hyperemesis gravidarum and

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Hyperemesis gravidarum and morning sickness

AuthorEdmund F Funai, MD

Section EditorCharles J Lockwood, MD

Deputy EditorVanessa A Barss, MD

Last literature review for version 17.1: enero 1, 2009 | This topic last updated: noviembre18, 2008

INTRODUCTION — Morning sickness and hyperemesis gravidarum are terms used to describe mildversus severe nausea and vomiting induced by pregnancy. Nausea is so common that it can beconsidered a normal physiological sign of early pregnancy. Nevertheless, the presence and severity ofnausea and vomiting significantly impact the pregnant woman's quality of life [1].

DEFINITIONS

Morning sickness — Some degree of nausea with or without vomiting occurs in 50 to 90 percent ofall pregnancies. The mean onset of symptoms is at five to six weeks of gestation, peaking at nineweeks, and usually abating by 16 to 18 weeks of gestation; however, symptoms continue until thethird trimester in 15 to 20 percent of gravida and until delivery in 5 percent [2,3]. Although the layterm for mild pregnancy-related nausea and vomiting is "morning sickness," the symptoms may occurat any time of day and often (80 percent) persist throughout the day.

Interestingly, women with mild nausea and vomiting during pregnancy experience fewer miscarriagesand stillbirths than women without these symptoms [2,4]. In one meta-analysis, the odds ofmiscarriage in women with nausea and vomiting in the first 20 weeks of pregnancy was OR 0.36(95% CI 0.2-0.42) [5].

Hyperemesis gravidarum — Hyperemesis gravidarum is considered the severe end of the spectrumof nausea and vomiting, although there is no clear demarcation between common pregnancy-related"morning sickness" and the infrequent pathologic disorder. An objective definition of hyperemesis thatis often used is persistent vomiting accompanied by weight loss exceeding 5 percent of prepregnancybody weight and ketonuria unrelated to other causes [6]. The incidence of woman with severesymptoms is not well-documented; reports vary from 0.3 to 2 percent [7-10]. Ethnic differences anddifferences in the definition of the disease may account, in part, for this variability. Hyperemesistends to improve in the last half of pregnancy, but may persist until delivery. If vomiting persistsbeyond a few days postpartum [11], other etiologies should be investigated.

PATHOGENESIS — The pathogenesis of hyperemesis is unknown. The predominant theories thathave been proposed are described below.

Psychologic factors — Two general theories are that hyperemesis reflects (1) a conversionor somatization disorder or (2) a response to stress [12]. In particular, a feeling ofambivalence about the pregnancy has been offered as an etiologic or contributing factor.However, no study has definitively demonstrated that the psychologic makeup of patientswith hyperemesis gravidarum differs from those without the disorder, although thepsychological response to persistent nausea and vomiting may exacerbate symptoms[12,13].

Hormonal changes — No single hormonal profile can accurately predict the presence ofhyperemesis gravidarum. Elevated serum concentrations of estrogen and progesteronehave long been implicated in the pathogenesis of this disorder. Although several lines ofevidence support a role, especially for estrogen, the fact that sex hormone levels peak in


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the third trimester, long after symptoms of hyperemesis gravidarum have typicallyresolved, is inconsistent with this theory [14,15].

By comparison, serum concentrations of human chorionic gonadotropin (hCG) peak during the firsttrimester, the time when hyperemesis gravidarum is typically seen. The observation that serum hCGconcentration is higher in women with hyperemesis than in other pregnant women also supports apossible etiologic role for this hormone [16,17]. In addition, their hCG has more thyroid-stimulatingactivity because more of it is desialylated [16,18]. An increased prevalence of hyperemesis in womenwith gestational trophoblastic disease, which is characterized by very high hCG levels, has beenwell-described. Nevertheless, an association between hCG levels and hyperemesis gravidarum has notbeen firmly established.

Abnormal gastric motility — Gastric motility may be abnormal (delayed or dysrhythmic) inhyperemesis gravidarum. Studies addressing motility disturbances have shown conflictingresults, suggesting that these abnormalities are not highly predictive of the disease. (See"Pathogenesis of delayed gastric emptying").

Women with diabetes may have gastroparesis. (See "Diabetic autonomic neuropathy of thegastrointestinal tract").

