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    Nausea and Vomiting of Pregnancy and Hyperemesis Gravidarum

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    Nov.08.2022

    Nausea and Vomiting of Pregnancy and Hyperemesis Gravidarum

    Synopsis

    Key Points

    • Nausea and vomiting of pregnancy refers to nausea and/or vomiting during early pregnancy for which there are no other causes r1
    • Hyperemesis gravidarum is a form of severe and prolonged nausea and vomiting during pregnancy resulting in dehydration, ketonuria, and a loss of more than 5% body weight r1
    • Diagnosis is clinical after exclusion of other causes of nausea and vomiting r2
      • Initiate workup by verifying viable intrauterine pregnancy r3
      • Use laboratory analyses to assess severity, inform treatment, and aid in differential diagnosis in patients with severe or persistent nausea and vomiting r1
    • First line treatment of mild-to-moderate nausea and vomiting includes dietary and lifestyle changes r1
    • Antiemetic pharmacologic therapy is indicated to reduce symptoms if nonpharmacologic therapy is not successful r2
    • If patient is severely dehydrated, initial treatment is supportive, involving IV rehydration and electrolyte replacement r4
      • Enteral or parenteral feeding may be necessary for patients unable to maintain weight and who are not responding to medical therapy r1
    • Maternal complications
      • Wernicke encephalopathy is a serious complication associated with vitamin B₁ deficiency that may be associated with vitamin deficiencies from excessive vomiting or with parenteral feeding r1
      • Severe disease is associated with malnutrition and end-organ damage r5
      • Persistent retching or vomiting may lead to splenic avulsion, esophageal rupture, pneumothorax, Mallory-Weiss tears, and acute tubular necrosis r1
      • Psychosocial morbidities include depression, posttraumatic stress disorder, emotional dysfunction, and anxiety r1
      • Patients who present in second trimester are at increased risk for placental abruption r5
    • Fetal complications may include low birth weight, preterm birth, and small for gestational age r1
    • Rarely, complications can be fatal,r6 but typically symptoms resolve as the condition resolves,r4usually by 20 weeks of gestationr1

    Urgent Action

    • Because hyperemesis gravidarum is characterized by dehydration, metabolic disturbances, and difficulty in maintaining weight, initiate supportive care immediately after diagnosis r7

    Pitfalls

    • Symptoms almost always manifest before 9 weeks of gestation; carefully consider other conditions if initial symptoms begin after this time r1
    • Administer thiamine supplementation before administration of dextrose or parenteral nutrition to prevent Wernicke encephalopathy r4
    • Patients may be unable to tolerate oral medications; in these cases, consider other routes of administration, including IV or rectal suppositories r1

    Terminology

    Clinical Clarification

    • Nausea and vomiting of pregnancy can be defined as nausea and/or vomiting during early pregnancy for which there are no other causes r4
      • Common condition affecting 50% to 80% of patients in the first trimester r2
      • Symptoms are usually relatively mild, resolve early in the second trimester, and have no adverse fetal sequelae r4
    • Hyperemesis gravidarum lies at the extreme end of the spectrum of nausea and vomiting of pregnancy r1
      • While no single definition currently exists, cited criteria commonly include: r1
        • Persistent vomiting not related to another cause
          • Although persistent is not often defined, some studies alternatively use the terms protracted or intractable; several studies define vomiting of hyperemesis gravidarum to occur at least 3 to 4 times per day r8
        • Some measure of acute starvation (eg, ketonuria)
        • Discrete measure of weight loss (typically at least 5% of prepregnancy weight)
        • May include fluid and electrolyte disturbances
      • Affects 0.3% to 3% of all pregnancies r1
      • Can diminish quality of life and be debilitating for the pregnant patient; can adversely affect health of mother and fetus r1

