Nausea and Vomiting of Pregnancy and Hyperemesis Gravidarum

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

• 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

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

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

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

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

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

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