Other — Several other theories to explain hyperemesis have been suggested, includingspecific nutrient deficiencies (eg, zinc), alterations in lipid levels, changes in the autonomicnervous system, genetic factors, and infection with Helicobacter pylori [19,20]. None isconsistently associated with or highly predictive of the disease.

RISK FACTORS — Studies of risk factors for hyperemesis gravidarum have generally included only asmall number of affected women, and results have not been definitive [19,21-23]. Nonpregnantwomen who experience nausea and vomiting after estrogen exposure, from motion sickness, withmigraine, or with exposure to certain tastes (supertasters) are more likely to have pregnancy-relatednausea and vomiting [2]. In contrast, anosmic women appear to be at low risk for this disorder [24].Psychiatric illness and pregestational diabetes are other purported risk factors, but these arecontroversial [25,26]. Interestingly, studies have consistently shown a preponderance of femalefetuses among pregnancies complicated by hyperemesis [21,25,27-30].

Advanced maternal age (age >35) and cigarette smoking (perhaps due to the effect of nicotine)appear to be protective.

CLINICAL FEATURES AND DIAGNOSIS — Hyperemesis gravidarum is a clinical diagnosis, withoutuniform criteria. As discussed above, the diagnosis can be made in a woman with persistent vomiting,weight loss exceeding 5 percent of prepregnancy body weight, and ketonuria beginning in the firsttrimester, after other causes have been excluded [6]. The onset of symptoms is typically at 4 to 10weeks of gestation. Hospitalization rates peak at about nine weeks, then fall, plateauing at around 20weeks of gestation [25]. Abdominal pain is infrequent.

Laboratory abnormalities — Laboratory abnormalities may or may not be present:

Electrolyte derangements, such as hypokalemia and metabolic alkalosis.

An increase in hematocrit, indicating hemoconcentration due to plasma volume depletion.The degree of hemoconcentration may be underestimated unless the physiologic decline inhematocrit seen in normal pregnancies is considered.

Abnormal liver enzyme values occur in approximately 50 percent of patients who arehospitalized with hyperemesis [31]. The most striking abnormality is an increase in serumaminotransferases. Alanine aminotransferase (ALT) is typically elevated to a greaterdegree than aspartate aminotransferase (AST). Values for both are typically only mildlyelevated, eg in the low hundreds, and rarely as high as 1000 U/L. Hyperbilirubinemia alsocan occur, but rarely exceeds 4 mg/dL [32]. Serum amylase and lipase may increase as


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much as five-fold (as opposed to a 5 to 10-fold increase in acute pancreatitis) and are ofsalivary rather than pancreatic origin [33]. The degree of abnormality in liver testscorrelates with the vomiting; the highest elevations are seen in patients with the mostsevere or protracted vomiting. Abnormal liver biochemical tests resolve promptly uponresolution of the vomiting.

Mild hyperthyroidism, possibly due to high serum concentrations of human chorionicgonadotropin which has thyroid-stimulating activity [16]. One report noted low serum TSHconcentrations more often in women with hyperemesis gravidarum than in normalpregnant women; TSH was suppressed in 60 percent of hyperemesis patients versus 9percent of controls [17]. Some of these women had elevated serum free T4 concentrationsand therefore met the definition of hyperthyroidism. (See "Diagnosis and treatment ofhyperthyroidism during pregnancy").

Features that distinguish the transient hyperthyroidism of hyperemesis gravidarum fromhyperthyroidism of other causes (which in a pregnant woman is most likely to be due to Graves'disease) are the vomiting, absence of goiter and ophthalmopathy, and absence of the commonsymptoms and signs of hyperthyroidism (heat intolerance, muscle weakness, tremor). In addition,serum free T4 concentrations are only minimally elevated and serum T3 concentrations are notelevated in women with hyperemesis gravidarum, whereas both are usually unequivocally elevated inpregnant women with true hyperthyroidism. Treatment of hyperthyroidism should NOT be undertakenwithout clear evidence of a primary thyroid disorder (eg, goiter, elevated free thyroid hormone orelevated TSH receptor antibody levels). (See "Diagnosis and treatment of hyperthyroidism duringpregnancy").

Hypercalcemia due to hyperparathyroidism [34,35]. This is uncommon, but should beconsidered as hypercalcemia may contribute to the vomiting.

