Treatment of Hyperemesis Gravidarum
Start with doxylamine-pyridoxine combination as first-line pharmacologic therapy, escalate to metoclopramide if inadequate response, reserve ondansetron for second-line use (with caution before 10 weeks gestation), and use methylprednisolone only as a last resort for severe refractory cases. 1, 2
Initial Assessment and Stabilization
Before initiating treatment, assess severity using the Motherisk Pregnancy-Unique Quantification of Emesis (PUQE) score (maximum score 15: ≤6 = mild, 7-12 = moderate, ≥13 = severe) 3, 1. Check electrolyte panel, liver function tests (approximately 50% will have abnormal AST/ALT, rarely >1,000 U/L), and urinalysis for ketonuria 1, 2. Perform abdominal ultrasonography to detect multiple or molar pregnancies and rule out hepatobiliary causes 1, 2.
Immediately start IV fluid resuscitation to correct dehydration, which often improves associated liver enzyme abnormalities 1, 2. Replace electrolytes with particular attention to potassium (aim for ≥3.0 mmol/L) and magnesium levels 1, 2.
Critical Thiamine Supplementation
Thiamine 100 mg daily orally for minimum 7 days is mandatory to prevent Wernicke encephalopathy, as pregnancy depletes thiamine stores within 7-8 weeks of persistent vomiting 1, 2. If vomiting persists or the patient cannot tolerate oral intake, switch immediately to IV thiamine 200-300 mg daily for at least 3-5 days 1, 2. For suspected or confirmed Wernicke's encephalopathy, escalate to thiamine 500 mg IV three times daily (1,500 mg total daily dose) 1.
Stepwise Pharmacologic Algorithm
First-Line: Doxylamine-Pyridoxine
Doxylamine-pyridoxine combination (available as 10 mg/10 mg or 20 mg/20 mg) is the FDA-approved and ACOG-recommended first-line pharmacologic treatment, safe throughout pregnancy and breastfeeding 3, 1, 2. Alternative first-line agents include other antihistamines (promethazine, cyclizine) and phenothiazines (prochlorperazine, chlorpromazine), all sharing similar safety profiles 1, 2.
Second-Line: Metoclopramide (Preferred) or Ondansetron
Metoclopramide is the preferred second-line agent when first-line antihistamines fail, causing less drowsiness, dizziness, dystonia, and fewer discontinuations compared to promethazine in hospitalized patients 1, 2. Metoclopramide is compatible throughout pregnancy and breastfeeding 1.
Ondansetron should be reserved as second-line therapy due to concerns about congenital heart defects when used before 10 weeks gestation, though recent data suggest the risk is low 1, 2. ACOG recommends using ondansetron on a case-by-case basis before 10 weeks of pregnancy 1, 2. Monitor for QT interval prolongation, especially in patients with electrolyte abnormalities 1.
A meta-analysis of 25 studies found no significant efficacy difference among commonly used antiemetics (metoclopramide, ondansetron, promethazine), so medication selection should be based on safety profile and gestational age rather than efficacy alone 1, 2.
Third-Line: Methylprednisolone (Last Resort Only)
Methylprednisolone should be reserved as last resort for severe hyperemesis gravidarum that fails other therapies: 16 mg IV every 8 hours for up to 3 days, then taper over 2 weeks to lowest effective dose, maximum duration 6 weeks 1, 2. Use with caution in first trimester due to slight increased risk of cleft palate when given before 10 weeks gestation 1, 2.
Alternative Refractory Therapies
For cases refractory to standard antiemetics, consider olanzapine, gabapentin, or mirtazapine 1, 4. Mirtazapine acts on noradrenergic, serotonergic, histaminergic, and muscarinic receptors to produce antiemetic, sedative, and appetite-stimulating effects without independent increased risk of birth defects 5.
Non-Pharmacologic Interventions
Implement dietary modifications including small, frequent, bland meals (BRAT diet: bananas, rice, applesauce, toast), high-protein and low-fat meals, and avoidance of spicy, fatty, acidic, and fried foods 3, 1. Identify and avoid specific triggers such as foods with strong odors or certain activities 3. Ginger 250 mg capsule 4 times daily can be helpful 3.
Nutritional Support for Severe Cases
Severe cases with persistent weight loss (>5% of pre-pregnancy weight) and inability to tolerate oral intake may require enteral or parenteral nutrition 1, 4. Feeding jejunostomy is a safe, effective, and well-tolerated mode of nutrition support when standard therapy fails, with minimal complications limited to tube dislodgement 6. For patients on total parenteral nutrition, provide thiamine 200-300 mg daily given the increased metabolic demands and depletion risk 1.
Monitoring and Follow-Up
Regularly assess hydration status, electrolyte balance, and symptom control using PUQE score 1, 2. Check thiamine status (RBC or whole blood thiamine diphosphate) every trimester, particularly in patients with inadequate weight gain or continued weight loss 1. Perform monthly fetal growth monitoring scans from viability in severe cases 1, 2.
Symptoms resolve by week 16 in >50% of patients and by week 20 in 80%, though 10% experience symptoms throughout pregnancy 3, 1, 2. Educate patients about the high recurrence risk (40-92%) in subsequent pregnancies 1.
Critical Pitfalls to Avoid
Withdraw phenothiazines or metoclopramide immediately if extrapyramidal symptoms develop 1, 2. Do not continue escalating promethazine doses when side effects emerge—switch to metoclopramide instead 2. Persistent liver chemistry abnormalities despite symptom resolution should prompt investigation for another etiology 1.
Multidisciplinary Management
Severe refractory cases require coordination of care involving obstetricians, gastroenterologists, nutritionists, and mental health professionals, preferably managed at tertiary care centers with multidisciplinary teams experienced in high-risk pregnancies 1, 2, 4.