Abstract
OBJECTIVE: To evaluate the association between maternal analgesic exposure in late pregnancy and fetal ductal and pulmonary hemodynamics using serial echocardiographic assessment, and to explore potential differences between metamizole and acetaminophen. METHODS: In this prospective cohort study, 67 third-trimester pregnancies were evaluated: 47 exposed to analgesics (27 metamizole and 20 acetaminophen) and 20 unexposed controls. Two standardized fetal echocardiograms were performed: during exposure (T1) and after a 5-7 day drug-free interval (T2). Ductal Doppler parameters, including systolic velocity, diastolic velocity, and pulsatility index (PI), were used to define ductal constriction based on established criteria (PI < 1.9 and/or increased velocities). Right-heart and pulmonary hemodynamic parameters, including mean pulmonary artery pressure (MPAP) and acceleration time/ejection time ratio (AT/ET), were also assessed. RESULTS: In the primary pooled analysis, ductal constriction occurred in 38.3% (18/47) of exposed fetuses and in 0% (0/20) of controls (p = 0.00065). When stratified by exposure, constriction was observed in 52% (14/27) of metamizole-exposed fetuses and in 20% (4/20) of acetaminophen-exposed fetuses. In multivariable analysis, metamizole use (OR 2.05; 95% CI 1.28-3.28), exposure within 48 h (OR 1.96; 95% CI 1.12-3.44), and dose > 1 g (OR 2.64; 95% CI 1.31-5.32) were independently associated with ductal constriction. Within the metamizole group, higher doses were associated with a greater proportion of constriction, although subgroup size limited statistical precision. After metamizole withdrawal, PI increased significantly (1.86 ± 0.43 to 2.28 ± 0.41; p < 0.001), accompanied by reductions in systolic and diastolic velocities (p < 0.05). In the acetaminophen group, mild and reversible constriction was observed, with modest PI improvement at T2 (2.20 ± 0.44 to 2.40 ± 0.29; p = 0.040) and no major velocity changes. Neither exposure significantly altered MPAP or AT/ET. CONCLUSIONS: Maternal exposure to analgesics in late pregnancy was associated with fetal ductal constriction compared with unexposed controls. The association was stronger for metamizole and consistent with a dose-related pattern. Acetaminophen was associated with mild, reversible ductal involvement in a subset of fetuses. Reversibility after drug withdrawal supports a functional, prostaglandin-mediated mechanism. These findings have important implications for maternal analgesic use in late gestation and highlight the value of Doppler surveillance following exposure to prostaglandin-modulating agents.