Hyperemesis Gravidarum

See Also

Morning Sickness

Definitions

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
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

Epidemiology

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%
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]

Pathophysiology

Hyperemesis Gravidarum reflects a more severe, intractable Vomiting in Pregnancy that affects daily activity
1. Contrast with the less severe Morning Sickness
Hormonally related changes that peak in early pregnancy
1. High bHCG levels (e.g. Twin Gestation)
2. High Estrogen levels
Gastrointestinal function changes in early pregnancy
1. Gastrointestinal motility decreased
2. Lower esophageal sphincter relaxed
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

Risk Factors

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

History

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
Intractable Vomiting with systemic effects
1. Ketonuria (Acetonuria)
2. Weight loss (typically 5% of pre-pregnant weight)
3. Dehydration
4. Electrolyte disturbance
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)
Urinary symptoms
1. Decreased Urine Output
2. Dysuria
3. Flank Pain

Signs

Weight loss, or no weight gain
Tachycardia
Dry mucus membranes
Poor Skin Turgor
Fever
Uterine Size
External Fetal heart tone monitoring

Differential Diagnosis

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
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)
Genitourinary causes
1. Acute Pyelonephritis (common)
2. Ureterolithiasis
3. Ovarian Torsion
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
Endocrine causes
Neurologic causes
1. Migraine Headache (common)
2. Pseudotumor Cerebri
3. Vertigo (e.g. BPPV, Meniere Disease)
Miscellaneous conditions
1. Pneumonia
2. Medication Induced Vomiting
  1. Iron-containing supplements (including Prenatal Vitamins)
Substance Use Disorder

Labs

Basic Chemistry Panel (basic metabolic panel)
1. Starvation Ketosis may demonstrate Metabolic Acidosis with Anion Gap
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
Complete Blood Count
Serum Lipase
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]
Quantitative bhCG
1. Consider in early pregnancy (esp. before first Ultrasound)
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

Imaging

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)
Ultrasound Right Upper Quadrant
1. Gallbladder and Pancreas

Management
Non-prescription Management

See Morning Sickness for non-pharmacologic measures
Dietitian Consultation
See Morning Sickness
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
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)
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
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

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

See other general management and OTC Medication options above
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
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
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]

Management
Agents to avoid (mixed or absent safety data)

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

Management
Emergency Department protocol

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
Thiamine indications (prevention of Wernicke Encephalopathy)
1. Transitioning to dextrose solutions
2. Vomiting >3 weeks or IV fluid >3 days
Inpatient (intractable symptoms, persistent weight loss)
1. Follow daily weights
2. Follow Input and Output
3. Enteral feeding may be needed (preferred over TPN)

Complications

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

Resources

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

References

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