    Diagnosis

    Clinical Presentation

    History

    • Pertinent historical information
      • History of: r1
        • Nausea and vomiting or hyperemesis gravidarum with a previous pregnancy c1c2
        • Motion sickness c3
        • Migraine headaches c4
        • Chronic medical conditions associated with nausea and vomiting before pregnancy (eg, cholelithiasis, diabetic gastroparesis, chronic Helicobacter pylori infection) c5c6c7
      • Family history of nausea and vomiting with pregnancy or hyperemesis gravidarum r1c8c9
      • Review of systems to aid in excluding other causes such as abdominal pain, urinary symptoms, infection, or medication r4c10c11c12c13c14
    • Primary symptoms are nausea and vomiting c15
      • Timing, severity, and duration of symptoms vary
        • Timing of nausea and vomiting onset is important
          • Typically begins between 4 and 7 weeks of gestation; peaks at 9 weeks of gestation r4
            • Almost always manifests before 9 weeks of gestation; carefully consider other conditions if initial symptoms begin after this time r1
          • Symptoms resolve in majority of patients (87%) by 20 weeks of gestation r9
        • While the condition is often termed morning sickness, about 80% of patients report symptoms lasting all day; only 1.8% report symptoms in the morning only r9
        • Hyperemesis gravidarum is characterized by severe and persistent nausea and vomiting r1c16c17
    • Ptyalism (hypersalivation) is also common r6c18
    • Complaints of dizziness, lightheadedness, weakness, syncope, and weight loss may be present with severe, persistent vomiting c19c20c21c22c23
    • Symptoms such as abdominal pain, fever, and headache are atypical and suggest an alternative cause for nausea and vomiting r1c24c25c26

    Physical examination

    • Physical examination findings are often unremarkable in patients with nausea and vomiting of pregnancy c27
    • Severe, persistent vomiting, suggestive of hyperemesis gravidarum, can result in signs of dehydration and starvation c28c29c30
      • Dry mucous membranes c31
      • Decreased skin turgor c32
      • Orthostatic hypotension c33
      • Weight loss and muscle wasting c34c35

    Causes and Risk Factors

    Causes

    • Cause is largely unknown and believed to be multifactorial, but elevated hormone levels, evolutionary adaptation, gastrointestinal infection, and genetic predisposition have been thought to play a role r1c36c37c38c39
      • Hormonal causes may include elevated β-hCG, estrogen, and progesterone levels associated with pregnancy r10c40c41c42
        • Although studies have not shown a direct causal association between these hormones and hyperemesis gravidarum, there is an association between hyperemesis gravidarum and conditions characterized by increased pregnancy hormones (eg, molar pregnancies, multiple gestations)
      • Infection with Helicobacter pylori may be associated r10c43

    Risk factors and/or associations

    Genetics
    • There may be a genetic component to hyperemesis gravidarum, as risk increases in those with positive family history (mother and/or sister) r1c44c45
    Other risk factors/associations
    • Maternal factors
      • Conditions that increase placental mass r1c46
        • Hydatidiform mole c47
        • Multiple gestation c48
        • Trophoblastic disease c49
      • Hyperemesis gravidarum with previous pregnancy r2c50
        • Recurrence rates with subsequent pregnancies range from 15% to 81% r1
        • For patients who have experienced hyperemesis gravidarum with a previous pregnancy, incidence of recurrence is lower if paternity of fetus is different with subsequent pregnancy r4
      • History of motion sickness or migraines r1c51c52
      • Psychiatric or mood disorders r2c53c54
        • Thought to contribute to cause; however, findings are inconsistent
      • Supplemental iron, as is typically contained in prenatal vitamins r2c55
    • Fetal factors

    Diagnostic Procedures

    Primary diagnostic tools

    • Diagnose nausea and vomiting of pregnancy when symptoms begin in first trimester and other causes of nausea and vomiting have been excluded r4
      • Clinical diagnosis of exclusion; based on typical presentation in absence of other conditions to explain findings r1c60c61
        • Other causes of nausea and vomiting must be excluded (eg, gastrointestinal, genitourinary, central nervous system, toxic/metabolic) r2
    • Many practitioners do not rely on specific scoring systems but evaluate weight loss, ketonuria, other laboratory findings, and physical signs of dehydration to determine severity c62c63c64c65c66c67c68c69c70c71c72
    • No universal definition of hyperemesis gravidarum exists; however, commonly cited criteria include: r1
      • Severe nausea and vomiting not related to other causes
      • Some measure of acute starvation (eg, ketonuria) c73
      • Discrete measure of weight loss (typically associated with distinct weight loss greater than 5% of prepregnancy weight) r1c74
      • May include fluid and electrolyte disturbances c75
    • Laboratory
      • Most patients with nausea and vomiting of pregnancy do not require invasive laboratory evaluation, but urine dipstick is often obtained r1c76
      • For patients with severe or persistent nausea and vomiting, laboratory studies can assess severity of condition and assist in establishing differential diagnosis of hyperemesis gravidarum r1
        • Severe hyperemesis gravidarum may include metabolic abnormalities such as carbohydrate depletion, dehydration, and electrolyte imbalance r2c77c78
      • Perform the following tests for refractory, recurrent cases or in cases that present after the normal peak of nausea and vomiting (eg, second trimester) to establish differential diagnosis, assess severity, and/or identify complications: r4
        • Thyroid function tests to evaluate for hypo- or hyperthyroidism (eg, transient hyperthyroidism of hyperemesis gravidarum) c79c80c81c82
        • Liver function tests to exclude other liver diseases (eg, hepatitis, gallstones) and monitor malnutrition c83c84c85c86
        • Calcium and phosphate levels c87c88
        • Serum lipase level to exclude pancreatitis c89
      • Consider testing for Helicobacter pylori infection in patients with persistent hyperemesis gravidarum unresponsive to standard therapy r1c90c91
    • Imaging
      • Begin workup by verifying viable intrauterine pregnancy using ultrasonography r3c92
      • Use ultrasonography to exclude multiple gestation and trophoblastic disease r4c93
    • The Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) scoring system may be used to assess severity and monitor response to treatment r1c94