DIAGNOSTIC EVALUATION — The standard initial evaluation of pregnant women with persistentvomiting includes measurement of weight, orthostatic blood pressures, serum free T4 concentration,serum electrolytes, and urine ketones. An ultrasound examination is performed to exclude gestationaltrophoblastic disease and multiple gestation, both of which are associated with hyperemesis.

Given the characteristic clinical manifestations of hyperemesis gravidarum, a liver biopsy is notneeded in women with abnormal liver function tests to exclude other causes for the laboratoryfindings. When a liver biopsy has been performed, it was either normal or showed nonspecificfindings. Inflammation was absent, but necrosis with cell drop out, steatosis centrilobularvacuolization, and rare bile plugs have been seen [32,36,37]. These changes help to explain themechanism for the liver test abnormalities.

Differential diagnosis — Hyperemesis is generally a diagnosis of exclusion, based on its firstoccurrence in early in pregnancy, with gradual resolution over weeks to months. Nausea and vomitingthat develop after 10 weeks of gestation are not likely due to hyperemesis gravidarum. The presenceof associated symptoms, such as abdominal pain, fever, headache, goiter, abnormal neurologicfindings, diarrhea, constipation, or hypertension, also suggests another diagnosis is likely; manyconditions unrelated to pregnancy can cause persistent nausea and vomiting (show table 1A-B). (See"Approach to the adult patient with nausea and vomiting").

Preeclampsia, HELLP syndrome (Hemolysis, Elevated Liver function tests, Low Platelets), and fattyliver of pregnancy are also causes of pregnancy-related nausea and vomiting, but onset is typically inthe latter half of pregnancy. (See "HELLP syndrome" and see "Acute fatty liver of pregnancy").

TREATMENT — Treatment is primarily supportive; symptoms usually resolve by midpregnancyregardless of therapy.

Fluids and nutrition — Many patients respond to intravenous hydration and a short period of gutrest, followed by reintroduction of oral intake. Significant dehydration is corrected with intravenous


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fluids, such as Lactated Ringers supplemented with appropriate electrolytes and vitamins. Relief ofsymptoms is common within one to two days of rehydration [2]. Hospitalization, as well asreplenishment of fluids and electrolytes, may contribute to palliation of symptoms.

It is important to pay close attention to replenishing vitamins, electrolytes, and minerals, such asmagnesium, phosphorous, and potassium [38]. Thiamine supplementation (100 mg intravenouslydaily for two or three days) is recommended for women who have vomited for more than three weeks[2]. (See "Overview of parenteral and enteral nutrition"). The American GastroenterologicalAssociation (AGA) technical review for parenteral nutrition [39], as well as other AGA guidelines, canbe accessed through the AGA web site at http://www.gastro.org/wmspage.cfm?parm1=4453.

An overly rapid correction in the plasma sodium concentration in women with chronic hyponatremiacan lead to an osmotic demyelination syndrome (also called central pontine myelinolysis). Therefore,the plasma sodium concentration in hyponatremic patients should be elevated at a maximum rate of10 to 12 meq/L during the first day and 18 meq/L over the first two days. (See "Manifestations ofhyponatremia and hypernatremia", section on osmotic demyelination syndrome).

Patients whose symptoms are related to delayed gastric emptying should do better with a dietcomprised of liquids and low fat solids 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 inwomen with hyperemesis. Patients who have not eaten for several days may develop edema whenresuming feeding with carbohydrates [40]. This results from the retention of sodium during fastingcombined with enhanced sodium resorption due to the actions of insulin once carbohydrates arereintroduced [41]. No intervention is required; the edema will gradually resolve.

Nutritional status and methods of alimentation (eg, tube feedings, parenteral nutrition) should beassessed in conjunction with a nutritionist or nutrition service. The optimal timing for initiatingenteral or parenteral nutrition has not been established; the decision is based upon clinicaljudgement. In general, enteral nutrition is begun in women who cannot maintain their weightbecause of vomiting and despite a trial of the interventions described below. Enteral nutrition viagastric or duodenal intubation is preferable to the parenteral route and may relieve the nausea andvomiting [42]. Parenteral nutrition requires a peripherally inserted central catheter (PICC), whichmay lead to catheter-related infection or thrombosis [43].

