of intervention, including placebo interventions, and natural regression of NVP were not evaluated.Self-administered nerve stimulation therapy over the volar aspect of the wrist at the P6 acupressure point using a commercial device showed mixed results in two randomized trials [26,27].

Other — Psychotherapy can be a useful adjunctive therapy, as it may reduce distress caused by nausea, the pregnancy, and other coincident events [28,29]. It is particularly useful when psychological sources of anxiety are identified and can be ameliorated.

Initial pharmacotherapy

Pyridoxine (vitamin B6) monotherapy — We suggest pyridoxine as initial pharmacotherapy of nausea. Pyridoxine can improve nausea, has a good safety profile with minimal side effects, and can be obtained over the counter without a prescription.

●Dose – As a single agent, the typical pyridoxine dose is 10 to 25 mg orally every six to eight hours, as needed. Where the 10 mg tablet is unavailable, the 25 mg tablet can be used safely (splitting the tablet can be difficult).

This dose is substantially less than doses potentially associated with maternal side effects. Sensory neuropathy has been reported with chronic pyridoxine intake at doses >500 mg/day [30,31], but cumulative doses up to 500 mg/day appear to be safe for the pregnant individual [32]. 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 [33]. Pyridoxine 100 mg/kg was not teratogenic in animal studies [34].

Systematic reviews of randomized trials and/or controlled studies have reported that pyridoxine (vitamin B6) improves mild to moderate nausea but does not significantly reduce vomiting [35-40]. 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 when given together [41]. Although vitamin B6 levels decrease as gestation advances, a correlation between maternal vitamin B6 levels and incidence or severity of nausea has not been established [42].

Doxylamine-pyridoxine — We suggest the combination doxylamine-pyridoxine when pyridoxine treatment alone fails to improve nausea. Formulations of doxylamine-pyridoxine are available under various names and as extended-release tablets (eg, Diclectin in Canada, Diclegis and Bonjesta in the United States).

●Dose – The typical dose starts with two extended-release tablets (Diclegis; each tablet contains doxylamine 10 mg and pyridoxine 10 mg) at bedtime [43,44]. 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 midafternoon, two tablets at bedtime). 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 [45].

A higher dose extended-release tablet containing 20 mg of doxylamine succinate and 20 mg of pyridoxine (Bonjesta) is also available. One tablet is taken at bedtime, and if symptoms persist into the next day, one additional tablet is taken in the morning.

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 can be used off-label as an antiemetic. Pyridoxine (vitamin B-6) 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 [20] and appears to be more effective than either therapy alone. Less information is available on doxylamine alone, but available data are reassuring [46,47]

Unproven and possibly harmful interventions

●Alternative and complementary treatments – Most alternative and complementary treatments 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 [48]. Nzu may be sold under such names as Calabash clay, Calabar stone, Mabele, Argile, or La Craie.

●Cannabis (marijuana) – Cannabis use during pregnancy has been increasing, and pregnant individuals increasingly self-report using it to alleviate the symptoms of NVP [49]. Medical marijuana is not safer than recreational marijuana and there are no indications for its use in pregnancy. Although cannabis has been used to mitigate nausea and vomiting in nonpregnant individuals, the American College of Obstetricians and Gynecologists and public health authorities advise pregnant individuals and those considering becoming pregnant to avoid using it or other cannabinoids because of fetal safety concerns [50,51]. Individuals may not receive this information from cannabis dispensary employees, some of whom have been found to endorse its use for pregnant people with NVP [52]. Some individuals who have used cannabis long-term experienced cannabinoid hyperemesis syndrome, which presents with nausea and vomiting and may mimic or exacerbate NVP. Potential adverse effects of cannabis use in pregnancy are reviewed separately. (See "Substance use during pregnancy: Overview of selected drugs", section on 'Cannabis (marijuana)'.)

MANAGEMENT OF NAUSEA AND VOMITING WITHOUT HYPOVOLEMIA — 

Patients with persistent nausea and dry heaves or occasional vomiting can benefit from more intensive pharmacotherapy, as it can help them tolerate an appropriate level of fluid intake (ie, fluid intake that exceeds fluid losses), as well as food intake.

Initial approach — Patients with nausea and vomiting who are not hypovolemic (able to keep down some fluids; no lassitude, postural dizziness, thirst, tachycardia, decreased urine volume and frequency) are likely to have normal or near normal laboratory results (eg, BUN, electrolytes, acid-base balance). A reasonable approach in this setting is to discuss combining conservative measures with doxylamine-pyridoxine as described above, rather than pyridoxine alone. (See 'Dietary changes' above and 'Trigger avoidance' above and 'Doxylamine-pyridoxine' above.)

Additional pharmacotherapeutic choices — If conservative measures plus doxylamine-pyridoxine are ineffective, then other medications with reported efficacy and a good maternal-fetal safety profile are tried in a stepwise progression. Doxylamine-pyridoxine is continued if partially effective and discontinued if ineffective. In many patients, a combination of medications is necessary to control symptoms and improve quality of life (algorithm 1 and table 1) [53,54].

When initiating a new medication, we typically continue it for a week to determine whether symptoms are improving. If the patient does not have adequate improvement, then adding another class of medication to the existing regimen is necessary, with careful monitoring for side effects while trying different combinations of pharmacotherapies to see what works.