    Laboratory

    • Midstream urine specimen r1c95
      • May demonstrate elevated specific gravity level and/or ketonuria
        • However, no association was found between ketonuria and severity of hyperemesis gravidarum (as indicated by hospital readmission or length of hospital stay)
    • Electrolyte analyses r4
      • Hyponatremia and hypokalemia are the most common abnormalities, but these levels are rarely significantly abnormal unless accompanied by prolonged symptoms (over weeks) or very limited oral intake c96c97
    • Liver function tests c98
      • In hyperemesis gravidarum:
        • Results are abnormal in up to 40% of patients;r4 may show elevated:
          • Transaminases (up to 300 units/L) r1c99c100
          • Bilirubin (mild, not associated with jaundice; up to 4 mg/dL) r4c101
        • These abnormalities improve as hyperemesis gravidarum resolves r4
    • CBC r4
      • Elevated hematocrit level (secondary to hemoconcentration) c102

    Imaging

    • Ultrasonography c103
      • Use in initial workup to confirm viable intrauterine pregnancy r4
      • Can identify potential cause (eg, multiple or molar gestation, trophoblastic disease) r1c104

    Procedures

    c105

    Other diagnostic tools

    • The Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) scoring system r1
      • Based on 3 questions; used to assess severity of nausea and vomiting of pregnancy (including hyperemesis gravidarum) during first trimester and monitor response to treatment
        • Modified-PUQE score evaluates wider period of pregnancy (first trimester) r1r11c106
          • Patient indicates most appropriate answer describing their experience from beginning of pregnancy
            • On an average day, for how long do you feel nauseated or sick to your stomach?
              • Not at all: 1 point
              • 1 hour or less: 2 points
              • 2 to 3 hours: 3 points
              • 4 to 6 hours: 4 points
              • More than 6 hours: 5 points
            • On an average day, how many times do you vomit or throw up?
              • I did not throw up: 1 point
              • 1 to 2 times: 2 points
              • 3 to 4 times: 3 points
              • 5 to 6 times: 4 points
              • 7 or more times: 5 points
            • On an average day, how many times do you have retching or dry heaves without bringing anything up?
              • None: 1 point
              • 1 to 2 times: 2 points
              • 3 to 4 times: 3 points
              • 5 to 6 times: 4 points
              • 7 or more times: 5 points
          • Total score determines severity of disease r12
            • Mild: 6 points or less
            • Moderate: 7 to 12 points
            • Severe: 13 points or more
        • Original Motherisk-PUQE scoring system allows for more frequent evaluations and ability to monitor efficacy of therapy r12
          • Questions are asked relating to symptoms over the previous 12 hours; answers and total scoring/severity are the same as Modified-PUQE score
            • In the last 12 hours, for how long have you felt nauseated or sick to your stomach?
            • In the last 12 hours, have you vomited or thrown up?
            • In the last 12 hours, how many times have you had retching or dry heaves without bringing anything up?
        • Motherisk-PUQE-24 scoring system similarly evaluates the preceding 24 hours r4

