Hyperemesis Gravidarum: Comprehensive Overview
Definition
Hyperemesis gravidarum is an intractable form of nausea and vomiting in pregnancy characterized by persistent vomiting, weight loss ≥5% of pre-pregnancy weight, dehydration, and ketonuria, affecting 0.3-2% of pregnancies. 1
- Symptoms typically begin before week 22 of gestation 1
- Resolution occurs by week 16 in >50% of patients and by week 20 in 80% 1, 2
- 10% of patients experience symptoms throughout the entire pregnancy 1, 2
- This represents a distinct entity from typical morning sickness, requiring medical intervention 3
Pathophysiology
The underlying mechanisms involve multiple interacting factors:
Hormonal Factors
- Elevated human chorionic gonadotropin (hCG) levels correlate with symptom severity 1
- Increased estrogen levels contribute to nausea and vomiting 1
- Elevated growth or differentiation factor-15 (GDF-15) levels in maternal blood play a role 1
Gastrointestinal Dysfunction
- Pregnancy-induced gastrointestinal dysmotility contributes to symptom development 4
- Possible association with Helicobacter pylori infection 4
Metabolic Consequences
- Thiamine depletion occurs rapidly within 7-8 weeks of persistent vomiting 1
- Thiamine reserves can be completely exhausted after only 20 days of inadequate oral intake 1
- Pregnancy itself increases thiamine requirements, accelerating depletion 1
Risk Factors
Prior history of hyperemesis gravidarum is the strongest predictor of recurrence, with a 40-92% risk in subsequent pregnancies. 1, 2
Medical Risk Factors
- Hyperthyroid disorders 1
- Previous molar pregnancy 1
- Pre-existing diabetes mellitus 1
- Pre-existing asthma 1
- Psychiatric illness 1
Pregnancy-Related Factors
Clinical Assessment and Diagnosis
Essential History Components
- Previous pregnancy outcomes and history of hyperemesis 1
- Pre-existing medical conditions 1
- Vomiting frequency (≥5-7 episodes daily indicates severe disease) 1
- Ability to maintain oral intake (<1000 kcal/day for several days indicates need for escalation) 1
Physical Examination Focus
- Signs of dehydration (decreased urine output, elevated BUN/creatinine ratio) 1
- Evaluation for malnutrition and weight loss 1
- Neurologic examination for confusion, ataxia, or eye movement abnormalities suggesting Wernicke's encephalopathy 1
Severity Assessment
- Use the Pregnancy-Unique Quantification of Emesis (PUQE) score serially to track symptom severity 1, 2
Laboratory Evaluation
- Electrolyte panel with particular attention to potassium and magnesium 1, 2
- Liver function tests (50% of patients have abnormal AST/ALT, rarely >1,000 U/L) 1
- Urinalysis for ketonuria 1, 2
- Venous blood gas for metabolic alkalosis 1
- Thiamine status (RBC or whole blood thiamine diphosphate) every trimester 1
- Thyroid function tests only if clinical signs of hyperthyroidism present 1
Imaging
- Abdominal ultrasonography to detect multiple or molar pregnancies and rule out hepatobiliary, vascular, or renal causes 1, 2
Management Strategies
Initial Stabilization
Immediate IV fluid resuscitation to correct dehydration is the cornerstone of acute management, targeting urine output of at least 1 L/day. 1, 2
Fluid Management
- Monitor for resolution of ketonuria as objective marker of adequate rehydration 1
- Avoid hypotonic fluids; use glucose-electrolyte oral rehydration solutions when oral intake resumes 1
- Target near-zero fluid balance once initial dehydration is corrected 1
Electrolyte Replacement
- Correct potassium and magnesium immediately to prevent cardiac arrhythmias 1, 3
- Perform electrocardiography to assess QT interval, as hypokalemia with or without hypomagnesemia prolongs QT and increases arrhythmia risk 1
- During pregnancy, serum potassium decreases by 0.2-0.5 mmol/L around midgestation; hyperemesis exacerbates this 1
