Maternal methadone dose, placental methadone concentrations, and neonatal outcomes.
BACKGROUND
Few investigations have used placenta as an alternative matrix to detect in utero drug exposure, despite its availability at the time of birth and the large amount of sample. Methadone-maintained opioid-dependent pregnant women provide a unique opportunity to examine the placental disposition of methadone and metabolite [2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)], to explore their correlations with maternal methadone dose and neonatal outcomes, and to test the ability to detect in utero exposure to illicit drugs.


METHODS
We calculated the correlations of placental methadone and EDDP concentrations and their correlations with maternal methadone doses and neonatal outcomes. Cocaine- and opiate-positive placenta results were compared with the results for meconium samples and for urine samples collected throughout gestation.


RESULTS
Positive correlations were found between placental methadone and EDDP concentrations (r=0.685), and between methadone concentration and methadone dose at delivery (r=0.542), mean daily dose (r=0.554), mean third-trimester dose (r=0.591), and cumulative daily dose (r=0.639). The EDDP/methadone concentration ratio was negatively correlated with cumulative daily dose (r=-0.541) and positively correlated with peak neonatal abstinence syndrome (NAS) score (r=0.513). Placental EDDP concentration was negatively correlated with newborn head circumference (r=-0.579). Cocaine and opiate use was detected in far fewer placenta samples than in thrice-weekly urine and meconium samples, a result suggesting a short detection window for placenta.


CONCLUSIONS
Quantitative methadone and EDDP measurement may predict NAS severity. The placenta reflects in utero drug exposure for a shorter time than meconium but may be useful when meconium is unavailable or if documentation of recent exposure is needed.
Chemistry and Drug Metabolism, National Institute on Drug Abuse, NIH, Baltimore, MD 21224, USA.
Ana
A
de Castro
Hendreé E
HE
Jones
Rolley E
RE
Johnson
Teresa R
TR
Gray
Diaa M
DM
Shakleya
Marilyn A
MA
Huestis
D000701:Analgesics, Opioid / Q000652:urine; D001034:Apgar Score; D001724:Birth Weight / Q000187:drug effects; D049628:Body Size / Q000187:drug effects; D002508:Cephalometry; D003042:Cocaine / Q000652:urine; D005260:Female; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D018811:Maternal Exposure / Q000009:adverse effects; D008470:Meconium / Q000737:chemistry; D008691:Methadone / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D058850:Opiate Substitution Treatment / Q000379:methods*; D009293:Opioid-Related Disorders / Q000378:metabolism* / Q000534:rehabilitation / Q000652:urine; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism* / Q000534:rehabilitation / Q000652:urine; D011256:Pregnancy Outcome; D011264:Pregnancy Trimesters; D011759:Pyrrolidines / Q000378:metabolism; D014018:Tissue Distribution
D000701:Analgesics, Opioid; D011759:Pyrrolidines; D003042:Cocaine; D008691:Methadone; C010724:2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine
Ther Drug Monit. 2007 Feb;29(1):127-9
17304161
Drug Alcohol Depend. 2004 Sep 6;75(3):253-60
15283946
Dev Pharmacol Ther. 1985;8(6):384-95
4075937
Clin Pharmacokinet. 2004;43(8):487-514
15170365
J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Sep 1;856(1-2):267-72
17602899
Arch Dis Child Fetal Neonatal Ed. 2005 May;90(3):F276-7
15846024
J Chromatogr B Analyt Technol Biomed Life Sci. 2005 Jan 25;814(2):369-73
15639461
Drug Alcohol Depend. 2005 Jul;79(1):1-10
15943939
Obstet Gynecol. 1993 Jun;81(6):936-40
8497359
Expert Opin Drug Metab Toxicol. 2005 Oct;1(3):447-71
16863455
J Subst Abuse Treat. 2007 Jan;32(1):19-25
17175395
J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Apr 13;834(1-2):188-94
16517229
J Chromatogr B Biomed Sci Appl. 1998 Aug 21;713(1):137-46
9700556
Arch Dis Child Fetal Neonatal Ed. 2004 Sep;89(5):F390-3
15321955
Anal Bioanal Chem. 2009 Apr;393(8):1977-90
19241063
Clin Toxicol (Phila). 2007;45(3):295-8
17453885
Forensic Sci Int. 2002 Aug 14;128(1-2):20-30
12208017
Drug Alcohol Depend. 2000 Dec 22;61(1):47-54
11064183
Am J Obstet Gynecol. 1974 Dec 1;120(7):895-900
4429107
J Hum Lact. 2007 May;23(2):184-90
17478871
Clin Pharmacol Ther. 2004 Sep;76(3):250-69
15371986
J Chromatogr B Analyt Technol Biomed Life Sci. 2008 May 15;867(2):219-25
18436488
J Paediatr Child Health. 1991 Apr;27(2):96-100
1883657
Pediatrics. 2008 Jan;121(1):106-14
18166563
Anal Bioanal Chem. 2009 May;394(2):513-22
19247639
Biochem Pharmacol. 2004 Aug 1;68(3):583-91
15242824
Biochem Pharmacol. 2005 Jan 1;69(1):187-97
15588727
J Anal Toxicol. 2009 Jun;33(5):243-52
19671243
Pharmacol Ther. 1999 Dec;84(3):429-45
10665839
J Pediatr. 1976 Jun;88(6):1044-8
1271174