    Differential Diagnosis

    Most common

    • Gastrointestinal conditions
      • Gastroenteritis c107d1
        • Inflammation of mucous membranes of the gastrointestinal tract, often due to infection
        • Although typically characterized by vomiting and diarrhea, acute infection may present predominantly as vomiting, similar to severe nausea and vomiting of pregnancy r13
        • Unlike nausea and vomiting of pregnancy, symptoms may also include abdominal cramping and fever r14
        • Diagnose definitively using stool culture r13
      • Hepatitis c108d1
        • Inflammation of the liver; can be caused by viral infection or excessive alcohol or drug use
        • Similarly to nausea and vomiting of pregnancy, hepatitis—regardless of cause—may be associated with nausea and vomiting
        • Unlike nausea and vomiting of pregnancy, hepatitis may be accompanied by jaundice and dark-colored urine
        • Differentiate by laboratory analysis; hepatitis is characterized by a greater increase in liver enzyme levels (greater than 1000 units /L) than those of hyperemesis gravidarum (up to 300 units/L) r1
      • Gastroparesis r15c109
        • Syndrome of delayed gastric emptying that presents predominantly with nausea and vomiting
        • Unlike nausea and vomiting of pregnancy, abdominal pain is a common symptom
        • Differentiate using solid-phase gastric scintigraphy (gold standard diagnostic tool) to demonstrate delayed gastric emptying
      • Biliary tract disease r16c110
        • Both gallstones and cholecystitis may present with nausea and vomiting c111c112d2
        • Unlike nausea and vomiting of pregnancy, these conditions typically present with characteristic abdominal pain
          • Gallstones: mild-to-moderate right upper quadrant or epigastric pain that may radiate and frequently starts at night c113
          • Cholecystitis: severe pain below the right costal margin that often radiates c114
        • Differentiate using transabdominal ultrasonography
          • Gallstones appear as hyperechoic foci with acoustic shadowing
          • Cholecystitis is characterized by gallbladder thickening more than 4 mm, sonographic Murphy sign, and inflammatory fluid inside and surrounding the gallbladder
      • Peptic ulcer disease c115d3
        • Condition of inflamed stomach (gastric ulcer) or duodenum (duodenal ulcer) that penetrates the muscularis mucosae layer r17
        • Characterized by epigastric pain, which often wakes patient from sleep and is relieved with food intake r17
        • Similar to nausea and vomiting of pregnancy, peptic ulcer disease may also be associated with vomiting and weight loss r17
        • Consider gastric ulcer diagnosis in any patient with persistent nausea and vomiting that is unresponsive to standard hyperemesis gravidarum therapy r1
        • Testing for Helicobacter pylori infection, which is a common cause of peptic ulcer disease, helps with differentiation, although nausea and vomiting of pregnancy can coexist with Helicobacter pylori infection r1
        • Definitive diagnosis of peptic ulcer disease should be made by visualization of the ulcer using radiography or upper gastrointestinal tract endoscopy r17
      • Pancreatitis c116d4
        • Inflammation of pancreas, increasing risk for pancreatic cancer r18
        • Typically presents with severe epigastric stomach pain, but nausea and vomiting are associated symptoms, similar to hyperemesis gravidarum r18
        • Unlike nausea and vomiting of pregnancy, pancreatitis usually presents with more severe pain and can be associated with: r18
          • Turner sign
          • Cullen sign
        • Differentiate through laboratory analyses; acute pancreatitis is typically associated with increased serum lipase level that is 3 times the upper reference limit r19
        • MRI can also confirm diagnosis by demonstrating pancreatic inflammation r19
      • Appendicitis c117d5
        • Inflammation of vermiform appendix
        • Presents as generalized or periumbilical abdominal pain that may be centralized or localized to right lower quadrant
        • Similarly to nausea and vomiting of pregnancy, appendicitis may cause nausea and vomiting
        • Appendicitis is primarily a clinical diagnosis, but CT is considered the most accurate imaging test for establishing diagnosis r20
          • Findings include appendix larger than 6 mm, appendiceal wall thicker than 2 mm, periappendiceal fat stranding, wall enhancement, and presence of appendicolith (25% of cases) r21
    • Genitourinary tract disorders c118
      • Pyelonephritis r22c119
        • Infection of renal parenchyma and renal pelvis with a wide spectrum of signs and symptoms
        • May present with symptoms of infection, including nausea and vomiting
        • Unlike nausea and vomiting of pregnancy, pyelonephritis presents with other signs of infection, including fever and chills, as well as flank pain and costovertebral angle tenderness
        • Diagnose with urinalysis and urine culture: 10,000 CFU/mm³ is diagnostic in the setting of symptoms consistent with pyelonephritis
    • Metabolic conditions c120
      • Diabetic ketoacidosis r23c121d6
        • Acute metabolic complication of diabetes mellitus characterized by elevated serum glucose and ketone levels and low pH and bicarbonate level
        • Similarly to severe nausea and vomiting of pregnancy, diabetic ketoacidosis is associated with vomiting and weight loss as well as other symptoms that may be generally associated with pregnancy (eg, fatigue, polyuria)
        • Diagnose using laboratory analysis; characteristic findings include: serum glucose level greater than 250 mg/dL, elevated serum ketone level, pH below 7.3, and serum bicarbonate level less than 18 mEq/L
      • Thyrotoxicosis c122d7
        • Condition of having excess circulating thyroid hormones r24
        • Depending on the cause of hormone elevation, thyrotoxicosis may present with symptoms similar to those of nausea and vomiting of pregnancy, including nausea, vomiting, and weight loss r24
        • Unlike nausea and vomiting of pregnancy, thyrotoxicosis is associated with palpitations and tremor; also may be associated with ocular symptoms such as diplopia and eye irritation r24
        • Differentiate by serum analysis; decreased serum levels of TSH with elevated serum levels of free thyroxine (T₄) and/or free triiodothyronine (T₃) are diagnostic r25
    • Migraines r26c123d8
      • Severe headache disorder characterized by unilateral pulsating head pain and possible sensitivity to light or noise
      • May be accompanied by nausea
      • Differentiate clinically
      • Diagnose using patient history and neurologic examination
    • Iron sensitivity c124
      • Ferrous sulfate supplementation has been shown to be associated with adverse gastrointestinal effects, including nausea r27
      • It is recommended that pregnant patients experiencing nausea and vomiting of pregnancy discontinue iron-containing supplements, which may help ease symptoms r2
      • Unlike nausea and vomiting of pregnancy, iron supplementation is also associated with diarrhea and constipation r27
      • Differentiate by confirming symptom resolution after discontinuing iron supplements
    • Preeclampsia r28c125d9
      • Complication of pregnancy defined by proteinuria and elevated blood pressure, beginning after 20 weeks of gestation and resolving by 6 weeks postpartum
      • Closely associated with the development of HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), which may cause vomiting, similar to that of nausea and vomiting of pregnancy
      • Unlike nausea and vomiting of pregnancy, preeclampsia is associated with a myriad of other symptoms, including headaches, tinnitus, visual disorders, oliguria, epigastric pain, and dyspnea
      • Differentiate using physical examination and clinical workup; preeclampsia is diagnosed by:
        • 24-hour proteinuria level of 300 mg/day or higher
        • Systolic blood pressure greater than 140 mm Hg or diastolic blood pressure of 90 mm Hg higher measured twice, at least 4 to 6 hours apart and no less than 7 days apart

