Hyperemesis Gravidarum

Aka: Hyperemesis Gravidarum, Antiemetic in Pregnancy

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II. Definitions

  1. Morning Sickness
    1. Nausea and/or Vomiting onset in pregnancy starting between 4 and 10 weeks gestation
    2. Despite the name, Morning Sickness commonly occurs throughout the day
    3. Unlike hyperemesis, patients can still perform daily activities
    4. Improves spontaneously by 20 weeks gestation
  2. Hyperemesis Gravidarum (Windsor Definition)
    1. Severe, intractable Nausea and/or Vomiting onset in pregnancy starting before 16 weeks gestation
    2. May be associated with Starvation Ketosis and weight loss >5% under pre-pregnancy weight
    3. Inability to eat or drink normally, strongly affecting daily activities

III. Epidemiology

  1. Incidence: 1-2 per 200 pregnancies (up to 3% in some series)
    1. Contrast with Morning Sickness which affects up to 70-80% of pregnancies
    2. Isolated Nausea in 30%
  2. Hyperemesis is the most common cause of first trimester hospital admission in high income countries
    1. Trovik (2016) Is J Heath Policy Res 5:43 +PMID: 27766142 [PubMed]

IV. Pathophysiology

  1. Hyperemesis Gravidarum reflects a more severe, intractable Vomiting in Pregnancy that affects daily activity
    1. Contrast with the less severe Morning Sickness
  2. Hormonally related changes that peak in early pregnancy
    1. High bHCG levels (e.g. Twin Gestation)
    2. High Estrogen levels
  3. Gastrointestinal function changes in early pregnancy
    1. Gastrointestinal motility decreased
    2. Lower esophageal sphincter relaxed
  4. Other factors
    1. Helicobacter Pylori may be causal factor in some cases
    2. Large placenta size
    3. Thyroid dysregulation
    4. Family History in patients with the most severe of hyperemesis (e.g. requiring TPN)
    5. Associated genes
      1. Growth differentiation factor 15
      2. Insulin like growth factor binding Protein 7

V. Risk Factors

  1. Younger maternal age
  2. Multiparity
  3. Multiple Gestation
  4. Hyperemesis Gravidarum with first pregnancy
  5. Family History of Hyperemesis Gravidarum
  6. Female fetus
  7. Associated Comorbid Conditions
    1. Thyroid dysfunction
    2. Parathyroid dysfunction
    3. Hyperlipidemia
    4. Type 1 Diabetes Mellitus

VI. History

  1. Severe, intractable Nausea and/or Vomiting
    1. See Pregnancy-Unique Quantification of Emesis and Nausea Score (Modified PUQE Score)
    2. Vomiting frequency
    3. Difficulty tolerating oral fluids and foods
    4. Strongly affects daily activities
  2. Intractable Vomiting with systemic effects
    1. Ketonuria (Acetonuria)
    2. Weight loss (typically 5% of pre-pregnant weight)
    3. Dehydration
    4. Electrolyte disturbance
  3. Onset in pregnancy starting before 16 weeks gestation (typically in first trimester)
    1. Peak Incidence at 10-12 weeks
    2. Often worse in morning (but typically persists throughout the day)
  4. Urinary symptoms
    1. Decreased Urine Output
    2. Dysuria
    3. Flank Pain

VII. Signs

  1. Weight loss, or no weight gain
  2. Tachycardia
  3. Dry mucus membranes
  4. Poor Skin Turgor
  5. Fever
  6. Uterine Size
  7. External Fetal heart tone monitoring

VIII. Differential Diagnosis

  1. Precautions
    1. Neurologic findings suggests alternative diagnosis
    2. Hyperemesis onset before 4 weeks or after 9-12 weeks gestation may suggest other cause
      1. Consider differential diagnosis as below
  2. Gastrointestinal causes
    1. Peptic Ulcer Disease
    2. Biliary tract disease (Biliary Colic, Acute Cholecystitis)
    3. Acute Pancreatitis
    4. Bowel Obstruction
    5. Volvulus
    6. Appendicitis
    7. Gastroenteritis (common)
    8. Gastroesophageal Reflux (common)
  3. Genitourinary causes
    1. Acute Pyelonephritis (common)
    2. Ureterolithiasis
    3. Ovarian Torsion
  4. Pregnancy-Related causes
    1. Acute Fatty Liver of Pregnancy
    2. Pregnancy Induced Hypertension (e.g. Preeclampsia, HELLP Syndrome)
    3. Molar Pregnancy
    4. Multiple Gestation
    5. Down Syndrome (affecting fetus)
    6. Hydrops fetalis
  5. Endocrine causes
    1. Diabetes Mellitus (esp. Diabetic Ketoacidosis)
    2. Hyperthyroidism
    3. Hypercalcemia (Hyperparathyroidism)
    4. Addison Disease (Adrenal Insufficiency)
  6. Neurologic causes
    1. Migraine Headache (common)
    2. Pseudotumor Cerebri
    3. Vertigo (e.g. BPPV, Meniere Disease)
  7. Miscellaneous conditions
    1. Pneumonia
    2. Medication Induced Vomiting
      1. Iron-containing supplements (including Prenatal Vitamins)
  8. Substance Use Disorder
    1. Alcohol Withdrawal
    2. Drug Withdrawal
    3. Cannabinoid Hyperemesis