Nonpharmacologic interventions

Avoidance of triggers — The cornerstone of nonpharmacologic therapy of hyperemesisgravidarum is avoidance of environmental triggers (show table 2) [44]. Examples of some triggersinclude: stuffy rooms, odors (eg, perfume, chemicals, food, smoke) [24], heat, humidity, noise, andvisual or physical motion (eg, flickering lights, driving) [45]. Brushing teeth after eating, quicklychanging position, and not getting enough rest may also aggravate symptoms. Supplementscontaining iron should be avoided until symptoms resolve, as iron causes gastric irritation.

Dietary changes — Women with hyperemesis should eat before or as soon as they feel hungry inorder to avoid an empty stomach that may aggravate nausea [46]. Dietary management generallyconsists of frequent high carbohydrate, low fat, small meals. Dietary manipulations, such aseliminating spicy foods or eating salty or high protein snacks/meals appear to help some women[44,47]. Fluids are better tolerated if cold, clear, and carbonated or sour (eg, ginger ale, lemonade)and if taken in small amounts between meals [2]. Aromatic therapies involving lemon (lemonade),mint (tea), or orange have also been described as useful.

Acupuncture and acupressure — P6 acupuncture or acupressure wristbands (show picture 1) donot require a prescription and have become a popular self-administered intervention [48]. ACochrane review of randomized trials did not find P6 acupuncture or acupressure wristbands weresignificantly more effective than sham therapy, although some individual trials showed a benefit [49].One reason may be that a strong placebo effect has been observed in patients who received shamtherapy [50-53]. Self-administered nerve stimulation therapy over the volar aspect of the wrist at the


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P6 using a commercial device showed some promise in a randomized, controlled study [54]. P6acupuncture or acupressure have not been associated with any adverse effects on pregnancy outcome[49].

Ginger — Randomized and controlled studies suggest that powdered ginger (1 to 1.5 grams individed doses over 24 hours) is more effective than placebo, and equivalent to vitamin B6(pyridoxine) (see "Pyridoxine and doxylamine succinate" below) for treatment of hyperemesis[55-60]. A meta-analysis has not been done because the trials used different control groups andmeasures to assess outcome [60]. An increased risk of adverse effects on pregnancy outcome has notbeen reported, but larger studies are needed to establish its safety and efficacy. We suggest the useof ginger containing foods (eg, ginger lollipops) for mild nausea and vomiting. However, sincestandard pharmacologic grade preparations are not readily available [61], we do not prescribepowdered ginger.

Hypnosis — Hypnosis has been reported to be helpful in some patients [62]. Psychotherapy canalso be a useful adjunctive therapy, particularly if psychological sources of anxiety are identified andcan be ameliorated [63,64].

Pharmacologic treatment — A number of reports have demonstrated that antiemetic drug therapyis more effective than placebo and does not increase the incidence of congenital anomalies [65].However, there is little evidence from well-designed comparative trials upon which to base atreatment plan for women with hyperemesis. A reasonable approach is to begin therapy with agentsthat appear to be effective and have shown minimal maternal side effects and, if these are ineffective,substitute other drugs in a step-wise progression. An algorithm for treatment of nausea and vomitingin pregnancy based upon results of a systematic review has been published (show algorithm 1) [66].

Pyridoxine and doxylamine succinate — Systematic reviews of randomized and/or controlledstudies have shown that pyridoxine (vitamin B6) (10 to 25 mg orally three or four times per day)improves mild to moderate nausea, but does not significantly reduce vomiting [49,55,67]. Thus, it ismost useful for women with morning sickness rather than hyperemesis.

Doxylamine succinate is an antihistamine that is usually taken with pyridoxine. The combinationappears to improve efficacy and was the formulation for Bendectin. Bendectin was voluntarilywithdrawn from the market in 1983 due to lawsuits alleging teratogenicity, although scientificevidence supports the safety [68-70] and efficacy [49,65] of the drug. A meta-analysis of studies onoutcome of pregnancies exposed to Bendectin reported no increase in the incidence of birth defects[70]; pooled analysis demonstrated efficacy (RR 0.53, 95% CI 0.41-0.68) [65].

Formulations similar to Bendectin are available outside the United States under various names (eg,Diclectin in Canada). We recommend these formulations, where available, for initial pharmacologictreatment of hyperemesis. Two delayed release tablets of Diclectin (a total of doxylamine 20 mg andpyridoxine 20 mg) are taken at bedtime. In the United States, doxylamine is available in someover-the-counter sleeping pills, one-half of the 25 mg tablet can be used off-label as an antiemetic.Some providers also prescribe pyridoxine to take with it.

