Maternal Analgesic Exposure and Fetal Ductal Constriction: A Prospective Cohort Study in Late Pregnancy

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.

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.

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.

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.