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    Nausea and Vomiting of Pregnancy and Hyperemesis Gravidarum

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    Nov.20.2024

    Nausea and Vomiting of Pregnancy and Hyperemesis Gravidarum

    Synopsis

    Key Points

    • Nausea and vomiting of pregnancy can be defined as nausea and/or vomiting during pregnancy with onset before 16 weeks 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 pregnancy with onset before 16 weeks 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
    • 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 the following: 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 c10c11c12c13c14
    • 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 believed to be multifactorial, but elevated hormone levels, evolutionary adaptation, gastrointestinal infection, and genetic predisposition have been thought to play a role r1c36c37c38c39
      • Hypersensitivity to growth differentiation factor-15 is the main mechanism underlying nausea and vomiting in pregnancy and hyperemesis gravidarum r4
        • Growth differentiation factor-15 is produced by placenta and causes loss of appetite, taste aversion, nausea, vomiting, and weight loss; circulating levels peak in the first half of pregnancy
        • Higher circulating levels have been found in patients taking medication for nausea and vomiting in pregnancy, patients with second trimester vomiting, and patients hospitalized for hyperemesis gravidarum
      • Other hormonal factors implicated 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
    • Genetic variants associated with expression of growth differentiation factor-15 have been identified in families with hyperemesis gravidarum r4
    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, migraines, or nausea with estrogen-containing medication r1r11c51c52
      • Prepregnancy nausea and vomiting r11
      • Psychiatric or mood disorders r2c53c54
        • Thought to contribute to cause; however, findings are inconsistent
      • Supplemental iron, as is typically contained in prenatal vitamins r2c55
      • Younger maternal age r11
    • Fetal factors

    Diagnostic Procedures

    Primary diagnostic tools

    • Diagnose nausea and vomiting of pregnancy when symptoms begin before 6 weeks gestation 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
    • PUQE (Pregnancy-Unique Quantification of Emesis and Nausea) scoring system may be used to assess severity and monitor response to treatment r1c62
    • 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 c63c64c65c66c67c68c69c70c71c72c73
    • 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) c74
      • Discrete measure of weight loss (typically associated with distinct weight loss greater than 5% of prepregnancy weight) r1c75
      • May include fluid and electrolyte disturbances c76
    • HyperEmesis Level Prediction Score scoring system quantifies hyperemesis gravidarum symptoms and can be used to monitor progress and response to treatment r12r13
    • Laboratory
      • Most patients with nausea and vomiting of pregnancy do not require invasive laboratory evaluation, but urine dipstick is often obtained r1c77
      • 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
        • Initial tests may include: r4
          • Complete blood count r11
          • Complete metabolic panel including blood urea nitrogen and creatinine, blood glucose r2r11c78c79
          • Urinanalysis r11
      • Additional tests for refractory or recurrent cases or cases that present after the normal peak of nausea and vomiting may be indicated to establish differential diagnosis, assess severity, and/or identify complications r4
        • May include:
          • Thyroid function tests to evaluate for hypo- or hyperthyroidism (eg, transient hyperthyroidism of hyperemesis gravidarum) c80c81c82c83
          • Liver function tests to exclude other liver diseases (eg, hepatitis, gallstones) and monitor malnutrition r11c84c85c86c87
          • Calcium and phosphate levels c88c89
          • Serum amylase to exclude pancreatitis c90
          • Quantitative HCG level; may be used in conjunction with ultrasonography in early pregnancy to assess for multiple gestation and trophoblastic disease r11
          • Venous blood gas to exclude metabolic disturbances r4
          • Testing for Helicobacter pylori infection; may be considered in patients with persistent hyperemesis gravidarum unresponsive to standard therapy r1c91c92
    • Imaging
      • Begin workup by verifying viable intrauterine pregnancy using ultrasonography r3c93
      • Use ultrasonography to exclude multiple gestation and trophoblastic disease r4r14c94
      • Abdominal ultrasound can be considered to evaluate for gallbladder disease r11