Safety profiles, patient tolerance, and cost in the choice of pharmacotherapeutic medications for management of NVP should be considered [55]. Historically, pregnant individuals have been excluded from most clinical drug trials, thus, only limited data exist to support the safety of medications used to treat NVP. A number of reports have demonstrated that antiemetic therapy is more effective than placebo and does not increase the incidence of congenital anomalies [12,20,37,38,54,56,57]. Well-designed comparative trials show no clear superiority of one medication over another.

Add an antihistamine (H1 antagonists) — We suggest diphenhydramine or dimenhydrinate 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. Common side effects of antihistamines include sedation, dry mouth, lightheadedness, and constipation. Antihistamines should be avoided in patients taking ondansetron or other medications that prolong the QT interval.

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 [57].

The safety of antihistamines was affirmed in a meta-analysis that examined the association between histamine 1 (H1) antihistamine use and major malformations [58]. 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.

Diphenhydramine — Diphenhydramine 25 mg can be given orally, intravenously, or intramuscularly every four to six hours or 50 mg orally, intravenously, or intramuscularly every six to eight hours, as needed. If the patient is taking doxylamine, the total dose of diphenhydramine should not exceed 100 mg/day to reduce the risk of side effects. Alternatively, discontinue doxylamine if it was completely ineffective.

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 [46,59,60].

Dimenhydrinate — Dimenhydrinate 25 to 50 mg can be given orally every four to six hours, as needed. Otherwise, 50 mg is administered intravenously over 20 minutes or 50 mg is administered rectally (where available [61]) every four to six hours, as needed. If the patient is taking doxylamine, the total dose of dimenhydrinate should not exceed 200 mg/day to reduce the risk of side effects. Alternatively, discontinue doxylamine if it was completely ineffective.

Available safety data are generally reassuring that it is not a teratogen [46,59,60,62].

Other antihistamines

●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 at least one country [63].

Meclizine can be given 25 mg orally every four to six hours, as needed. 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 [64-66]. It has caused cleft palate in rats but at exposures far higher than those used therapeutically.

●Scopolamine patch is used to prevent motion sickness and postoperative nausea and/or vomiting. There are no data on its use for NVP. Scopolamine should be avoided in patients with preeclampsia with severe features as eclamptic seizures have been reported after parenteral administration [67]; however, NVP typically occurs much earlier in pregnancy than preeclampsia so patients are unlikely to have both conditions concurrently.

Add a dopamine antagonist — Several types of dopamine receptor antagonists can be used for the treatment of NVP. These medications have the advantage of being available in numerous formulations, which enables administration in patients without adequate IV access. 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 [68]. We do not use subcutaneous pumps for timed release of metoclopramide. Although this approach has been reported to be effective for outpatient management of NVP, experience is very limited [69]. 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.

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 a randomized trial, dystonia was more common with promethazine than metoclopramide (14 in 73 [19.2 percent] versus 4 in 70 [5.7 percent]) [70]. Use of metoclopramide with diphenhydramine or hydroxyzine may mask a dystonic reaction.

Higher dose, older age, and female sex are risk factors for developing side effects [71], but tardive dyskinesia (involuntary and repetitive movements of the body) is rare in young patients. Early detection and abrupt discontinuation of metoclopramide are important for preventing permanent tardive dyskinesia; tapering is unnecessary. However, metoclopramide-induced tardive dyskinesia can be irreversible in some cases. More information on side effects is available separately. (See "Characteristics of antiemetic drugs", section on 'Benzamides'.)

In randomized trials of patients with hyperemesis, metoclopramide 10 mg was as effective as promethazine 25 mg [70] 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.

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. Other antiemetics are preferred when parenteral therapy is indicated. If administered parenterally, deep intramuscular administration is the preferred route. The intravenous route of administration should only be used as a last resort because inadvertent intra-arterial 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 and maternal efficacy in relief of both nausea and vomiting have been reported in most studies including large numbers of patients [57,70,76-79]. Disadvantages include prominent sedation and risk of dystonic reactions. These risks are increased with prolonged use and high doses. Use of promethazine appears to lower the seizure threshold, which may be important in patients with seizure disorders or in the rare patient with both preeclampsia and NVP in the second half of pregnancy.

There are conflicting reports regarding a potential risk of neonatal respiratory depression following the administration of promethazine during labor. 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 NVP.

Prochlorperazine — Prochlorperazine 5 to 10 mg orally, intravenously, or intramuscularly every six hours or 25 mg per rectum every 12 hours, as needed, appears to benefit some patients [74].

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 [80].

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. Overall, prochlorperazine is well tolerated with rare serious side effects, although QT prolongation is a potential side effect.

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 early 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

●Pregnancies <10 weeks of gestation – For patients at <10 weeks of gestation whose symptoms are refractory to the medications discussed above, the American College of Obstetricians and Gynecologists recommends discussing the available data (see below) and weighing the potential risks against the effectiveness of ondansetron in treating nausea and vomiting on a case-by-case basis [1]. Some other organizations have recommended avoidance in the first trimester or use as a second-line agent only [81,82].

●Dose – Ondansetron 4 mg can be taken orally or intravenously by bolus injection every eight hours, as needed. The dose can be increased, if necessary, to 8 mg IV or orally every 8 to 12 hours. 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 [83]. 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 [84]. At doses above 16 mg, 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 [85]. More detailed information on side effects is available separately. (See "Characteristics of antiemetic drugs", section on '5-HT3 receptor antagonists'.)

Serotonin syndrome is a very rare but 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)".)

●Efficacy – 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 [86]. In another randomized trial, it was more effective than metoclopramide for reducing vomiting but not nausea [87].