    Treatment

    Goals

    • Provide symptom relief r5
    • Prevent and treat complications, such as dehydration and electrolyte imbalances and nutritional deficiency r5r29
    • Provide significant support for patients with hyperemesis gravidarum, who often require more frequent prenatal visits and follow-up calls to prevent admission and readmission

    Disposition

    Admission criteria

    Hyperemesis gravidarum is the most common indication for hospital admission during first part of pregnancy r1

    Inpatient care is indicated to treat dehydration and electrolyte imbalance for patients with continued nausea and vomiting who satisfy at least 1 of the following conditions: r4

    • Failure to respond to outpatient treatment r1
    • Inability to tolerate oral antiemetics
    • Ketonuria and/or weight loss greater than 5% of body weight despite oral antiemetics
    • Change in vital signs or mental status r1

    After initial workup and treatment, patients can be discharged home with IV hydration, nutritional support, and modification of antiemetic therapy r1

    Criteria for ICU admission
    • Severe, life-threatening electrolyte abnormalities refractory to treatment

    Recommendations for specialist referral

    • Owing to the nature of adverse effects, patients treated for hyperemesis gravidarum benefit from management by obstetrician r4
      • Consult with gastroenterologist and nutritionist for patients requiring parenteral feeding

    Treatment Options

    Treatment options cover all stages of nausea and vomiting of pregnancy, including hyperemesis gravidarum, which lies at the extreme end of the spectrum r1

