Transplacental transport of N-acetylcysteine in an ovine model

Study objective: Acetaminophen freely crosses the placenta, and acetaminopheningestion is the most frequent intentional overdose in pregnancy. Although most patients do well after maternal treatment with the antidote N-acetylcysteine (NAC), fetal death with massive hepatic necrosis has occurred. It has never been shown whether NAC crosses the placenta to yield fetal plasma levels equal to those associated with hepato-protective effects in human beings. Our study objective was to evaluate this in a widely accepted large animal model for maternal-fetal research. Design and type of participants: A nonblinded experiment was performed using four domestic sheep at near-term gestation. Interventions: NAC 150 mglkg IV was administered to the ewe over 15minutes. After induction of anesthesia, the fetal head was delivered surgically and a neck vein cannulated for blood sampling. Maternal and fetal blood samples were obtained at the end of NAC infusion, at 30- and then at 60-minute intervals for four hours. Plasma NAC levels were determined by gas chromatography/mass spectroscopy (detection limit, 2 μg/m; quantification limit, 5 μg/mL). Results: Maternal peak plasma NAC levels were 619, 631, 1.757, and 2.512, μg/mL, respectively, within 30 minutes of infusion. However, NAC was only minimally detectable in plasma of two fetal animals and transiently reached quantifiable levels in two others. None of the fetal animals attained serial plasma NAC levels that equalled those associated with therapeutic dosing or hepatoprotective effects in human beings. Conclusion: Transplacental transport of NAC is clinically insignificantin a mammalian model resembling the human being. These findings suggest that the human fetal liver is not protected from acetaminophen toxicity by maternal NAC therapy.