●Risk of congenital anomalies – The use of ondansetron in pregnancy is probably safe. Although some studies have reported increases in the risk of orofacial clefts and ventricular septal defects [88-92], others have not and the absolute increase above baseline may be only 0.03 and 0.3 percent, respectively [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 congenital malformations overall after adjustment for known confounders (RR 1.01, 95% CI 0.98-1.05) [88]. 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].

•In a 2021 meta-analysis of cohort studies including over 450,000 pregnancies in three countries (Canada, United Kingdom, United States), the overall risk of major congenital malformations was not significantly increased (OR 1.06, 95% CI 0.91-1.22) [96].

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 in symptoms in pregnant patients treated with intravenous or transdermal granisetron [97]. The transdermal formulation was convenient for patients who could not tolerate oral pharmacotherapy and effective, but it is very expensive.

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'.)

Human data on reproductive effects are sparse [98-100]. 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 [98]. 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 [99].

Adjunctive therapy

Acid-reducing agents — Acid-reducing medications can be used as adjunctive therapy (table 1). 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 [101]. In many patients with significant NVP, the ability to ascertain whether 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 [102]. Sucralfate (aluminum sucrose sulfate) is likely safe during pregnancy because it is poorly absorbed.

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 [103]. Rates of congenital malformations, low birth weight, and preterm birth (PTB) were similar for exposed and nonexposed fetuses. (See "Initial management of gastroesophageal reflux disease in adults", section on 'Patients who are pregnant or breastfeeding'.)

There is less experience using proton pump inhibitors (PPIs; eg, lansoprazole orally or esomeprazole intravenously or orally) during pregnancy. Taking a PPI at least one hour prior to the evening meal may help control symptoms. Overall, they probably have a good maternal-fetal safety profile [104,105]. However, use with caution in patients with kidney disease, as some studies have linked chronic use of PPIs with an increased risk of acute kidney injury and end-stage kidney disease [106].

Safety data for acid-reducing agents are reviewed in more detail separately. (See "Initial management of gastroesophageal reflux disease in adults", section on 'Patients who are pregnant or breastfeeding'.)

MANAGEMENT OF VOMITING WITH HYPOVOLEMIA

General principles

●Patients who are vomiting most food and liquids should be clinically evaluated to assess their volume and metabolic status, exclude other diagnoses that could account for their symptoms, and guide fluid and electrolyte replacement and pharmacologic therapy. (See "Nausea and vomiting of pregnancy: Clinical findings and evaluation", section on 'Evaluation'.)

●We instruct patients with NVP to go 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 hospital admission is reasonable for patients with normal electrolyte levels and normal acid-base balance.

Hospital admission for close monitoring and ongoing treatment is appropriate for those with persistent inability to tolerate oral intake resulting in hypovolemia requiring intravenous replacement fluid, and failure of oral and/or intravenous antiemetic therapy. Patients who present with laboratory abnormalities requiring repletion, vitamin deficiencies requiring supplementation, or multiple outpatient visits to the emergency department or obstetric care clinic should also be considered for inpatient management [2]. The goal of inpatient management is to restore oral intake to enable adequate hydration and nutrition and use of oral antiemetic therapy after discharge.

The decision to admit versus discharge to home also needs to be individualized based on the patient's ability to access outpatient resources (eg, home health care, infusion pump for administration of intravenous replacement fluids and medications at home), ability to comply with recommendations, and personal preferences [107].

●These patients and their families/close contacts often need emotional support to help deal with stress and anxiety that often accompanies maternal illness and its effect on the fetus, as well as the disruption to their home- and work-related activities and overall quality of life [108]. Support resources are available in some communities and online (see 'Support resources' below). In addition, referral for social work or care manager consultation may be indicated. In some cases, psychosocial counseling can be helpful to teach the patient relaxation and coping techniques and/or address underlying psychopathology, if present [109]. A nutrition or dietary consultation also should be considered.

●Most hospitalized patients respond to intravenous hydration and a short period of gut rest, followed by reintroduction of oral intake and pharmacologic therapy. Relief of symptoms is common within one to two days of replacement fluid therapy [56]. Relocation from the home environment, as well as replenishment of fluids and electrolytes, may contribute to palliation of symptoms. However, a single episode of inpatient treatment often is 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 [110]. To reduce this risk, 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 these measures, the clinician needs to be vigilant about excluding underlying disorders that could account for or contribute to their symptoms. (See "Nausea and vomiting of pregnancy: Clinical findings and evaluation", section on 'Differential diagnosis'.)

Fluid and electrolyte replacement — Hypovolemia due to persistent vomiting and inability to tolerate fluids is often associated with electrolyte abnormalities. We suggest a baseline electrocardiogram in patients with electrolyte abnormalities requiring repletion.

●Fluids and electrolytes (algorithm 2)

•Fluid replacement – We aggressively rehydrate with up to 2 liters of IV crystalloid over two hours. Lactated Ringer's solution is preferred due to decreased incidence of acute kidney injury compared with normal or isotonic saline [111]. After initial resuscitation, IV fluids can be titrated to maintain urine output of at least 100 mL/hour or continued at a rate of 125 to 150 mL/hour, with close monitoring of oral intake and urine production.

We switch to dextrose 5 percent in 0.45 percent saline with 20 mEq potassium chloride at 150 mL/hour for patients with normal potassium levels.

The optimum replacement fluid regimen has not been well-studied. 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 reported no 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 prior to rehydration [112]. A limitation of this trial is that only 60 percent of the patients had severe disease (eg, weight loss ≥5 percent body weight).