    Treatment is symptomatic, involving supportive care and pharmacologic therapy r5

    • If dehydration is present, initial management should focus on rehydration and electrolyte replacement r4
      • Switch patient to NPO status r10
        • Initiate oral diet once patient can tolerate liquids; recommend dietary changes to improve oral intake r30
      • Begin IV hydration (normal saliner6 or lactated Ringerr10 solutions) for any patient who cannot tolerate oral liquids for a prolonged period or those with signs of dehydration r1
        • Administer thiamine 100 mg IV with initial rehydration solution (before dextrose addition) and 100 mg IV daily for 2 to 3 days to prevent Wernicke encephalopathy r1
        • Maintain continuous hydration with a solution containing 5% dextrose r10
        • Add electrolytes as necessary, including potassium, magnesium, and phosphate r10
    • Nonpharmacologic approach is first line therapy for mild-to-moderate cases, including: r1
      • Dietary and lifestyle modifications
    • Pharmacotherapy is indicated to reduce symptoms when dietary and lifestyle modifications are unsuccessful r2
      • No single approach has been found to be most effective r1
        • Balance safety and efficacy; weigh benefits, potential risks, and side effects of treatment for each patient and fetus r31
        • Early intervention with antiemetic therapy is recommended to prevent progression of hyperemesis gravidarum r1
        • Use caution when multiple antiemetic medications are used concurrently
          • Use of dopamine antagonist (eg, metoclopramide) and phenothiazine medication (eg, promethazine, prochlorperazine) may increase risk of extrapyramidal effects and, rarely, neuroleptic malignant syndrome
          • Use of serotonin 5-HT3 inhibitor (eg, ondansetron) and phenothiazine medication (eg, chlorpromazine) may produce QT interval prolongation, a potential cardiac risk
      • Use pyridoxine (monotherapy or in combination with doxylamine) as first line pharmacotherapy for nausea and vomiting during pregnancy r2
        • Combination therapy has been shown to be safe for the fetus and is associated with central nervous system effects (eg, drowsiness) in the mother r1
      • Antihistamines (eg, doxylamine, dimenhydrinate, diphenhydramine) are considered effective and relatively safe, having no known association with birth defects r1
        • Adverse effects include sedation, dry mouth, lightheadedness, and constipation
      • Consider adding dopamine antagonists (eg, metoclopramide or promethazine) in patients refractory to other treatments r10
        • Multiple routes of administration available (oral, rectal, intramuscular, IV)
        • Certain adverse effects (eg, drowsiness, dizziness, dystonia) are less common with metoclopramide
      • Ondansetron is frequently used in cases with persistent symptoms r1r10
        • Weigh risks and benefits of treatment on individual basis, as ondansetron may interact with several medications and is more expensive than other available medications r2
        • Common adverse effects include headache, drowsiness, fatigue, and constipation, but more serious effects may occur (eg, prolonged QT interval) r1
          • Perform electrolyte and ECG monitoring for patients with risk factors for arrhythmia
        • There is inconsistent evidence for an association between ondansetron use and birth defects; use with caution during early gestation (less than 10 weeks) r1
      • Corticosteroids may be used for refractory cases of hyperemesis gravidarum associated with dehydration r2
        • Restrict use to after 10 weeks of gestation owing to increased risk of developing oral clefting
        • May reduce rate of rehospitalization compared with promethazine r2
        • Considered a last-resort treatment r1
      • For patients unable to tolerate oral medications, consider other routes of administration, such as IV, rectal suppository, oral disintegrating tablets, or transdermal patches, where available r1
    • Initiate enteral tube feeding (nasogastric or nasoduodenal) for patients with hyperemesis gravidarum unresponsive to medical therapy and who cannot maintain their weight r1
      • Generally only required in refractory cases, particularly when steroids fail
      • First line therapy to provide nutritional support r1
      • A retrospective cohort study found that 19% of patients with a hyperemesis gravidarum diagnosis between 2002 and 2011 were treated with enteral nutrition r32
      • Use a polymeric formula with or without fiber for most patients r30
      • Advise patient to take only small sips of water with medications and not to eat until the goal enteral nutrition schedule is reached r30
      • Advise patient to sit up straighter than 30° to prevent regurgitation r30
      • Begin an oral diet before weaning patient from oral nutrition; then, decrease enteral nutrition while monitoring maternal weight gain and fetal growth
        • Discontinue enteral nutrition when patient can tolerate at least 75% of estimated calorie, protein, and fluid needs r30
    • Consider total parenteral nutrition for patients who cannot tolerate enteral feeding
    • Consider counseling or crisis intervention as necessary to address psychosocial complications of the condition r6
    • A good resource for patients is the Hyperemesis Education and Research Foundation r33
    • Provide significant support for patients with hyperemesis gravidarum, who often require more frequent prenatal visits and follow-up calls to prevent admission and readmission

