Toxicological and histological analyses for a stillborn delivered by a mother under methadone maintenance therapy
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.
Complete fetal autopsy, placental examination and toxicological and histological analyses were performed on a 39-week-old 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. A fully validated toxicological analytical method was developed.
High levels of MTD and EDDP were present in all samples. The EDDP-to-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) diffusely found in the parenchyma.
High levels of MTD and EDDP correlated 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.
KeywordsMethadone EDDP Human fetus Placenta Stillborn Histopathology
Compliance with ethical standards
Conflict of interest
The authors have no financial or other relations that could lead to a conflict of interest.
In Italy, there is no legislation that forbids the use of human tissues collected during an autopsy, provided that the samples are made anonymous and linked exclusively to codes.
- 2.Jones HE, Johnson RE, Jasinski DR, O’Grady KE, Chisholm CA, Choo RE, Crocetti M, Dudas R, Harrow C, Huestis MA, Jansson LM, Lantz M, Lester BM, Milio L (2005) Buprenorphine versus methadone in the treatment of pregnant opioid-dependent patients: effects on the neonatal abstinence syndrome. Drug Alcohol Depend 79:1–10CrossRefPubMedGoogle Scholar
- 4.Zedler BK, Mann AL, Kim MM, Amick HR, Joyce AR, Murrelle EL, Jones HE (2016) Buprenorphine compared with methadone to treat pregnant women with opioid use disorder: a systematic review and meta-analysis of safety in the mother, fetus and child. Addiction 111:2115–2128CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Kraus FT, Redline RW, Gersell DJ, Nelson DM, Dicke JM (eds) (2005) Placental pathology (atlas of nontumor pathology), 1st edn. American Registry of Pathology, Rockville (Series Fascicle 3) Google Scholar
- 33.Wigglesworth J (1996) Prenatal pathology, 2nd edn. Saunders, PhiladelphiaGoogle Scholar