Toxicological and histological analyses for a stillborn delivered by a mother under methadone maintenance therapy

Abstract

Purpose Based on autopsy findings and toxicological results, it was ascertained whether chronic fetal exposure to methadone (MTD) could have caused intrauterine death of a fetus born to a mother under MTD maintenance therapy.Methods Complete fetal autopsy, placental examination and toxicological and histological analyses were performed on a 39-week stillborn fetus, whose mother had regularly taken MTD during the pregnancy. The MTD and its main metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) were quantified in fetal tissues (brain, liver and kidney) by ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). A fully validated toxicological analytical method was developed.Results High levels of MTD and EDDP were present in all samples. The EDDP/MTD ratios were similar in the liver and kidney, but in the brain MTD was predominant. Placental histology showed a thrombotic, partially organised lesion in the first branches of the umbilical vein (chorionic venous vessels) and delayed villous maturation (DVM) was diffusely found in the parenchyma.Conclusions High levels of MTD and EDDP correlate with chronic fetal exposure to MTD maintenance therapy in pregnancy. Placenta DVM can be associated with the MTD exposure, indirectly affecting glycaemic balance. Fetal cause of death seemed to be related to a global hypoxic-ischemic status as a combination of chronic fetal MTD intoxication, placental DVM and impaired placenta blood flow due to chorionic thrombosis.

Fetal and Infant Effects of Maternal Opioid Use during Pregnancy: A Literature Review including Clinical, Toxicological, Pharmacogenomic, and Epigenetic Aspects for Forensic Evaluation

“…The results of the literature search are summarized in Figure 1 . A total of 87 studies met the inclusion criteria and were included in the review [ 1 , 2 , 5 , 6 , 9 , 11 , 12 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , …”

“…A recent case concerned a stillborn infant whose mother was receiving MTD maintenance therapy. The reported cause of death was identified as a fatal hypoxic–ischemic condition resulting from a combination of chronic exposure to MTD during fetal development, widespread placental vascular abnormalities, and partial non-occlusive thrombosis in both the umbilical vein and its chorionic branches [ 47 ]. The IUFD occurred at 39 weeks of gestation, and the baby presented intrauterine growth restriction with asymmetrical growth and lower anthropometrical parameters (weight, head circumference, crown heel length).…”

“…Similar EDDP/methadone ratios were observed in the liver and kidneys, but in the brain, MTD was predominant. Difficulties of EDDP passing through the blood–brain barrier may be the explanation of the inverted EDDP/MTD ratio observed in the brain [ 47 ].…”

“…The stillborn was also homozygous for wild-type alleles in all typed SNPs in ABCB1 [rs1128503 (GG), rs2032582 (CC), rs1045642 (GG), rs2229109 (GG), and rs9282564 (TT) and for the wild-type allele rs1799971 in OPRM1 . The stillborn could not have had a consistent metabolism of methadone and consistent excretion, given the expected outcome of premature death [ 47 ].…”

Synthetic Cathinones and Neurotoxicity Risks: A Systematic Review

“…One case dealt with death in utero in a pregnant woman exposed to MDPHP [ 107 ]. Stillbirths secondary to drug exposure are rarely described in the literature; however, some case reports described death in utero after exposure to methadone [ 108 ] or to cocaine and methamphetamine [ 109 ].…”