What is the recommended stepwise treatment for hyperemesis gravidarum in a pregnant woman in the first or early second trimester who has persistent vomiting, inability to maintain oral intake, >5% pre‑pregnancy weight loss, dehydration, and electrolyte disturbances?

Hyperemesis Gravidarum Treatment

For a pregnant woman in the first or early second trimester with persistent vomiting, inability to maintain oral intake, >5% pre-pregnancy weight loss, dehydration, and electrolyte disturbances, initiate immediate intravenous fluid resuscitation with aggressive electrolyte replacement (particularly potassium and magnesium), thiamine supplementation, and stepwise antiemetic therapy starting with doxylamine-pyridoxine, escalating to metoclopramide or ondansetron for inadequate response, and reserving methylprednisolone only for severe refractory cases. 1

Immediate Stabilization

Fluid Resuscitation

• Begin IV fluid resuscitation targeting urine output ≥1 L/day and resolution of ketonuria as objective markers of adequate rehydration 1
• Monitor for resolution of orthostatic hypotension, improved skin turgor, and moist mucous membranes 1
• Check daily weights, electrolytes, renal function, and venous blood gas for metabolic alkalosis until stable 1

Critical Electrolyte Replacement

• Aggressively replace potassium and magnesium immediately because hypokalemia with hypomagnesemia prolongs QT interval and increases risk of ventricular arrhythmias 1
• Perform electrocardiography to assess QT interval in all patients with documented electrolyte abnormalities 1
• Note that normal pregnancy decreases serum potassium by 0.2-0.5 mmol/L around midgestation, so hyperemesis gravidarum necessitates early parenteral supplementation 1
• Avoid drugs that prolong QT interval or exacerbate hypomagnesemia (proton-pump inhibitors, macrolides, fluoroquinolones) 1

Thiamine Supplementation (Critical to Prevent Wernicke's Encephalopathy)

• If patient can tolerate oral intake: Thiamine 300 mg orally daily plus vitamin B compound strong 2 tablets three times daily 1
• If vomiting persists or oral intake impossible: Switch immediately to IV thiamine 200-300 mg daily for at least 3-5 days, then oral maintenance 50-100 mg daily once vomiting controlled 1
• Pregnancy increases thiamine requirements, and hyperemesis gravidarum depletes stores within 7-8 weeks of persistent vomiting; reserves can be exhausted after only 20 days of inadequate intake 1
• Continue thiamine supplementation until adequate oral intake is established and throughout pregnancy if symptoms persist 1

Stepwise Pharmacologic Management

First-Line Therapy (Initiate Immediately)

• Doxylamine-pyridoxine combination (10-20 mg each) is the preferred initial antiemetic and is safe throughout pregnancy and breastfeeding 1
• Alternative first-line agents include promethazine or other H1-antihistamines, all sharing similar safety profiles 1
• Pyridoxine (vitamin B6) alone at 10-25 mg every 8 hours may be used for milder cases 1
• Ginger 250 mg capsules four times daily can be added for additional symptom relief 1

Second-Line Therapy (If First-Line Fails After 24-48 Hours)

• Metoclopramide 5-10 mg IV or orally every 6-8 hours is the preferred second-line agent due to less drowsiness, dizziness, dystonia, and fewer discontinuations compared to promethazine 1
• Metoclopramide has no increased risk of major congenital defects based on meta-analysis of 33,000 first-trimester exposures (OR 1.14,99% CI 0.93-1.38) 1
• Ondansetron 8 mg IV or orally every 8 hours 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
• Use ondansetron on a case-by-case basis before 10 weeks of pregnancy 1
• Monitor for QT interval prolongation with ondansetron, especially in patients with electrolyte abnormalities 1
• Withdraw phenothiazines or metoclopramide immediately if extrapyramidal symptoms develop 1

Third-Line Therapy (Severe Refractory Cases Only)