    Drug therapy

    • Pyridoxine or pyridoxine-doxylamine r2c126
      • Pyridoxine alone or in combination with doxylamine is the first line treatment of severe nausea and vomiting in pregnancy or persistent mild cases
        • Pyridoxine c127
          • Vitamin B6 (Pyridoxine) Oral tablet; Adult pregnant females: 10 mg to 25 mg PO (taken either alone or in combination with doxylamine 12.5 mg PO), 3 or 4 times per day.
        • Pyridoxine-doxylamine combination c128
          • Oral dosage (Diclegis delayed-release tablets containing doxylamine 10 mg with pyridoxine 10 mg)
          • Doxylamine Succinate, Vitamin B6 (Pyridoxine hydrochloride) Gastro-resistant tablet; Pregnant Adults: 2 tablets PO (on an empty stomach) at bedtime on day 1; if dose controls symptoms the next day, continue taking 2 tablets PO daily at bedtime. If symptoms persist on the afternoon of day 2, continue 2 tablets PO at bedtime, then take 3 tablets PO starting on day 3 (1 tablet every morning and 2 tablets at bedtime); if regimen controls symptoms, continue regimen. If symptoms persist, on day 4 take 4 tablets PO (1 tablet every morning, 1 tablet mid-afternoon, and 2 tablets at bedtime). Max: 4 tablets/day PO.
    • Antihistamine r1
      • Dimenhydrinate c129
        • Dimenhydrinate Oral tablet; Adult pregnant females: 25 to 50 mg PO every 4 to 6 hours as needed (not to exceed 200 mg/day when used concomitantly with doxylamine).
      • Diphenhydramine c130
        • Diphenhydramine Hydrochloride Oral tablet; Adult pregnant females: 25 to 50 mg PO every 4 to 6 hours; second-line agent.
    • Dopamine receptor antagonist c131
      • Metoclopramide r2c132
        • Metoclopramide Hydrochloride Oral tablet; Adult pregnant females: 5 to 10 mg PO every 6 to 8 hours is considered a third-line option to other preferred treatments; limit to shortest duration possible.
        • May be given orally, rectally, intramuscularly, or intravenously r1
        • Do not administer for longer than 12 weeks r10
      • Phenothiazines c133
        • Promethazine Hydrochloride Oral tablet; Adult and Adolescent Pregnant Females: 12.5 to 25 mg PO every 4 to 6 hours PRN. Second-line pharmacologic option.
    • Serotonin 5-HT₃ receptor antagonists
      • Ondansetron r2c134
        • Oral dosing
          • Ondansetron Hydrochloride Oral tablet; Adult pregnant females: 4 mg PO every 8 hours.
        • IV dosing
          • Ondansetron Hydrochloride Solution for injection; Adult pregnant females: 8 mg IV over 15 minutes every 12 hours.
    • Corticosteroids c135
      • Methylprednisolone c136
        • Indicated for treatment of refractory hyperemesis gravidarum after 10 weeks of gestation r1
        • Methylprednisolone Oral tablet; Pregnant females: 16 mg PO or IV every 8 hours for 3 days. Taper over 2 weeks to lowest effective dose. For recurrent vomiting, the lowest effective dose may be continued for up to 6 weeks. r1
        • Discontinue treatment if patient's condition does not respond within 3 days

    Nondrug and supportive care

    Dietary modifications for mild-to-moderate nausea and vomiting and recommendations to improve oral tolerance after hyperemesis gravidarum c137

    • Most recommendations are empirical, as there are few published studies evaluating the effect of dietary changes r1
      • Avoid foods that trigger nausea r6c138
      • Eat frequent small meals every 1 to 2 hours; avoid an empty or completely full stomach r1c139c140c141
      • Avoid spicy or fatty foods r1c142c143
      • Choose foods low in fat and high in carbohydrates and/or protein r1c144c145c146
      • Eat a bland carbohydrate snack before getting out of bed in the morning r1c147c148c149
      • Discontinue iron-containing vitamins while maintaining folic acid supplements r2c150c151

    Lifestyle modifications

    • Increase rest as necessary r2c152
    • Avoid sudden movements, as when getting out of bed r30c153
    • Avoid sensory stimuli that may trigger nausea (eg, strong odors, heat, humidity, noise, flickering lights) r1c154c155c156

    Nondrug treatments c157

    • Use ginger in food preparation or as an extract to mitigate symptoms r2c158c159
      • Use of ginger has been shown to reduce nausea, but not vomiting r1c160
      • Ginger Root Extract Oral capsule; Adult Pregnant Females: 250 mg PO 4 times per day with a max of 1 g/day has been used in a controlled trial. c161
    Procedures
    c162

