Developmental effects of propyphenazone in analgesic and antipyretic combination with caffeine or paracetamol

The aim of the study was to determine the influence of an over-the-counter (OTC) mixture of propyphenazone with caffeine or paracetamol on prenatal development. Propyphenazone:caffeine and propyphenazone:paracetamol mixtures were prepared with constant 3:1 and 3:5 ratios, respectively. Three dose levels of each of the mixtures were administered separately in Tween-80 water suspension once a day to pregnant Wistar rats on gestation days 8-14. The low dose was similar to the OTC preparations, 2.1 mg/kg of propyphenazone, 0.7 mg/kg of caffeine or 3.5 mg/kg of paracetamol. The middle dose was 21.0, 7.0 or 35.0 mg/kg, and the highest 210.0, 70.0 or 350.0 mg/kg for propyphenazone, caffeine or paracetamol, respectively. On day 21 of gestation the fetuses were delivered by hysterectomy. Dead or live fetuses, resorptions and the number of implantation sites were counted. Live fetuses were examined for external, visceral and skeletal malformation. Postimplantation mortality was calculated. Dose-dependent effects in the middle and high dose groups on fetal body weight/length and placental weight were found. No increase in external or internal congenital anomalies was found in any of the mixture-exposed groups. Prenatal coadministration of propyphenazone with caffeine or paracetamol caused intrauterine growth retardation but did not increase external or internal congenital anomalies. The risk of midline defects (umbilical hernia and gastroschisis) is discussed.