• Methylprednisolone 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
• Reserve corticosteroids only for severe hyperemesis gravidarum that fails both first-line antihistamines and second-line metoclopramide/ondansetron 1
• Use with caution in first trimester due to slight increased risk of cleft palate when given before 10 weeks gestation 1
• Note that one randomized controlled trial showed no reduction in rehospitalization rates with corticosteroids (34% vs 35%, P=0.89), though this may reflect inadequate dosing or timing 2

Dietary Modifications (Implement Concurrently)

• Small, frequent, bland meals using BRAT diet (bananas, rice, applesauce, toast) 1
• High-protein, low-fat meals 1
• Avoidance of strong odors and specific food triggers 1
• When oral intake resumes, use glucose-electrolyte oral rehydration solutions rather than plain water, as hypotonic fluids can worsen fluid losses 1

Monitoring and Reassessment

Objective Markers of Clinical Improvement

• Sustained oral intake without immediate vomiting 1
• Weight stabilization or gain (not continued loss) 1
• Resolution of ketonuria 1
• Normalization of electrolytes 1
• Reduced vomiting frequency 1
• Improved functional capacity 1

Serial Assessment

• Use the Motherisk Pregnancy-Unique Quantification of Emesis (PUQE) score serially to track symptom severity 1
• Reassess every 1-2 weeks during the acute phase 1
• Check thiamine status every trimester, particularly in patients with inadequate weight gain or continued weight loss 1

Management of Refractory Cases

When Symptoms Worsen Despite Treatment

• Switch from PRN or intermittent dosing to around-the-clock scheduled antiemetic administration if symptoms worsen after intermittent IV treatments 1
• Consider hospitalization for continuous therapy rather than twice-weekly outpatient IV treatments 1

Enteral Feeding Indications

• Consider nasojejunal feeding (preferred over nasogastric due to better tolerance) for patients with: 1
  • Frequent vomiting ≥5-7 episodes daily despite maximal antiemetics
  • Progressive weight loss ≥5% of pre-pregnancy weight
  • Inability to maintain oral intake of 1000 kcal/day for several days
• Nasojejunal feeding should be considered before escalating to total parenteral nutrition 1

Alternative Pharmacotherapeutics (Exceptional Cases Only)

• Olanzapine should only be considered in exceptional cases and is not included in current guideline-directed therapy 1
• Do not skip the stepwise approach and jump directly to olanzapine, as this violates evidence-based guidelines 1
• Mirtazapine has been described in case studies for refractory cases but lacks robust evidence in pregnancy 3, 4

Expected Timeline and Prognosis

• Symptoms resolve by week 16 in >50% of patients and by week 20 in 80% 1
• 10% may experience symptoms throughout pregnancy 1
• Recurrence risk in subsequent pregnancies ranges from 40-92% 1

Multidisciplinary Coordination for Severe Cases

• Involve maternal-fetal medicine, gastroenterology, nutrition services, and mental health professionals for severe refractory cases 1
• Mental health support is important as anxiety and depression are common with severe hyperemesis gravidarum 1
• Preferably manage at tertiary care centers with multidisciplinary teams experienced in high-risk pregnancies 1

Critical Pitfalls to Avoid

• Do not delay thiamine supplementation – start immediately with IV or oral route depending on ability to tolerate oral intake 1
• Do not use PRN antiemetics in refractory cases – switch to scheduled around-the-clock administration 1
• Do not tell patients to "drink more water" – use glucose-electrolyte solutions when oral intake resumes 1
• Do not withhold aggressive potassium and magnesium replacement – these are critical to prevent cardiac arrhythmias 1
• Do not skip the stepwise approach – reserve corticosteroids and alternative agents only for true refractory cases 1

Special Considerations

• Biochemical hyperthyroidism is common in hyperemesis gravidarum but rarely requires treatment, as it is self-limited and resolves as the condition improves 1
• Routine thyroid testing is not recommended unless other signs of clinical hyperthyroidism are present 1
• Elevated liver enzymes occur in 40-50% of patients (rarely >1,000 U/L); persistent abnormalities despite symptom resolution should prompt investigation for alternative hepatobiliary causes 1
• Abdominal ultrasound should be performed to exclude multiple or molar pregnancy, gallstones, cholecystitis, and other hepatobiliary disease 1