- Monitor electrolyte levels during labor if delivery occurs 1
Thiamine Supplementation (Critical)
Thiamine 100 mg daily orally for minimum 7 days, then 50 mg daily maintenance until adequate oral intake is established, is mandatory to prevent Wernicke's encephalopathy. 1, 2
- If vomiting persists or patient cannot tolerate oral intake, switch immediately to IV thiamine 200-300 mg daily 1, 2
- For suspected or confirmed Wernicke's encephalopathy: thiamine 500 mg IV three times daily (1,500 mg total daily dose) 1
- Use IV or IM route for any acute presentation with severe vomiting, as oral absorption is unreliable 1
- For patients on total parenteral nutrition: provide 200-300 mg daily 1
Dietary Modifications
- Small, frequent, bland meals (BRAT diet: bananas, rice, applesauce, toast) 1, 2
- High-protein, low-fat meals 1
- Avoidance of specific food triggers and strong odors 1, 2
- Advance slowly over days in patients at risk of refeeding syndrome 1
- Ginger supplementation 250 mg capsule four times daily may be considered 1
Pharmacologic Management: Stepwise Algorithm
First-Line Therapy
Doxylamine 10-20 mg combined with pyridoxine (vitamin B6) 10-20 mg every 8 hours is the preferred initial antiemetic, safe throughout pregnancy and breastfeeding. 1, 2
- Pyridoxine monotherapy (10-25 mg every 8 hours) may be used for mild cases 1
- Alternative first-line agents include other antihistamines (promethazine, cyclizine) and phenothiazines (prochlorperazine, chlorpromazine) with similar safety profiles 1, 2
- Promethazine is acceptable but causes significantly more drowsiness, dizziness, dystonia, and treatment discontinuations compared to metoclopramide 2
- Withdraw phenothiazines immediately if extrapyramidal symptoms develop 1, 2
Second-Line Therapy
Metoclopramide 5-10 mg orally every 6-8 hours is the preferred second-line agent when first-line antihistamines fail, with less drowsiness and fewer side effects than promethazine. 1, 2
- No increased risk of major congenital defects in meta-analysis of 33,000 first-trimester exposures (OR 1.14,99% CI 0.93-1.38) 1
- Withdraw immediately if extrapyramidal symptoms develop 1
- Compatible throughout pregnancy and breastfeeding 1
Ondansetron should be reserved as second-line therapy and used on a case-by-case basis before 10 weeks gestation due to concerns about congenital heart defects in the first trimester. 1, 2
Ondansetron Dosing Options
- 8 mg orally every 8 hours (oral dissolving tablet or oral soluble film) 2
- Alternative: 16 mg orally as single dose, then 8 mg twice daily 2
- IV: 8 mg IV or 0.15 mg/kg IV as single dose 2
- Refractory cases: 8 mg IV bolus followed by 1 mg/hour continuous infusion 2
- Monitor for QT interval prolongation, especially with electrolyte abnormalities 1
- Compatible throughout pregnancy and breastfeeding 1
Important Note: 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 Therapy (Severe Refractory Cases)
Methylprednisolone should be reserved as last resort for severe hyperemesis gravidarum that fails both antihistamines and metoclopramide/ondansetron. 1, 2
Methylprednisolone Protocol
- 16 mg IV every 8 hours for up to 3 days 1, 2
- Then taper over 2 weeks to lowest effective dose 1, 2
- Maximum duration 6 weeks 1, 2
- Use with caution before 10 weeks gestation due to slight increased risk of cleft palate 1, 2
- Reduces rehospitalization rates in severe refractory cases 1
Alternative Agents for Exceptional Cases
Olanzapine should only be considered in exceptional cases after failure of guideline-directed therapy, preferably at tertiary care centers with multidisciplinary involvement. 1
- Based on efficacy in chemotherapy-induced nausea (70% no emesis, 68% no nausea in oncology patients) 1
- Not included in current guideline-directed therapy 1