    Laboratory

    • Urinanalysis r1c95
      • Presence of nitrites may indicate urinary tract infection; if detected, obtain midstream urine for microscopy and culture r4
      • May demonstrate elevated specific gravity level and/or ketonuria
        • However, urinary ketosis may be misleading and should not be used for assessment or monitoring of hydration and nutrition status r4
        • No association was found between ketonuria and severity of hyperemesis gravidarum (as indicated by hospital readmission or length of hospital stay)
    • Metabolic panel
      • 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
      • Results are abnormal in up to 40% of patients with hyperemesis gravidarum; may show elevated levels of the following: r4
        • Transaminases (up to 300 units/L) r1c99c100
        • Bilirubin (mild, not associated with jaundice; up to 4 mg/dL) c101
      • 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

    Other diagnostic tools

    • 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) r1r15c105
          • 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 r16
            • 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 r16
          • 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

    Differential Diagnosis

    Most common

    • Gastrointestinal conditions
      • Gastroenteritis c106d1
        • 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 r17
        • Unlike nausea and vomiting of pregnancy, symptoms may also include abdominal cramping and fever r18
        • Diagnose definitively using stool culture r17
      • Hepatitis c107d1
        • 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 r19c108
        • 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 r20c109
        • Both gallstones and cholecystitis may present with nausea and vomiting c110c111d2
        • 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 c112
          • Cholecystitis: severe pain below the right costal margin that often radiates c113
        • 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 c114d3
        • Condition of inflamed stomach (gastric ulcer) or duodenum (duodenal ulcer) that penetrates the muscularis mucosae layer r21
        • Characterized by epigastric pain, which often wakes patient from sleep and is relieved with food intake r21
        • Similar to nausea and vomiting of pregnancy, peptic ulcer disease may also be associated with vomiting and weight loss r21
        • 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 r21
      • Pancreatitis c115d4
        • Inflammation of pancreas, increasing risk for pancreatic cancer r22
        • Typically presents with severe epigastric stomach pain, but nausea and vomiting are associated symptoms, similar to hyperemesis gravidarum r22
        • Unlike nausea and vomiting of pregnancy, pancreatitis usually presents with more severe pain and can be associated with the following: r22
          • 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 r23
        • MRI can also confirm diagnosis by demonstrating pancreatic inflammation r23
      • Appendicitis c116d5
        • 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 r24
          • 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) r25
    • Genitourinary tract disorders c117
      • Pyelonephritis r26c118
        • 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 c119
      • Diabetic ketoacidosis r27c120d6
        • 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 c121d7
        • Condition of having excess circulating thyroid hormones r28
        • 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 r28
        • 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 r28
        • Differentiate by serum analysis; decreased serum levels of TSH with elevated serum levels of free thyroxine and/or free triiodothyronine are diagnostic r29
    • Migraines r30c122d8
      • 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 c123
      • Ferrous sulfate supplementation has been shown to be associated with adverse gastrointestinal effects, including nausea r31
      • 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 r31
      • Differentiate by confirming symptom resolution after discontinuing iron supplements
    • Preeclampsia r32c124d9
      • 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 the following:
        • 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 r5r33
    • 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

    Patients who are unable to tolerate oral antiemetics or oral fluids can be managed in ambulatory day care setting r4

    Inpatient care is indicated to treat dehydration and electrolyte imbalance for patients with continued nausea and vomiting and any of the following conditions: r4

    • Failure to respond to adequate ambulatory day care treatment
    • Inability to tolerate oral antiemetics
    • Clinical dehydration or weight loss greater than 5% of body weight despite oral antiemetics
    • Change in vital signs or mental status r1
    • Presence of comorbidity requiring treatment (eg urinary tract infection and inability to tolerate oral antibiotics)
    • Presence of comorbidity in which inability to tolerate oral intake and medication could cause significant complications (eg, epilepsy, diabetes, HIV, hypoadrenalism, or psychiatric disease)

    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
      • 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