•Treatment of hyponatremia – For patients with asymptomatic or symptomatic mild hyponatremia (serum sodium level >120 mEq/L) and at low risk of complications from untreated hyponatremia or from excessively rapid correction of hyponatremia, isotonic/normal saline or near-isotonic Ringer's lactate infusion as described above is adequate. Correct hyponatremia slowly while monitoring electrolytes. Management of the rare patient with more severe hyponatremia is discussed separately. (See "Overview of the treatment of hyponatremia in adults".)

•Treatment of hypokalemia – For patients with asymptomatic mild hypokalemia (serum potassium level 3.0 to 3.4 mEq/L), 10 to 20 mEq of potassium chloride is administered in intravenous fluids two to four times per day, depending upon the severity of the hypokalemia. It can also be administered as 40 mEq/L IV over four hours. Potassium chloride must be given more rapidly to symptomatic patients and those with serum potassium less than 3.0 mEq/L: 20 mEq/hour or 60 mEq over six hours can be administered to these patients. Sequential monitoring of the serum potassium level is essential to determine the response. Management of the rare patient with more severe hypokalemia is discussed separately. (See "Clinical manifestations and treatment of hypokalemia in adults", section on 'Treatment'.)

Vitamins and minerals

●Thiamine – To mitigate the risk of Wernicke encephalopathy, 100 to 200 mg thiamine (vitamin B1) should be added to the initial fluid resuscitation and then daily thereafter while the patient is taking nothing-by-mouth or for two to three days in patients with oral intake [113,114]. If Wernicke encephalopathy is suspected, treat with 200 to 500 mg IV every eight hours for 2 to 7 days, followed by 250 mg once daily for an additional 3 to 5 days, followed by maintenance therapy 100 mg daily until no longer at risk for deficiency [115]. Thiamine should be administered before administering glucose. (See "Wernicke encephalopathy", section on 'Treatment'.)

●Other vitamins – A multivitamin (MVI) is given intravenously each day. We add 0.6 mg folic acid to one liter to bring the folic acid total to 1 mg and we add vitamin B6 (pyridoxine) 25 mg to every liter (see 'Pyridoxine (vitamin B6) monotherapy' above). Intravenous MVI has 150 mcg of vitamin K so 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 (<1.8 mg/dL) by giving a magnesium sulfate bolus based on the serum level:

•For a magnesium level of 1.6 to 1.7 mg/dL, give magnesium sulfate 2 g over one hour

•For a magnesium level of 1.3 to 1.5 mg/dL, give magnesium sulfate 4 g over two hours

•For a magnesium level of 1.1 to 1.2 mg/dL, give magnesium sulfate 6 g over three hours

•For a magnesium level of <1.0 mg/dL, give magnesium sulfate 6 g over three hours then recheck serum magnesium level and repeat if <1.2 mg/dL

When the normal serum magnesium level (1.8 to 2.0 mg/dL) is 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.

Pharmacotherapy — The combination of acid-reducing therapy and antiemetic therapy significantly improves hyperemesis gravidarum symptoms in patients with acid reflux [101] (see 'Acid-reducing agents' above). Proton pump inhibitors are acceptable medications for acid control, with caution in patients who have kidney disease if chronic use is anticipated. Typically various combinations of antihistamines, dopamine antagonists, and serotonin antagonists need to be tried before the combination that works is found. It is crucial to be aware of the potential antiemetic medication side effects and interactions (table 3).  

Ideally, one medication is scheduled and a second is administered as needed for breakthrough symptoms. We begin ondansetron 4 mg intravenously (IV push) once every eight hours upon hospitalization for intravenous fluid therapy and may increase to 8 mg IV every eight hours. After the patient has stabilized, ondansetron is discontinued. Per American College of Obstetricians and Gynecologists' guidelines, the risk-benefit ratio should be considered for those patients less than 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]. Some individuals, especially those with severe or refractory symptoms, will require multiple scheduled medications, and dosing should be titrated with the aim of using the lowest dose and fewest medications necessary to maintain symptomatic control.

Parenteral medications can be discontinued and oral medications started after 24 to 48 hours of gastrointestinal rest and when the patient is tolerating oral intake. Oral medication management should include a scheduled medication and a medication for breakthrough symptoms.

Diet — A diet that attempts to minimize nausea and vomiting can be resumed after a short period of gut rest. If a registered dietician or nutrition service is available, consultation before discharge can help guide the reintroduction of foods, especially for patients with comorbid conditions such as diabetes or who would benefit from more education on the most appropriate diet for managing their symptoms. There is no single diet that is recommended above others, but small meals every two to four hours is a reasonable starting point.

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 to prevent nausea. Additional dietary manipulations are described above. (See 'Dietary changes' above.)

Patients who have not eaten for several days may develop edema when resuming feeding with carbohydrates [116]. This results from the retention of sodium during fasting combined with enhanced sodium resorption due to the actions of insulin once carbohydrates are reintroduced [117]. No intervention is required; the edema will gradually resolve. In significantly malnourished patients, the initial stage of oral, enteral, or parenteral nutritional replenishment can cause electrolyte and fluid shifts that can precipitate serious medical complications (refeeding syndrome) [118-120]. (See "Anorexia nervosa in adults and adolescents: The refeeding syndrome", section on 'Refeeding syndrome'.)

Support resources — Connecting patients with advocacy organizations is an additional means of support. The Hyperemesis Education and Research Foundation has numerous resources for providers, patients, and their families.