    Monitoring

    • Perform serum electrolyte and ECG monitoring for patients taking ondansetron who have risk factors for arrhythmia r1c163
    • Monitor fluid, BUN, and serum electrolyte levels daily for patients receiving IV fluids r4c164c165c166
    • Provide significant support for patients with hyperemesis gravidarum, who often require more frequent prenatal visits and follow-up calls to prevent admission and readmission c167c168c169

    Complications and Prognosis

    Complications

    • Maternal complications
      • Severe disease may result in metabolic disturbances (eg, carbohydrate depletion, dehydration, electrolyte imbalance) r2
        • Dehydration increases risk for thrombosis r5c170
        • Thiamine (vitamin B₁) deficiency occurs in up to 60% of patients r30c171d10
      • Nutritional deficiency r29
        • Can cause weight loss
        • May cause vitamin deficiencies r34
          • Wernicke's encephalopathy can occur r34
      • Extreme cases may be associated with malnutrition and end-organ damage, as indicated by oliguria and abnormal liver function test results r5c172c173
        • Liver damage is rarely permanent c174
      • Persistent retching or vomiting may lead to splenic avulsion, esophageal rupture, pneumothorax, Mallory-Weiss tears, or acute tubular necrosis r1c175c176c177c178
      • Intractable vomiting may lead to gastroesophageal reflux disease, esophagitis, or gastritis r4c179c180
        • Evaluate patients with hematemesis or severe epigastric pain using esophageal gastroduodenoscopy
      • Placental abruption is a risk, particularly for patients who present with hyperemesis gravidarum in second trimester r5c181d11
      • Psychosocial morbidities (eg, depression, posttraumatic stress disorder [postpartum], emotional dysfunction, anxiety, mental health difficulties) have been associated with hyperemesis gravidarum r1c182c183c184c185c186c187c188
        • May be related to elective termination of pregnancy r35
        • Patients experiencing symptoms of posttraumatic stress disorder may experience difficulty with milk production; marital, work/education, or financial difficulties; and difficulty with self-care r10
      • Transient hyperthyroidism of hyperemesis gravidarum occurs in up to 67% of patients r4c189c190
        • Characterized by biochemical thyrotoxicosis, elevated free thyroxine level, and/or reduced TSH level
        • Presence of thyroid antibodies is rare
        • Clinically, patients are euthyroid
        • Biochemical thyrotoxicosis resolves as hyperemesis gravidarum improves
        • Typically, abnormal thyroid function test results resolve by second half of pregnancy without sequelae r1
      • May increase the risk of falls r36
    • Fetal complications
      • Depend on severity of nausea and vomiting r1c191
        • Little to no effect on pregnancy outcome if mild to moderate c192
      • Poor fetal outcomes are likely due to lack of maternal weight gainr6 or severe malnutritionr30 rather than nausea and vomiting
        • Low birth weight r1c193
        • Small for gestational age r2c194
        • Spontaneous preterm birth (less than 37 weeks of gestation) r6c195

    Prognosis

    • Although patients often report decreased quality of life and time lost from work,r6most cases of nausea and vomiting of pregnancy are self-limitedr9
      • About 60% of patients have symptom resolution by end of first trimester; 87% by 20 weeks of gestation r9
    • There is typically a lower rate of miscarriage associated with nausea and vomiting of pregnancy; this is attributed to a robust placental development indicating a healthy pregnancy rather than to nausea and vomiting r1
    • There is currently no evidence for an association between hyperemesis gravidarum and perinatal or neonatal mortality r1
    • Although significant morbidities may accompany severe nausea and vomiting of pregnancy and hyperemesis gravidarum, maternal death is rarely reported r1

    Screening and Prevention

    Prevention

    • Standard recommendation of a daily prenatal vitamin 1 month before conception has been shown to reduce incidence and severity of nausea and vomiting r1
    • Treat mild or moderate nausea and vomiting of pregnancy early (using lifestyle/dietary recommendations and antiemetic therapy) to prevent progression to hyperemesis gravidarum r1
    • For patients with history of hyperemesis gravidarum in previous pregnancy, early use of lifestyle/dietary modifications and antiemetics that were useful in the index pregnancy is advisable to reduce risk of nausea and vomiting of pregnancy and hyperemesis gravidarum in the current pregnancy r4
    • For multiparous patients at risk for recurrence of nausea and vomiting, recommend pyridoxine alone or in combination with doxylamine to reduce duration and severity of symptoms r2
      • Inform patients that medication should be taken regularly and is not indicated for acute treatment
      • To discontinue use, taper medication
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