IX. Labs

  1. Basic Chemistry Panel (basic metabolic panel)
    1. Starvation Ketosis may demonstrate Metabolic Acidosis with Anion Gap
  2. Liver Function Test (or as part of comprehensive metabolic panel)
    1. Aminotransferases (AST, ALT) may exceed 200 IU/L
    2. Serum Bilirubin and Alkaline Phosphatase may be increased up to twice normal
  3. Complete Blood Count
  4. Serum Lipase
  5. Urinalysis and Urine Culture
    1. Evaluate for Urinary Tract Infection
    2. Ketonuria (or Ketonemia) was previously used as a marker for hyperemesis severity
      1. Urine Ketones do NOT correlate with hyperemesis severity
      2. (2014) Am J Obstet Gynecol 211(2): 150 +PMID:24530975 [PubMed]
  6. Quantitative bhCG
    1. Consider in early pregnancy (esp. before first Ultrasound)
  7. Thyroid Function Test: Free T4 and Thyroid Stimulating Hormone (TSH)
    1. Previously recommended routinely
    2. As of 2015, only recommended for hyperemesis with Hyperthyroidism symptoms, signs

X. Imaging

  1. Ultrasound Pelvis
    1. Previously used to evaluate for Molar Pregnancy or Multiple Gestation
    2. However, ACOG does not recommend routine Ultrasound solely for hyperemesis (unless otherwise indicated)
  2. Ultrasound Right Upper Quadrant
    1. Gallbladder and Pancreas

XI. Management: Non-prescription Management

  1. See Morning Sickness for non-pharmacologic measures
  2. Dietitian Consultation
  3. See Morning Sickness
  4. Holding agents that may contribute to Vomiting
    1. Iron-containing supplements (including Prenatal Vitamins)
      1. Switch to Folate-only supplementation until Nausea and Vomiting improve
  5. Over the counter agents: Vitamins
    1. Pyridoxine (Vitamin B6)
      1. Dose: 25 mg orally every 6-8 hours
      2. Often used in combination with other agents below (e.g. Doxylamine)
  6. Over-the-counter agents: Antihistamines
    1. Precautions
      1. Anticholinergic adverse effects (e.g. sedation, Dry Mouth) may limit use
    2. Doxylamine (Unisom, Diclectin)
      1. Dose: 10 mg up to three times daily
      2. Best (but limited) evidence in hyperemesis of the Antihistamines
    3. Diphenhydramine (Benadryl)
      1. Dose: 25-50 mg IM/IV/PO every 4-6 hours
      2. Maximum: 400 mg in 24 hours
    4. Meclizine (Antivert)
      1. Oral: 25-50 mg orally every 6 hours
      2. Consider using concurrently with Phenergan
    5. Dimenhydrinate (Dramamine)
      1. Dose: 50-100 mg every 4-6 hours
      2. Maximum: 300 mg in 24 hours
  7. Combination
    1. Doxylamine 10 mg and Pyrodoxine 10 mg (Diclegis, previously Bendectin and Diclectin in Canada)
      1. Dose: Start with 2 tabs in PM and may advance to 1 in AM, 1 at Noon and 2 in PM
      2. Originally pulled from market due to safety concerns that were unsubstantiated
      3. Diclegis is very expensive ($570/month) until generic in 2019
        1. However, generic Doxylamine and Pyridoxine are inexpensive at $20/month
      4. Bonjesta (extended release Doxylamine 20 mg and Pyridoxine 20 mg)
        1. Released in 2018, very expensive and no significant added benefit aside from frequency
      5. References
        1. (2013) Presc Lett 20(6): 32-3
        2. (2018) Presc Lett 25(5): 29