    • Rehydration and electrolyte replacement
      • Focus of initial management if dehydration is present r4
      • Switch patient to nothing by mouth status r10
        • Reintroduce oral diet once patient can tolerate liquids; recommend dietary changes to improve oral intake r34
      • 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 IV before starting dextrose-containing rehydration solution and for at least 2 to 3 days to prevent Wernicke encephalopathy r1r4
        • Maintain continuous hydration with a solution containing 5% dextrose r10
        • Add electrolytes as necessary, including potassium, magnesium, and phosphate r10
    • Nonpharmacologic management r1
      • First line approach for mild-to-moderate cases; may include:
        • Dietary and lifestyle modifications r11
        • Consumption of ginger r35
        • Acupressure or acupuncture r35
    • Pharmacotherapy r2
      • Indicated to reduce symptoms when dietary and lifestyle modifications are unsuccessful
      • 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 r36
        • Early intervention with antiemetic therapy is recommended to prevent progression of hyperemesis gravidarum r1
        • Combination of antiemetic agents is often required r4
          • Use caution when multiple antiemetic medications are used concurrently r1
          • Use of serotonin 5-hydroxytryptamine 3 receptor antagonists (eg, ondansetron) and phenothiazine medication (eg, chlorpromazine) may produce QT interval prolongation, a potential cardiac risk
          • Use of dopamine receptor antagonist (eg, metoclopramide) and phenothiazine medication (eg, promethazine, prochlorperazine) may increase risk of extrapyramidal effects and, rarely, neuroleptic malignant syndrome
        • In addition to antiemetic therapy, offer laxatives if constipated and proton pump inhibitors if symptoms suggest gastro-esophageal reflux r4
        • 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
      • First line pharmacotherapy r2
        • Pyridoxine monotherapy
        • Doxylamine monotherapy r1r4r35
        • Pyridoxine combined with doxylamine r1r4
          • Available as combination extended release tablet or can be given separately
        • Other first-generation antihistamines (eg, dimenhydrinate, diphenhydramine) and phenothiazines (eg, prochlorperazine, chlorpromazine, and promethazine) are less commonly used but considered safe in pregnancy r1r4
      • Second line pharmacotherapy (for cases refractory to first line treatments)
        • Metoclopramide r10
          • Multiple routes of administration available (oral, intramuscular, IV)
          • Risk of short-term extrapyramidal disorders and tardive dyskinesia r4
        • Ondansetron 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
          • There is inconsistent evidence for an association between ondansetron use and birth defects; use with caution during early gestation (less than 10 weeks) r1r37
            • A large multicenter cohort study found no association between ondansetron exposure during pregnancy and increased risk of fetal death, spontaneous abortion, stillbirth, or major congenital malformations compared with exposure to other antiemetic drugs r37
            • Some studies have found an association between ondansetron use in the first trimester and orofacial clefts r38
      • 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
    • Nutritional support
      • Generally only required in refractory cases, particularly when steroids fail
      • Initiate enteral tube feeding (nasogastric or nasoduodenal) for patients with hyperemesis gravidarum unresponsive to medical therapy and who cannot maintain their weight r1
        • 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 r39
        • Use a polymeric formula with or without fiber for most patients r34
        • Advise patient to take only small sips of water with medications and not to eat until the goal enteral nutrition schedule is reached r34
        • Advise patient to sit up straighter than 30° to prevent regurgitation r34
        • 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 r34
      • Consider total parenteral nutrition for patients who cannot tolerate enteral feeding
    • Thromboprophylaxis for hospitalized patients
      • Initiate thromboprophylaxis with low-molecular-weight heparin or graduated compression stockings (if low-molecular-weight heparin is contra-indicated) in patients hospitalized for treatment of hyperemesis gravidarum r4