Antihistamines (H1 antagonists) — We suggest promethazine (12.5 to 25 mg every four hoursorally, intramuscularly, or per rectum) for the initial choice of antiemetic in women who do notrespond to pyridoxine and doxylamine, given that it is one of the least expensive of this class of drugs(show table 3) and safety and efficacy were demonstrated in a large group of patients [49,65,71,72].Dystonic reactions rarely occur in patients taking these drugs. (See "Characteristics of antiemeticdrugs"). If it is not effective, then any of the other antihistamines and antiemetics discussed belowcan be tried (show algorithm 1).

The efficacy of antihistamines (H1 antagonists) was demonstrated in a pooled analysis of controlledtrials that showed a significant reduction in pregnancy related nausea and vomiting with use of theseagents (RR 0.34, 95% CI 0.27-0.43) [65]. The safety of antihistamines (H1 antagonists) was affirmedin a meta-analysis that examined the association between antihistamine use and major


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malformations [71]. This review of 24 controlled studies including over 200,000 first trimesterexposures found that H1-receptor blockers actually had a protective effect on risk of malformations(OR 0.76, 95% CI 0.60-0.94). In addition, data from a Swedish registry on women who tookpromethazine or meclizine in the first trimester did not show an increase in the rate of birth defects[72].

Ondansetron, dolasetron — Ondansetron is a selective antagonist at the 5-HT3 serotoninreceptor. Animal data are reassuring as to its safety in pregnancy, but human data on safety orefficacy are limited to case reports and small series [65,73-76]. The dose is 8 mg every 12 hoursintramuscularly or orally. There is no information on the safety of the 5-HT3 receptor antagonistdolasetron in human pregnancy; animal studies did not show adverse pregnancy effects [77]. Wesometimes use these agents after trials of multiple other drugs have failed.

Metoclopramide, prochlorperazine, droperidol — Other antiemetics, including metoclopramide(5 to 10 mg every eight hours intravenously or orally), prochlorperazine (5 to 10 mg every three tofour hours intramuscularly or orally or 25 mg twice per day per rectum), or a combination ofdroperidol and diphenhydramine, appear to benefit some patients [76,78]. The best studied drugs inthis class are the phenothiazines, which are effective (RR 0.31, 95% CI 0.24-0.42) [65].

Evidence from systematic review (n = 2948 exposed patients) showed that dopamine antagonists (eg,phenothiazines, droperidol, metoclopramide) were not teratogenic (RR 1.03, 95% CI 0.88-1.22) [65].(See "Role of propofol and options for patients who are difficult to sedate for gastrointestinalendoscopy", regarding new drug warning for droperidol).

Corticosteroids — Corticosteroids have been used in women with severe and refractoryhyperemesis, although the mechanism of action is not well understood [79-82]. Controlled trials havereported discordant results [65,79,81,83,84]. The largest placebo controlled trial included 110 womenwith severe hyperemesis and reported that women who received corticosteroid therapy had a similarclinical course and need for rehospitalization as those given placebo [83]. The reasons for thedifferences among trials is not known.

The role of corticosteroids for hyperemesis is unsettled. Most obstetricians avoid chronicadministration of corticosteroids in pregnant women, when possible, because prolonged use appearsto increase the risk of preterm premature rupture of membranes (PPROM) [85]. There may also be aslightly increased risk of oral clefts when the drugs are administered before 10 weeks of gestation[86-90]. If administered after 10 weeks (when the palate has formed), the usual dose ismethylprednisolone 16 mg orally or intravenously every eight hours for three days. The drug can bestopped abruptly if there is no response, and tapered over two weeks in women who do have relief ofsymptoms.

We feel the efficacy of corticosteroids for treatment of hyperemesis is unproven and these agentsshould be used only as a last resort [91].

Antacids — Pregnant women are often plagued by gastroesophageal reflux, which may contributeto hyperemesis. A trial of antacids is indicated. (See "Medical management of gastroesophageal refluxdisease in adults" section on Pregnancy).