Discharge — Ideally, a patient who has been admitted for treatment is sent home when they have been stabilized on a scheduled oral antiemetic. They also should be given a second medication that has been effective for breakthrough symptoms. This prescribed regimen is continued for at least a week, or until the patient is beyond the first trimester, at which time they can be reevaluated to see if medications can be tapered or discontinued.

It is important to ensure that the patient and family members or support persons understand when and how to take the medications. The patient should be counseled that adhering to the prescribed medications upon discharge is crucial to prevent relapse and additional hospitalizations. Unfortunately, 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]. (See 'Management of stable and improving patients' below.)

MANAGEMENT OF PATIENTS WITH REFRACTORY SYMPTOMS

Consider testing for H. pylori infection — We consider Helicobacter pylori testing in patients unresponsive to standard therapy, who have symptoms beyond the first trimester, who require multiple hospitalizations, or who have symptoms of gastroesophageal reflux disease. Case reports and small series have reported improvement in symptoms in patients with severe disease after treatment of H. 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 of Helicobacter pylori infection 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.

Corticosteroids — A short course of corticosteroids can be added to the patient's current intravenous antiemetic regimen for treatment of refractory symptoms, given the risk of maternal side effects and uncertain efficacy. Corticosteroids are generally prescribed intravenously followed by a tapering period over a few days orally or intravenously, depending on the status of the patient; there is no one correct prescriptive practice. Corticosteroids can be stopped without a taper in the absence of a treatment response. Corticosteroid use may lead to hyperglycemia; therefore, blood glucose levels should be monitored in patients with preexisting and gestational diabetes. (See "Major adverse effects of systemic glucocorticoids".)

Methylprednisolone 125 mg intravenously followed by a tapering regimen of oral prednisone has been used [123]. 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. Methylprednisolone 16 mg orally three times a day for three days, followed by a tapering regimen (halving of dose every three days) to none during the course of two weeks was effective in a randomized trial [124]. Hydrocortisone was effective in another trial that used a daily dose of 300 mg intravenously for three days, followed by a tapering regimen of 200 mg intravenously for two days and then 100 mg intravenously for another two days, at which point steroids were discontinued [125].

The mechanism of action is not well understood [126-129], and there is a paucity of evidence that corticosteroids are effective [37,57]. 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 [123]. 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 [38]. We have also observed improvement in symptoms with corticosteroids use in some patients with refractory severe vomiting.

Corticosteroid use was associated with a slightly increased risk of oral clefts when administered before 10 weeks of gestation in early studies, but not more recent studies (see "Etiology, prenatal diagnosis, obstetric management, and recurrence of cleft lip and/or palate", section on 'Environmental factors'). If administered after 10 weeks, the palate has formed and is not at risk for developing defects. Although recent evidence is limited, shared decision-making and patient counseling are important when using corticosteroids between the sixth and ninth weeks of pregnancy, when the fetal palate is forming. The preferred corticosteroids for treatment of maternal disorders during pregnancy are hydrocortisone or prednisone because the placenta readily inactivates them, in contrast to betamethasone and dexamethasone [125].

Chlorpromazine — We use chlorpromazine in selected patients with refractory symptoms, such as those in whom the side effects of steroids may be more serious (eg, diabetes mellitus), because of the potential for serious adverse side effects. Chlorpromazine is a dopamine antagonist; maternal side effects are more frequent and/or severe compared with the other dopamine antagonists discussed above and include extrapyramidal reactions, orthostatic hypotension, anticholinergic effects, and altered cardiac conduction. (See 'Add a dopamine antagonist' above.)

The usual dose is 25 to 50 mg intravenously or intramuscularly or 10 to 25 mg orally every four to six hours.

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 [130]. No congenital anomalies were reported in 108 pregnancies. 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 [131]. The US Food and Drug Administration issued a boxed warning in 2001 [132], and the medication was removed from the European market in March 2001.

Gabapentin — The mechanism of action of gabapentin is unclear, but it is thought to involve the mitigation of calcium currents in central nausea and vomiting centers (ie, area postrema) by binding to the VGcc alpha-2/delta subunits of voltage-gated calcium channels that have been upregulated due to relevant central nervous system stressors that induce nausea and vomiting, such as chemotherapy, anesthesia, and even early pregnancy [133-135]. Other potential actions of gabapentin include modification of underlying autonomic nervous system pathology or gastric dysrhythmias and management of anxiety that is either preexisting or a result of hyperemesis gravidarum itself [136].

In a randomized double-blind trial comparing a seven-day course of oral gabapentin (1800 to 2400 mg/day) with an active comparator (either oral ondansetron 24 to 32 mg/day or oral metoclopramide 45 to 60 mg/day) in 21 patients with medically refractory hyperemesis gravidarum requiring intravenous hydration, gabapentin resulted in a 52 percent greater decrease in baseline adjusted total Motherisk-pregnancy-unique quantification of nausea and emesis score [134]. In addition, a review of human data on major congenital anomalies associated with first-trimester gabapentin monotherapy exposure reported a 1.7 percent incidence of major congenital anomalies, which was considered favorable when compared with the background rate of 2 to 4 percent among all births in the United States [137]. However, further study of the safety and efficacy of gabapentin is warranted before it can be recommended.

Mirtazapine and olanzapine — In refractory cases in which standard pharmacotherapeutic treatments are ineffective, the use of psychiatric drugs such as olanzapine and mirtazapine has been proposed [138]. It remains unclear whether psychiatric comorbidities predispose an individual to hyperemesis gravidarum or if hyperemesis gravidarum causes an exacerbation of symptoms in those with a history of a psychiatric disorder or precipitates the onset of depression, anxiety, or even posttraumatic stress disorder. Psychological responses can interact with hyperemesis gravidarum to exacerbate symptoms and response to available treatments [139-141].

