LAUSR

The indirect effect of maternal drug exposure on the fetus may include serious consequences such as neonatal abstinence syndrome or, more rarely, intrauterine fetal death (IUFD). Kalin [1] reported the incidence of fetal drug exposure in 39 of 58 fetal/neonatal deaths among a total of 23,400 general fatalities; notably, only 39 of the cases provided toxicological analyses. Toxicological analyses showed positive results in 22 of 39 cases (17/39 had negative toxicological results). In only 2/22 cases, IUFD was attributed to drug intoxication, as high levels of methamphetamine (1200–1500 ng/mL) were detected in fetal blood. In the other 20 cases, drug was detected in such a small amount that it was considered an occasional finding; the main causes of death were placental abruption/prematurity/stillbirth in 13 cases, maternal drug abuse associated with fetal asphyxia in two cases, chorioamnionitis in one case, drowning in one case, car accident in one case and undetermined in two cases. Focusing exclusively on direct fetal methadone (MTD) toxicity, IUFD due to maternal MTD exposure is extremely rare. Kalin [1] identified only one fetal death combined with MTD exposure but not directly caused by it. The mother was under MTD maintenance therapy (MMT) when she was involved in a car accident. The mother and fetus died because of lesions related to the accident, and despite a high MTD concentration in fetal chest blood [MTD: 410 ng/mL; 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) 58 ng/mL] and in liver tissue (1900 ng/mL), drug accumulation was considered an occasional finding. The previous report [2] by our group described the unique case of a stillborn delivered by a mother under MMT; the fetal death was directly ascribable to MTD. IUFD was associated with chronic MTD exposure and to drug accumulation in the liver, kidney and brain. A high MTD fetal tissue concentration likely caused cerebral asphyxia and delayed villous maturation in the placenta. Toxicological analyses revealed high levels of MTD and EDDP in the liver (2200 and 5720 ng/g, respectively), in the kidneys (15,000 and 31,300 ng/g, respectively) and in the brain (6180 and 530 ng/g, respectively); unfortunately, fetal blood was not available. The stillborn described by our group must be considered an exceptional event given that MTD has been recommended for treating heroin addiction during pregnancy since the early 1970s, and is considered extremely safe at therapeutic dosages. The IUFD rate is not increased during MTD usage [3]; merely report of reductions in fetal breathing and movements in MTD-exposed fetuses is available [4]. As previously stated, because of the safety of fetal MTD exposure, the stillborn case reported by our group may reveal a potential altered MTD metabolism due to a unique genetic profile [2]. Cytochrome P450 (CYP) 2B6 and ATP binding cassette sub-family-B member (ABCB1) polymorphic variations can modify MTD metabolism. CYP2B6 is the most popular gene studied in cases of MTD intoxication both in healthy patients [5–15] and fatalities [16–20]. CYP2B6 * Eva Montanari [email protected]