Hyperemesis gravidarum revisited: from GDF15 biology to precision multimodal therapy

Hyperemesis gravidarum (HG) is a severe and potentially life-threatening form of nausea and vomiting in pregnancy, characterized by intractable vomiting, dehydration, electrolyte imbalance, nutritional deficiencies, and significant weight loss. Despite being a leading cause of early pregnancy hospitalization, its management remains inconsistent and often empirical. Emerging evidence suggests a paradigm shift in the understanding of HG pathophysiology, moving beyond traditional hormonal theories toward an integrated model involving genetic susceptibility and metabolic signaling pathways, particularly Growth Differentiation Factor 15 (GDF15) and RYR2-related mechanisms. This narrative review critically synthesizes current evidence regarding the evolving biological basis of HG and evaluates established and emerging therapeutic strategies. A multimodal, stepwise approach remains the cornerstone of management. First-line pharmacotherapy includes doxylamine-pyridoxine, followed by dopamine antagonists or 5-HT3 receptor antagonists such as metoclopramide and ondansetron, which demonstrate reassuring safety profiles in large cohort studies. Corticosteroids may be considered in refractory cases. Early correction of dehydration, electrolyte disturbances, and thiamine deficiency is essential to prevent complications such as Wernicke's encephalopathy. Nutritional support, preferably through enteral tube feeding rather than parenteral nutrition, should be prioritized when oral intake is inadequate. Integrating biological insights with standardized, compassionate, and multidisciplinary care may improve clinical outcomes and reduce the substantial physical and psychological burden associated with HG.