●Mirtazapine is a noradrenergic and specific serotonergic antidepressant [140]. It acts on multiple receptors, including serotonergic and histaminergic receptors, with antidepressant, anxiolytic, antiemetic, sedative, and appetite-stimulating effects [142]. As a 5HT3 receptor antagonist, antinausea effects occur and anxiolysis occurs through 5HT2 receptor antagonism. H1 receptor antagonism causes antihistaminergic activities, which results in antidepressive effects, helps with insomnia, and augments the anxiolytic effects caused by blockage of 5HT2 receptors [138,140,143]. H1 receptor antagonism also can result in weight gain by stimulating the appetite, which is common with antidepressants in general [138,144].

Mirtazapine's antiemetic and weight-gain effects, in addition to its role as an antidepressant and anxiolytic, make it a reasonable option for management of refractory cases of hyperemesis gravidarum, especially with coexisting depression or anxiety. Studies have not shown an increased risk of major congenital anomalies with mirtazapine use in pregnancy, including use in the first trimester [145,146].

●Olanzapine is a second-generation atypical antipsychotic approved for treatment of psychotic disorders, bipolar disorder, and treatment-resistant depression. However, off-label uses include treatment of chemotherapy-induced and postambulatory surgery nausea and vomiting, cannabinoid hyperemesis syndrome, anorexia, acute agitation, and delirium [147]. Olanzapine acts by blocking numerous receptors, including dopaminergic, serotoninergic, and histaminergic receptors. Its antagonism at the 5HT3 receptor is similar to the actions of ondansetron. Antagonism at the 5HT2 receptor makes it potentially effective in treating patients with hyperemesis gravidarum with comorbid or subsequent development of depression or anxiety. In addition, 5HT2 and H1 receptor antagonism can stimulate appetite and lead to weight gain.

Olanzapine can be administered through numerous routes (oral, sublingual, intramuscular, IV). Common side effects include drowsiness, dizziness, fluid retention, constipation, dry mouth, akathisia, and hypotension. Data on the use of olanzapine for hyperemesis gravidarum are limited to a few case reports; however, the overall safety data for the use of second-generation antipsychotics such as olanzapine in pregnancy is increasing. Fetal safety data are largely reassuring [148-150], but one population-based cohort study found that first-trimester exposure to olanzapine was associated with an increased risk of major congenital anomalies, specifically of the musculoskeletal system [151]. Olanzapine can be considered in cases of severe hyperemesis gravidarum after other pharmacotherapeutics are found to be ineffective, particularly if the patient also has anxiety or depression, when potential benefit may justify any potential risk to the fetus.

Enteral and parenteral nutrition — Nutritional support during early pregnancy can reduce the frequency of late-pregnancy morbidities associated with hyperemesis gravidarum, but no data justify nutritional repletion solely for fetal benefit [142]. Patients with continued weight loss and symptoms refractory to the pharmacologic and nonpharmacologic interventions described above can be supported with enteral or parenteral nutrition (and intravenous fluids) [152,153]. These nutritional modalities typically are considered in the setting of persistent ketonuria, electrolyte abnormalities, suboptimal oral intake, altered maternal mental status, or prerenal acute kidney injury [142]. A threshold of 8 to 10 percent weight loss has been suggested for consideration of these other nutrition modalities.

Nutritional status and methods of alimentation 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. We begin with enteral nutrition and consider parenteral nutrition in patients with no improvement after five to seven days. Failure of enteral nutrition should occur before considering parenteral nutrition.

●Enteral nutrition – There are multiple ways to deliver enteral nutrition, including nasoenteric tubes (ie, nasogastric), nasojejunal or nasoduodenal tubes, and percutaneous endoscopy. Enteral nutrition with a nasogastric tube is preferred, but if not tolerated, a nasojejunal or nasoduodenal tube is another option. In addition to providing nutrition, either modality may relieve nausea and vomiting by bypassing the cephalic phase of digestion (ie, the stage in which the stomach responds to the sight, smell, taste, or thought of food) [154,155]. Pharmacotherapy can be useful as an adjunctive therapy. The mean time to resolution of vomiting was 4.5 days in retrospective studies, but weight did not stabilize/increase for another 3.6 days [155]. If a tube is not tolerated or needed for many weeks, percutaneous endoscopy gastrostomy or percutaneous endoscopic jejunostomy are minimally invasive procedures that can be effective, but site infection and tube dislodgement are potential risks.

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 [156]. In particular, nausea and vomiting symptoms and duration of hospital stay were similar in both groups. Enteral 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 of patients 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 adult patients: Enteral nutrition".)

●Parenteral nutrition – If enteral nutrition is unsuccessful or poorly tolerated, parenteral nutrition is the last resort. It is important to consider that parenteral nutrition is associated with a high rate of significant complications, including liver function aberrations, catheter-related sepsis, and thromboembolic events, as well as adverse neonatal outcomes.

Peripheral parenteral nutrition (PPN) typically is delivered by peripherally inserted central catheters (PICCs), whereas central parenteral nutrition is delivered by centrally inserted central catheters. PICCs can be used to avoid some of the complications of central access, but they are still associated with significant morbidity. PPN may be a reasonable alternative in patients with hyperemesis gravidarum who can tolerate some oral intake and are likely to be able to discontinue parenteral nutrition within 7 to 14 days [155]. Before considering parenteral nutrition via PICC or central access, a thorough discussion with the patient on the risks and benefits is necessary. If a joint decision is made to proceed with parenteral nutrition, close follow-up is essential.