OUTCOME AND PROGNOSIS — Hyperemesis gravidarum has been associated with significantmaternal morbidity, and even mortality, in the past. In the modern era, the availability ofintravenous fluids and parenteral nutrition has greatly reduced morbidity, and mortality is virtuallynonexistent in patients who are treated. If left untreated, micronutrient deficiency, Wernickeencephalopathy (from deficiency of vitamin B1), and sequelae of malnutrition (immunosuppression,poor wound healing) have been reported [92-97]. Esophageal tears and rupture are other rarecomplications.

There is no clear increase in the risk of birth defects among offspring of gravida with hyperemesisgravidarum, whether or not they take antiemetic medications [7-9,72,98]. Although there is good


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evidence that women with nausea and vomiting in early pregnancy have a lower rate of miscarriagethan women without these symptoms [5], these studies have not correlated outcome with respect tothe severity of the disorder. Most women in these studies have mild symptoms, rather thanhyperemesis.

Although weight gain in early pregnancy is lower in women with mild to moderate vomiting, outcomeis good when total weight gain during the entire pregnancy is similar to that in women with novomiting or only nausea [4]. Despite the severity of the illness and its attendant early weight loss,most studies have reported no difference in birth weight or gestational age at birth between affectedpregnancies and those unaffected by hyperemesis gravidarum, as long as prepregnancy weight wasnormal and there was catch-up weight gain later in pregnancy [8,9]. In contrast, women with severevomiting who require multiple hospitalizations may not have "catch up" weight gain; an adverseeffect on birthweight is more likely in these women [7,10,95,99,100].

The disease is likely to recur in subsequent pregnancies. Two population based series reported therisk of recurrent hyperemesis in a second pregnancy was 15 [101] and 20 [100] percent in womenwith previous hyperemesis, but only 0.7 percent in women with no such history [101].

PREVENTION — Taking a multivitamin at the time of conception, which is already routinelyrecommended for prevention of neural tube defects, may also decrease the frequency and severity ofnausea and vomiting during pregnancy [102,103].

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients.(See "Patient information: Nausea and vomiting in pregnancy"). We encourage you to print or e-mailthis topic, or to refer patients to our public web site www.uptodate.com/patients, which includes thisand other topics.

SUMMARY AND RECOMMENDATIONS

Some degree of nausea with or without vomiting occurs in most pregnancies, typically withonset at five to six weeks of gestation, then peaking at nine weeks, and usually abating by16 to 18 weeks of gestation. Hyperemesis gravidarum represents the severe end of thespectrum of symptoms. (See "Definitions" above).

The diagnosis of hyperemesis gravidarum is made clinically in a woman with onset ofpersistent vomiting accompanied by weight loss exceeding 5 percent of prepregnancy bodyweight and ketonuria in the first trimester, unrelated to other causes. (See "Clinicalfeatures and diagnosis" above).

The standard initial evaluation of pregnant women with persistent vomiting includesmeasurement of weight, orthostatic blood pressures, serum free T4 concentration, serumelectrolytes, urine ketones, and an ultrasound examination to exclude gestationaltrophoblastic disease and multiple gestation. (See "Diagnostic evaluation" above).

Women who are significantly dehydrated should receive intravenous fluids. We suggest ashort period of gut rest during hydration, followed by reintroduction of oral intake withliquids and low fat foods (Grade 2C). (See "Fluids and nutrition" above).

Women should try to become aware of and avoid environmental triggers and foods whichmight provoke their nausea and vomiting. Acupuncture and acupressure have not beenshown to significantly reduce nausea and vomiting. However, given the absence of harmand the strong placebo effect, some patients may benefit from a trial of acupressure wristbands. Ginger also appears to have beneficial effects and ginger containing foods, such asginger lollipops, may be helpful in women with mild nausea and vomiting. (See"Nonpharmacologic interventions" above).

Where available, we recommend pyridoxine-doxylamine succinate combination therapy forinitial pharmacologic treatment of hyperemesis gravidarum (Grade 1B). If this drug is notavailable, we suggest pyridoxine, adding doxylamine succinate if pyridoxine alone is not


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effective (Grade 2C). (See "Pyridoxine and doxylamine succinate" above).

If nausea and vomiting persist, we suggest promethazine (Grade 2B). (See"Antihistamines (H1 antagonists)" above).

We suggest not administering corticosteroids for treatment of hyperemesis (Grade 2B).(See "Corticosteroids" above).