- Do not skip the stepwise approach and jump directly to olanzapine 1
Escalation Criteria and Advanced Management
When to Switch from PRN to Scheduled Dosing
Worsening symptoms after intermittent treatments indicate inadequate continuous coverage; switch to around-the-clock scheduled antiemetic administration rather than PRN dosing. 1
Indications for Hospitalization
- Frequent vomiting (≥5-7 episodes daily) despite maximal antiemetics 1
- Progressive weight loss ≥5% of pre-pregnancy weight 1
- Inability to maintain oral intake of 1000 kcal/day for several days 1
- Electrolyte abnormalities requiring IV correction 1
- Need for continuous IV therapy 1
Enteral Feeding Indications
Enteral feeding should be considered only after failure of maximal medical therapy, not for nausea or food aversions alone. 1
- Nasojejunal feeding is preferred over nasogastric feeding due to better tolerance 1
- Consider before escalating to total parenteral nutrition 1
- Reserve for patients with escalating symptoms despite maximal antiemetics 1
Monitoring During Treatment
- Daily monitoring of body weight, urine output, electrolytes, and renal function until stable 1
- Serial PUQE scores to track symptom trajectory 1
- Monthly fetal growth monitoring scans from viability in severe cases 1, 2
- Check thiamine status every trimester, particularly with inadequate weight gain 1
Common Pitfalls and How to Avoid Them
Thiamine Deficiency
- Never delay thiamine supplementation in patients with prolonged vomiting; Wernicke's encephalopathy can develop rapidly 1, 2
- Always use IV thiamine if patient cannot tolerate oral intake 1
Electrolyte Management
- Do not tell patients to "drink more water"; hypotonic fluids worsen fluid losses 1
- Always correct potassium and magnesium before assuming cardiac symptoms are unrelated 1, 3
- Avoid drugs that prolong QT interval (proton-pump inhibitors, macrolides, fluoroquinolones) in patients with electrolyte abnormalities 1
Medication Sequencing
- Do not skip the stepwise approach; jumping to corticosteroids or olanzapine without trying first- and second-line agents violates evidence-based guidelines 1, 2
- Do not continue escalating promethazine doses when side effects emerge; switch to metoclopramide instead 2
Thyroid Testing
- Routine thyroid testing is not recommended unless other clinical signs of hyperthyroidism are present 1
- Biochemical hyperthyroidism is common but self-limited, rarely requiring treatment 1
Liver Enzyme Elevation
- Persistent liver chemistry abnormalities despite symptom resolution should prompt investigation for another etiology 1
- Perform abdominal ultrasound to rule out gallstones or cholecystitis 1
Multidisciplinary Management
Severe refractory cases require involvement of maternal-fetal medicine, gastroenterology, nutrition services, and mental health professionals, preferably at tertiary care centers. 1, 2
- Mental health support is important as anxiety and depression are common with severe hyperemesis 1
- Coordinate care early for high-risk pregnancies 1
- Consider delivery in hospital to reduce risks of maternal complications 1
Prognosis and Complications
Maternal Complications
- Wernicke's encephalopathy if thiamine deficiency develops 1, 2
- Electrolyte imbalances and cardiac arrhythmias 1, 3
- Refeeding syndrome with rapid nutritional repletion 1
- Decreased quality of life 1
Fetal Complications
Recurrence Risk
- 40-92% recurrence risk in subsequent pregnancies 1, 2
- Educate patients about this high recurrence risk for future pregnancy planning 1
Special Considerations
Patients with Adjustable Gastric Bands
- Deflation may be necessary to prevent band slippage and nutrient deficiencies 1
Patients with Bartter Syndrome
- Aim for plasma potassium levels ≥3.0 mmol/L 1