A prolonged period of IV administration [157] or adequate protein-caloric parenteral nutrition generally requires a central venous access device [158,159]. Peripheral parenteral nutrition requires either a large volume and/or a high-fat formulation to provide the full complement of energy and protein requirements, but may be a reasonable alternative in patients with hyperemesis who can tolerate some oral intake and are likely to be able to discontinue parenteral nutrition within 7 to 14 days [155]. The American Gastroenterological Association has published a technical review and position statement on parenteral nutrition [160,161]. Indications/contraindications, access, formulations and their components, delivery, monitoring, and complications of parenteral nutrition are discussed separately. (See "Nutrition support in critically ill adult patients: Initial evaluation and prescription" and "Nutrition support in critically ill adult patients: Parenteral nutrition".)

Role of thromboprophylaxis — We do not administer thromboprophylaxis routinely. Although hyperemesis may be a risk factor for venous thromboembolism [162,163] and at least one guideline [164] recommends offering low molecular weight heparin thromboprophylaxis to patients hospitalized with hyperemesis (unless there is a specific contraindication), this recommendation is based on low-quality evidence, including expert opinion and case reports. However, thromboprophylaxis may be appropriate in selected patients at high risk for venous thromboembolism. (See "Venous thromboembolism in pregnancy: Prevention".)

MANAGEMENT OF STABLE AND IMPROVING PATIENTS — 

We continue the antiemetic medication regimen that has been effective until the patient has been completely asymptomatic (no nausea or vomiting) for at least a week or until beyond the first trimester. 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.

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. Collaboration with a registered dietician or a certified diabetic educator is ideal. (See "Management of type 1 diabetes mellitus in children during illness, procedures, school, or travel", section on 'Sick-day management'.)

The approach to patients with diabetes-related gastroparesis is reviewed separately. (See "Diabetic autonomic neuropathy of the gastrointestinal tract", section on 'Gastroparesis'.)

OUTCOME AND PROGNOSIS

Short-term outcomes

●Nausea and vomiting of pregnancy

•Pregnancy outcome – Although the maternal course can be long and tedious [165], NVP is typically not associated with adverse pregnancy outcomes in the absence of severe malnutrition [166].

-The frequency of congenital anomalies does not appear to be increased among offspring of patients with NVP or hyperemesis [92,167].

-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 were reduced by over 60 percent (odds ratio [OR] 0.36, 95% CI 0.2-0.42) [168]. However, 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 [169]. 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

•Pregnancy outcome – 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 [170-172]. 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 [173-177]. Patients who have less than 7 kg weight gain are more likely to have preterm birth (PTB)/low birth weight/small for gestational age (SGA) newborns [152,177,178]. When studies of patients with hyperemesis gravidarum were pooled without regard to severity or prepregnancy weight or catch-up weight gain, the risks of PTB <34 weeks and birth weight <1500 g were increased (OR 2.81, 95% CI 1.69-4.67 and OR 1.43, 95% CI 1.02-1.99, respectively), but there was no increase in stillbirth (OR 0.92, 95% CI 0.85–0.99) [179].

•Maternal morbidity – The availability of parenteral and enteral nutrition has reduced maternal morbidity, and mortality related to hyperemesis gravidarum 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) [173,180-185]. 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 [186-193]. An association between second-trimester hyperemesis gravidarum and placental dysfunction (eg, preeclampsia, abruption, SGA) was reported in a population-based cohort study [194]. It is unclear whether there is a small increase in risk of perinatal death [167,195].

There can be significant psychosocial morbidity, including substantial effects on ability to work outside the home, household duties, parenting activities, and social interaction [196-199]. The risk for developing postpartum depression also appears to be increased [166,200]. 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 [201]. The burdens of caregiver time and use of health care resources also need to be considered.

•Risk for postcesarean nausea and vomiting – 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 [202]. 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 – A 2022 meta-analysis of long-term outcomes of children born to mothers with hyperemesis found possible small increases in adverse health outcomes, including neurodevelopmental disorders, mental health disorders, and possibly testicular cancer but cautioned that few studies were available and were generally of low quality, with high heterogeneity and inconsistent findings [203]. A longitudinal study of 155 offspring of mothers with early pregnancy weight loss >5 kg usually occurring as a manifestation of hyperemesis gravidarum did not show an adverse effect on glucose or lipid levels or body mass index at five to six years of age, but diastolic blood pressure was 1.4 mmHg higher in this group [204].

More large follow-up studies are needed, using well-defined criteria for the severity of the disease and adjusting for key maternal characteristics, such as prepregnancy weight and weight gain during pregnancy. Long-term metabolic and cardiovascular outcomes should be evaluated since SGA birth has been linked to chronic disease in adult life [205].

●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 [206,207]. Patients with hyperemesis appear to have a similar risk of cardiovascular death as those without this disorder [207].

RECURRENCE RISK

●NVP is likely to recur in subsequent pregnancies [177,208-210], usually with similar severity.

●Five population-based studies reported the risk of recurrent hyperemesis in a second pregnancy was 15, 20, 24, 29, and 89 percent in patients with previous hyperemesis [177,208,211-213], but only 0.7 percent in those with no such history [208]. In one of these studies, the frequency of hyperemesis gravidarum recurrence at the third pregnancy was 55 percent [213].