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GRAPHICS

Diff diagnosis nausea AGA I

Differential diagnosis of nausea and vomitingMedications and toxic etiologies

Cancer chemotherapySevere-cisplatinum, dacarbazine, nitrogenmustardModerate-etoposide, methotrexate, cytarabineMild-fluorouracil, vinblastine, tamoxifen

AnalgesicsAspirinNonsteroidal anti-inflammatory drugsAuranofinAntigout drugs

Cardiovascular medicationsDigoxinAntiarrhythmicsAntihypertensives

-blockersCalcium channel antagonists

DiureticsHormonal preparations/therapiesOral antidiabeticsOral contraceptives

Antibiotics/antiviralsErythromycinTetracyclineSulfonamidesAntituberculous drugsAcyclovir

Gastrointestinal medicationsSulfasalazineAzathioprine

NicotineCNS activeNarcoticsAntiparkinsonian drugsAnticonvulsants

AntiasthmaticsTheophylline

Radiation therapyEthanol abuseJamaican vomiting sicknessHypervitaminosis

Infectious causes

GastroenteritisViralBacterial

Nongastrointestinal infectionsOtitis media

Disorders of the gut and peritoneum

Mechanical obstructionGastric outlet obstructionSmall bowel obstruction

Functional gastrointestinaldisordersGastroparesisChronic intestinal pseudo-obstructionNonulcer dyspepsiaIrritable bowel syndromeOrganic gastrointestinal disordersPancreatic adenocarcinomaInflammatory intraperitoneal diseasePeptic ulcer diseaseCholecystitisPancreatitisHepatitisCrohn's diseaseMesenteric ischemiaRetroperitoneal fibrosisMucosal metastases

CNS causes

MigraineIncreased intracranialpressureMalignancyHemorrhageInfarctionAbscessMeningitisCongenital malformationHydrocephalusPseudotumor cerebri

Seizure disordersDemyelinating disordersEmotional responsesPsychiatric diseasePsychogenic vomitingAnxiety disordersDepressionPainAnorexia nervosaBulimia nervosa

Labyrinthine disordersMotion sicknessLabyrinthitisTumorsMeniere's diseaseIatrogenicFluorescein angiography

Reproduced with permission from: the American Gastroenterological Association. Gastroenterology 2001; 120:263.


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Differential diagnosis of nausea and vomiting (continued)

Endocrinologic and metabolic causesPregnancyOther endocrine and metabolicUremiaDiabetic ketoacidosisHyperparathyroidismHypoparathyroidismHyperthyroidismAddison's diseaseAcute intermittent porphyria

Postoperative nausea and vomitingCyclic vomiting syndromeMiscellaneous causesCardiac diseaseMyocardial infarctionCongestive heart failureRadiofrequency ablationStarvationReproduced with permission from: the American Gastroenterological Association. Gastroenterology 2001; 120:263.


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Nonpharmacologic options for treatment of hyperemesis gravidarum

Avoidance of environmental triggers, especially strong odorsPowdered ginger extract 1g/day or ginger capsules 250 mg TID or QID*Acupressure wristbands (acupuncture pressure point pericadium 6)Acupuncture (pressure points liver meridian 3 and spleen 6)PsychotherapyHypnotherapy* Efficacy shown in randomized controlled studies.Courtesy of Errol Norwitz, MD, PhD.


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P6 acupressure point

Pressure or massage at the P6 acupressure point is reported in somestudies to relieve motion sickness. The point is found three of the patient'sfingerbreadths proximal to the proximal wrist fold, between the palmarislongus and flexor carpi radialis tendons, shown in this picture by the tip ofthe pen.


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Nausea and vomiting of pregnancy: treatment algorithm *

If no improvement, proceed to the next step. * This algorithm assumes that other causes ofnausea and vomiting have been ruled out.

At any step, consider parenteral nutrition, if indicated. In the United States, doxylamine is available as the active ingredient in Unisom Sleep Tabs; one half of

a scored 25mg tablet can be used to provide a 12.5 mg dose of doxylamine. Diclectin (doxylamine10mg and pyridoxine 10mg) is currently available only in Canada in a delayed-release formulation that istypically prescribed 3 to 4 times daily.