XII. Management: Prescription Antiemetics (Take 1/2 hour prior to meals)

  1. See other general management and OTC Medication options above
  2. First-line agents
    1. Consider adding Pyridoxine (Vitamin B6) with or without Doxylamine as listed above
    2. Metoclopramide (Reglan)
      1. Dose: 5 to 10 mg orally or IV every 6-8 hours as needed
      2. Less sedation than other agents
      3. Black box warning to avoid use longer than 12 weeks
      4. Risk of Dystonic Reaction (as high as 20% esp. in first 5 days) and Tardive Dyskinesia (rare)
        1. Has resulted in Metoclopramide use decline to a second-line agent
  3. Second-line agents
    1. Prochlorperazine (Compazine)
      1. Parenteral and oral: 5-10 mg IM/IV/PO every 4-6 hours
      2. Suppository: 25 mg PR q6-8 hours
    2. Promethazine (Phenergan)
      1. Risk of neonatal respiratory depression near term or during labor
      2. Dose: 12.5-25 mg PO/PR q4-6 hours
      3. Maximum: 100 mg in 24 hours
    3. Trimethobenzamide (Tigan)
      1. Does not cause QTc Prolongation
      2. Dose: 300 mg orally or 200 mg IM every 6 to 8 hours
    4. Hydroxyzine (Atarax, Vistaril)
      1. Dose: 25-50 mg IM/PO every 4-6 hours
  4. Refractory hyperemesis management
    1. Ondansetron ODT (Zofran ODT)
      1. Dose: 4 mg orally up to every 6 hours
      2. Commonly used in U.S. for hyperemesis
      3. Although had appeared safe in pregnancy, longterm data were lacking (compared with other agents)
        1. Ondansetron may be associated with 1.5 to 2 fold risk of Congenital Heart Defects and Cleft Palate
          1. Orofacial clefting risk may increase with Ondansetron from 11 to 14 cases per 10,000 births
        2. ACOG recognizes the inconsistent findings and notes low risk to the fetus
        3. (2014) Presc Lett 21(1): 5
        4. Koren (2012) Can Fam Physician 58(10):1092-3 [PubMed]
    2. GERD Management
      1. Lifestyle modifications (e.g. upright after eating for 2 hours, 64 ounces fluid per day) are first-line
      2. Medications
        1. H2 Blockers (e.g. Famotidine)
        2. Proton Pump Inhibitors (e.g. Omeprazole)
    3. Corticosteroid regimen
      1. Consult obstetrics
      2. Methylprednisolone 16 mg IV every 8 hours for up to 3 days, then tapered over 2 weeks
      3. Risk of Cleft Palate with first trimester use
        1. Safari (1998) Am J Obstet Gynecol 179:921-4 [PubMed]

XIII. Management: Agents to avoid (mixed or absent safety data)

  1. Avoid Droperidol in pregnancy
  2. Avoid Phosphorated Carbohydrates (Emetrol)
    1. No evidence of benefit and as much Glucose as 2 cans of regular soda
  3. Avoid Scopolamine in first trimester (risk of limb and trunk abnormalities)

XIV. Management: Emergency Department protocol

  1. Initial Fluid Replacement
    1. Approach
      1. Dextrose containing solutions may be preferred
      2. Consider Thiamine replacement at the same time as dextrose
      3. Tan (2013) Obstet Gynecol 12(2 Pt 1): 291-8 +PMID:23232754 [PubMed]
    2. First: Isotonic Saline (D5LR) 1-2 liter bolus
    3. Next: D5LR with 20 KCl at 150 cc/h
  2. Thiamine indications (prevention of Wernicke Encephalopathy)
    1. Transitioning to dextrose solutions
    2. Vomiting >3 weeks or IV fluid >3 days
  3. Inpatient (intractable symptoms, persistent weight loss)
    1. Follow daily weights
    2. Follow Input and Output
    3. Enteral feeding may be needed (preferred over TPN)

XV. Complications

  1. Vomiting-induced GI Trauma (e.g. Mallory Weiss Tear)
  2. Electrolyte abnormalities (e.g. Hypokalemia, Hyponatremia)
  3. Thiamine Deficiency (Wernicke Encephalopathy)
  4. Acute Kidney Injury (including Acute Tubular Necrosis)
  5. Severe weight loss in pregnancy
  6. Splenic avulsion
  7. Rhabdomyolysis
  8. Associated increased frequency of pregnancy complications
    1. Small for Gestational Age infant (placental insufficiency, IUGR)
    2. Preterm Hypertensive Disorders of Pregnancy
    3. Placental Abruption
  9. Associated Increased frequency of mental health diagnoses
    1. Anxiety Disorder
    2. Major Depression and Suicidality
    3. Post-Traumatic Stress Disorder

XVI. Resources

  1. Gardner in U.S. Pharmacist
    1. http://legacy.uspharmacist.com/oldformat.asp?url=newlook/files/Feat/ACF2F23.cfm&pub_id=8&article_id=54

XVII. References

  1. Delaney in Herbert (2018) EM:Rap 18(1): 12-4
  2. Mayo and Welsh (2021) Crit Dec Emerg Med 33(5): 12
  3. (2015) Obstet Gynecol 126(3): 687-8 +PMID: 26287781 [PubMed]
  4. Broussard (1998) Gastroenterol Clin North Am 27(1):123 [PubMed]
  5. Eliakim (2000) Am J Perinatol 17(4):207-18 [PubMed]
  6. Herrell (2014) Am Fam Physician 89(12): 965-70 [PubMed]
  7. Kuscu (2002) Postgrad Med 78(916):76-9 [PubMed]
  8. Quinlan (2003) Am Fam Physician 68(1):121-8 [PubMed]
  9. Williamson (2026) Am Fam Physician 113(6): 559-65 [PubMed]

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