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 [209]. Of 100 respondents, 57 had become pregnant again, of whom 46 (81 percent) 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 (MVI) with 0.4 to 0.8 mg 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 [214-216]. The positive effects of MVIs are likely due to the general optimization of nutritional status and metabolism. (See "Preconception and prenatal folic acid supplementation".)

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 [217]. (See "Initial management of gastroesophageal reflux disease in adults", section on 'Patients who are pregnant or breastfeeding'.)

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 5^th to 6^th 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 10^th to 12^th 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 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

●Assess symptom severity – Most pregnant people experience nausea with or without vomiting in early pregnancy. Symptom severity should be assessed at each patient encounter as it can vary from day to day and worsening symptoms may require pharmacotherapy, a change in pharmacotherapy, and/or intravenous fluids. (See 'Assessment of severity and treatment goals' above.)

●Treatment goals (see 'Assessment of severity and treatment goals' above):

•Reduce severity of symptoms and improve quality of life

•Correct hypovolemia, ketonuria and electrolyte abnormalities, if present

•Prevent serious complications of persistent vomiting (eg, vitamin deficiencies, electrolyte abnormalities, weight loss)

•Minimize the potential fetal effects of maternal pharmacotherapy

●Treatment algorithm – A stepwise approach to treatment of nausea and vomiting of pregnancy (NVP) is provided in the algorithm (algorithm 1 and table 1). The steps are based on quality of evidence of efficacy and safety profiles, but efficacy are low quality and safety data are limited.

•Nausea – For patients whose primary symptom is nausea, we discuss conservative measures (eg, dietary changes, trigger avoidance, ginger supplements, P6 acupressure wristbands). If these measures are inadequate, we suggest pyridoxine (Grade 2C). For patients with persistent bothersome symptoms on pyridoxine, we suggest doxylamine-pyridoxine (Grade 2C). (See 'Dietary changes' above and 'Trigger avoidance' above and 'Ginger supplements' above and 'Initial pharmacotherapy' above and 'Unproven and possibly harmful interventions' above.)

•Persistent nausea plus dry heaves or occasional vomiting – Patients with persistent nausea plus dry heaves or occasional vomiting can benefit from more intensive pharmacotherapy. If conservative measures plus doxylamine-pyridoxine are ineffective, then other medications with reported efficacy and a good maternal-fetal safety profile are tried in a stepwise progression. When initiating a new medication, we typically continue it for a week to determine whether symptoms are improving. If the patient does not have adequate improvement, then adding another class of medication to the existing regimen is necessary, with careful monitoring for side effects while trying different combinations of pharmacotherapies to find what works. (See 'Initial approach' above and 'Additional pharmacotherapeutic choices' above.)

•Vomiting but normal electrolyte levels and acid-base balance – Patients who are vomiting most food and liquids should be clinically evaluated to assess their volume and metabolic status and exclude other diagnoses that could account for their symptoms.

A trial of replacement fluid and intravenous antiemetic therapy before considering hospital admission is reasonable for those with normal electrolyte levels and acid-base balance. These patients and their families/close contacts often need emotional support to help deal with stress and anxiety that often accompanies maternal illness, as well as the disruption to their home- and work-related activities and overall quality of life. (See 'Management of vomiting with hypovolemia' above.)

•Persistent vomiting, abnormal electrolyte levels or acid-base balance – For many patients with persistent vomiting after an infusion of replacement fluid and intravenous antiemetic therapy, abnormal electrolyte levels, or abnormal acid-base balance, hospitalization is required. The decision to admit 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 'General principles' above.)

●Management of hospitalized patients

•Fluid replacement and thiamine – Patients with hypovolemia require fluid replacement with up to 2 liters of isotonic crystalloid fluids. Patients with prolonged vomiting are at risk for Wernicke's encephalopathy. While this is a rare complication, the consequences can be dire, and adding thiamine to fluid replacement is a safe and effective means to prevent it.

We then switch to maintenance fluid (eg, dextrose 5 percent in 0.45 percent saline with 20 mEq potassium chloride at 150 mL/hour) for patients with normal potassium levels. The infusion rate is adjusted to maintain a urine output of at least 100 mL/hour. (See 'Fluid and electrolyte replacement' above and 'Vitamins and minerals' above.)

•Ondansetron – For patients who are hospitalized because of hypovolemia, we suggest intravenous ondansetron (Grade 2C). (See 'Pharmacotherapy' above and 'Ondansetron' above.)

•Role of glucocorticoids – For patients with refractory symptoms after the first trimester, we suggest a short course of glucocorticoids (Grade 2C) in addition to the patient's current antiemetic medications. (See 'Corticosteroids' above.)

•Diet – A short period of gut rest is useful during fluid replacement, followed by reintroduction of oral intake with liquids and bland, low-fat foods. (See 'Dietary changes' above and 'Fluid and electrolyte replacement' above.)

-Enteral and parenteral – The timing for initiating enteral or parenteral nutrition is based upon clinical judgment. In general, enteral nutrition is preferred and begun in patients who cannot maintain their weight because of vomiting and despite a step-wise trial of pharmacologic interventions. (See 'Enteral and parenteral nutrition' above.)

●Outcome – In patients with NVP, the risk of congenital anomalies is not increased and the risk of miscarriage is decreased. In those with hyperemesis gravidarum, birth weight tends to be normal as long as prepregnancy weight was in the normal range and catch-up weight gain occurred later in pregnancy. Nausea and vomiting is likely to recur in subsequent pregnancies. (See 'Outcome and prognosis' 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.