Safety, particularly in the first trimester of pregnancy, not yet determined; has no major effect onnausea.§ No study has compared different fluid replacements for NVP.¥ 100 mg thiamin IV daily for 2 to 3 days (followed by IV multivitamins) is recommended for everywoman who requires IV hydration and has vomited for more than 3 weeks.

Steroids may increase risk for oral clefts in first 10 weeks of gestation.Reproduced with permission from: Levichek, Z, Atanachovic, G, Oepkes, D, et al. Nauseaand vomiting of pregnancy. Evidence-based treatment algorithm. Can Fam Physician2002; 48:267. Copyright © 2002 Canadian Family Physician.


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Pharmacologic therapy for hyperemesis gravidarum

Drug DoseAntiemetics

Metoclopramide 10 to 30 mg PO QID10 mg IM/IV Q4 to 6h

Ondansetron 4 to 8 mg PO Q8h8 mg IV Q4 to 8h

Droperidol 2.5 mg IV/IM Q3 to 6h1 to 2.5 mg/h IV infusion

Promethazine 12.5 to 50 mg PO/PR/IM Q4 to 6hProchlorperazine 5 to 10 mg PO/IV/IM Q4 to 6h

25 mg PR Q12hChlorpromazine 10 to 50 mg PO/IM Q6 to 8hAntihistamines

Meclizine 25 to 100 mg PO dailyChlorpheniramine 8 to 12 mg PO dailyDiphenhydramine 50 to 75 mg PO/IM/IV Q4 to 6hTrimethobenzamide 250 mg PO TID or QID

200 mg PR/IM Q6 to 8hCourtesy of Errol Norwitz, MD, PhD.


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Grade 2C recommendation

A Grade 2C recommendation is a very weak recommendation; other alternatives may beequally reasonable.Explanation:

A Grade 2 recommendation is a weak recommendation. It means "this is our suggestion, but youmay want to think about it." It is unlikely that you should follow the suggested approach in all yourpatients, and you might reasonably choose an alternative approach. For Grade 2 recommendations,benefits and risks may be finely balanced, or the benefits and risks may be uncertain. In decidingwhether to follow a Grade 2 recommendation in an individual patient, you may want to think aboutyour patient's values and preferences or about your patient's risk aversion.Grade C means the evidence comes from observational studies, unsystematic clinical experience, orfrom randomized, controlled trials with serious flaws. Any estimate of effect is uncertain.Recommendation grades1. Strong recommendation: Benefits clearly outweigh the risks and burdens (or vice versa) for most, if not all, patients2. Weak recommendation: Benefits and risks closely balanced and/or uncertain

Evidence gradesA. High-quality evidence: Consistent evidence from randomized trials, or overwhelming evidence of some other formB. Moderate-quality evidence: Evidence from randomized trials with important limitations, or very strong evidence of some other formC. Low-quality evidence: Evidence from observational studies, unsystematic clinical observations, or from randomized trials with seriousflaws

For a complete description of our grading system, please see the UpToDate editorial policy which can be found by clicking "AboutUpToDate" and then selecting "Policies".


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Grade 1B recommendation

A Grade 1B recommendation is a strong recommendation, and applies to most patients.Clinicians should follow a strong recommendation unless a clear and compelling rationale foran alternative approach is present.Explanation:

A Grade 1 recommendation is a strong recommendation. It means that we believe that if you followthe recommendation, you will be doing more good than harm for most, if not all of your patients.Grade B means that the best estimates of the critical benefits and risks come from randomized,controlled trials with important limitations (eg, inconsistent results, methodologic flaws, impreciseresults, extrapolation from a different population or setting) or very strong evidence of some otherform. Further research (if performed) is likely to have an impact on our confidence in the estimatesof benefit and risk, and may change the estimates.Recommendation grades1. Strong recommendation: Benefits clearly outweigh the risks and burdens (or vice versa) for most, if not all, patients2. Weak recommendation: Benefits and risks closely balanced and/or uncertain

Evidence gradesA. High-quality evidence: Consistent evidence from randomized trials, or overwhelming evidence of some other formB. Moderate-quality evidence: Evidence from randomized trials with important limitations, or very strong evidence of some other formC. Low-quality evidence: Evidence from observational studies, unsystematic clinical observations, or from randomized trials with seriousflaws

For a complete description of our grading system, please see the UpToDate editorial policy which can be found by clicking "AboutUpToDate" and then selecting "Policies".


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hyperemesis gravidarum and

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