The importance of the toxicological analysis in newborns: Clearing the case of a tetralogy of Fallot with a paradoxical reaction to 1-hydroxymidazolam

Short half-life benzodiazepines like midazolam are used as premedication to relieve intra-partum pain, and are known to have no adverse effects to the newborn. However, such short-acting drugs are known to induce paradoxical reactions when their concentration is abnormally elevated respect to the age of the subject. In a 1 day-old newborn, admitted to the Cardiology Unit of the "Bambino Gesù" Children Hospital of Rome due to a prenatal diagnosis of tetralogy of Fallot, a paradoxical reaction with a spontaneous resolution was observed. The analysis of urines, performed by gas chromatography/ mass spectrometry after a drug screening, showed the presence of the active metabolite 1-hydroxymidazolam at 9.7 μg/mL with no detectable trace of its precursor midazolam and of the alternative metabolite 4-hydroxymidazolam. On the basis of these evidences, we speculated that 1-hydroxymidazolam, produced by the mother's liver enzymes, passed to the newborn whose reduced volume of distribution (for the shunted circulation) favoured the onset of such a reaction. Hence, the toxicological approach should be carried out on both mother and child wherever the clinical picture may appear unexplainable or does not match with the other findings collected.