    Drug therapy

    • B vitamins
      • Pyridoxine c125
        • Vitamin B6 (Pyridoxine) Oral tablet; Adolescents: 10 to 25 mg PO 3 to 4 times daily. Adjust dose and frequency based on symptom severity.
        • Vitamin B6 (Pyridoxine) Oral tablet; Adults: 10 to 25 mg PO 3 to 4 times daily. Adjust dose and frequency based on symptom severity.
      • Thiamine
        • For prevention of Wernicke encephalopathy
          • Vitamin B1 (Thiamine Hydrochloride) Solution for injection; Adults: 100 mg IV/IM once daily for 3 to 5 days.
    • Pyridoxine-doxylamine combination c126
      • Delayed-release tablet (Diclegis)
        • Doxylamine Succinate, Vitamin B6 (Pyridoxine hydrochloride) Gastro-resistant tablet; Adults: 20 mg doxylamine; 20 mg pyridoxine PO once daily at bedtime, initially. May increase the dose to 10 mg doxylamine; 10 mg pyridoxine PO once daily in the morning and 20 mg doxylamine; 20 mg pyridoxine PO once daily at bedtime starting on day 3 if symptoms persist. May further increase the dose to 10 mg doxylamine ;10 mg pyridoxine PO twice daily in the morning and mid-afternoon and 20 mg doxylamine; 20 mg pyridoxine PO once daily at bedtime if symptoms persist. Max: 40 mg/day doxylamine; 40 mg/day pyridoxine.
      • Biphasic release tablet (Bonjesta)
        • Doxylamine Succinate, Vitamin B6 (Pyridoxine hydrochloride) Oral tablet, biphasic release; Adults: 20 mg doxylamine; 20 mg pyridoxine PO once daily at bedtime, initially. May increase the dose to 20 mg doxylamine; 20 mg pyridoxine PO twice daily on day 2 if symptoms persist. Max: 40 mg/day doxylamine; 40 mg/day pyridoxine.
    • Antihistamines
      • Dimenhydrinate c127
        • Oral
          • Dimenhydrinate Oral tablet; Adults: 25 to 50 mg PO every 4 to 6 hours as needed. Max: 400 mg/day; limit to 200 mg/day if used concomitantly with doxylamine.
        • Intravenous
          • Dimenhydrinate Solution for injection; Adults: 50 mg IV every 4 to 6 hours as needed.
      • Diphenhydramine c128
        • Diphenhydramine Hydrochloride Oral tablet; Adults: 25 to 50 mg PO every 4 to 6 hours as needed.
    • Dopamine receptor antagonist c129
      • Metoclopramide c130
        • Oral
          • Metoclopramide Hydrochloride Oral tablet; Adults: 5 to 10 mg PO every 6 to 8 hours as needed. Limit use to no more than 12 weeks.
        • IV or intramuscular
          • Metoclopramide Hydrochloride Solution for injection; Adults: 5 to 10 mg IV/IM every 6 to 8 hours as needed. Limit use to no more than 12 weeks.
    • Phenothiazines c131
      • Promethazine
        • Oral
          • Promethazine Hydrochloride Oral tablet; Adolescents: 12.5 to 25 mg PO every 4 to 6 hours as needed.
          • Promethazine Hydrochloride Oral tablet; Adults: 12.5 to 25 mg PO every 4 to 6 hours as needed.
        • Rectal
          • Promethazine Hydrochloride Rectal suppository; Adolescents: 12.5 to 25 mg rectally every 4 to 6 hours as needed.
          • Promethazine Hydrochloride Rectal suppository; Adults: 12.5 to 25 mg rectally every 4 to 6 hours as needed.
        • Intramuscular or IV
          • Promethazine Hydrochloride Solution for injection; Adolescents: 12.5 to 25 mg IM/IV every 4 to 6 hours as needed.
          • Promethazine Hydrochloride Solution for injection; Adults: 12.5 to 25 mg IM/IV every 4 to 6 hours as needed.
    • Serotonin 5-HT₃ receptor antagonists
      • Ondansetron c132
        • Oral
          • Ondansetron Hydrochloride Oral tablet; Adults: 4 mg PO every 8 hours as needed.
        • Intravenous
          • Ondansetron Hydrochloride Solution for injection; Adults: 8 mg IV every 12 hours as needed.
    • Corticosteroids c133
      • Methylprednisolone c134
        • Oral
          • Methylprednisolone Oral tablet; Adults: 16 mg PO every 8 hours for 3 days, initially. Taper dose over 2 weeks to the lowest effective dose. Limit use to 6 weeks. Discontinue use if no response within 3 days.
        • Intravenous
          • Methylprednisolone Sodium Succinate Solution for injection; Adults: 16 mg IV every 8 hours for 3 days, initially. Taper dose over 2 weeks to the lowest effective dose. Limit use to 6 weeks. Discontinue use if no response 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 c135
      • Most recommendations are empirical, as there are few published studies evaluating the effect of dietary changes r1
        • Avoid foods that trigger nausea r6c136
        • Eat frequent small meals every 1 to 2 hours; avoid an empty or completely full stomach r1c137c138c139
        • Avoid spicy or fatty foods r1c140c141
        • Choose foods low in fat and high in carbohydrates and/or protein r1c142c143c144
        • Eat a bland carbohydrate snack before getting out of bed in the morning r1c145c146c147
        • Discontinue iron-containing vitamins while maintaining folic acid supplements r2c148c149
    • Lifestyle modifications
      • Increase rest as necessary r2c150
      • Avoid sudden movements, as when getting out of bed r34c151
      • Avoid sensory stimuli that may trigger nausea (eg, strong odors, heat, humidity, noise, flickering lights) r1c152c153c154
    • Psychosocial support
      • 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 r40
      • Provide significant support for patients with hyperemesis gravidarum, who often require more frequent prenatal visits and follow-up calls to prevent admission and readmission
    • Nondrug treatments c155
      • Use ginger in food preparation or as an extract to mitigate symptoms r2c156c157
        • First line treatment r35
        • Use of ginger has been shown to reduce nausea, but not vomiting r1r41c158
        • Ginger Root Extract Oral tablet; Adults: 250 mg PO 4 times daily.
      • Acupressure or acupuncture r35r42
        • Commonly used and unlikely to be harmful; however, efficacy has not been established
      • Cannabis is sometimes used to relieve nausea and vomiting in nonpregnant individuals; however, it is not recommended during pregnancy owing to association with adverse neurocognitive outcomes in offspring r43

    Monitoring

    • Perform serum electrolyte and ECG monitoring for patients taking ondansetron who have risk factors for arrhythmia r1c159
    • Monitor fluid, BUN, and serum electrolyte levels daily for patients receiving IV fluids r4c160c161c162
    • Provide significant support for patients with hyperemesis gravidarum, who often require more frequent prenatal visits and follow-up calls to prevent admission and readmission c163c164c165

    Complications and Prognosis

    Complications

    • Maternal complications
      • Severe disease may result in metabolic disturbances (eg, carbohydrate depletion, dehydration, electrolyte imbalance) r2
        • Dehydration increases risk for venous thromboembolism r5r43c166
        • Thiamine (vitamin B₁) deficiency occurs in up to 60% of patients r34c167d10
      • Nutritional deficiency r33
        • Can cause weight loss
        • May cause vitamin deficiencies r44
          • Wernicke encephalopathy can occur r44
      • Extreme cases may be associated with malnutrition and end-organ damage, as indicated by oliguria and abnormal liver function test results r5c168c169
        • Liver damage is rarely permanent c170
      • Persistent retching or vomiting may lead to splenic avulsion, esophageal rupture, pneumothorax, Mallory-Weiss tears, or acute tubular necrosis r1c171c172c173c174
      • Intractable vomiting may lead to gastroesophageal reflux disease, esophagitis, or gastritis r4c175c176
        • 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 r5c177d11
      • Psychosocial morbidities (eg, depression, posttraumatic stress disorder [postpartum], emotional dysfunction, anxiety, mental health difficulties) have been associated with hyperemesis gravidarum r1c178c179c180c181c182c183c184
        • May be related to elective termination of pregnancy r45
        • 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 two-thirds of patients r4c185c186
        • 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 r46
    • Fetal complications
      • Depend on severity of nausea and vomiting r1c187
        • Poor fetal outcomes are likely due to lack of maternal weight gainr6 or severe malnutritionr34 rather than nausea and vomiting
        • Little to no effect on pregnancy outcome if mild to moderate c188
      • Hyperemesis gravidarum is associated with increased risk of the following: r47
        • Low birth weight r1c189
        • Small for gestational age r2c190
        • Spontaneous preterm birth (less than 37 weeks of gestation) r6c191
        • Resuscitation or admission to neonatal intensive care unit r47
      • Neonatal vitamin K deficiency may accompany maternal vitamin deficiency as a result of hyperemesis gravidarum r43
      • Nausea and vomiting in pregnancy is not associated with increased risk of birth defects r38
      • Hyperemesis gravidarum is associated with small increase in neurodevelopmental disorders and mental health disorders in offspring followed long term r14

    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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