P39: Predictive value of meconium concentrations of buprenorphine and methadone in neonatal abstinence syndrome (NAS)

Abstract

Introduction Buprenorphine (BPN) and methadone (MTD) are two drugs authorized during pregnancy for opioid-dependence treatment. Substitution by MTD or BPN reduce fetal heroin exposure, obstetric complications, and neonatal morbidity and mortality (OFDT, 2003; Lejeune, 2004). Few days after birth newborns exposed in utero to MTD or BPN may suffered of neonatal abstinence syndrome (NAS), consisting in hyperirritability, gastrointestinal dysfunction, respiratory distress, and neurovegetative dysregulations and sometimes convulsions. NAS is treated with morphine, depending of the intensity of the symptoms (measured with Lipsitz scale). Previous studies show that maternal buprenorphine or methadone dose does not predict the severity or duration of NAS. Aim Meconium, the first neonatal feces, could represent the cumulative exposure to drugs in utero all along the gestation. A cohort of 80 opioid-dependent women and their newborn was enrolled for an inter-regional clinical assay managed by Caen university hospital. We assayed in meconium MTD and BPN concentrations, their metabolites and other drugs, and try to correlate them as prognostic factors of time, severity and duration of NAS. Methods 10 women treated with buprenorphine, 12 with methadone, and their newborns were currently included. NAS was followed by repeated Lipsitz scores (positive when >4). Meconium sample preparation included deproteinization followed by solidphase extraction (SPE) with Strata XC ® column. BPN, MTD with their main metabolites norbuprenorphine and EDDP, and morphine were quantified by a liquid chromatography - tandem mass spectrometry (LC-MS/MS) method, developed and validated for this study. Separation was done with a Macherey-Nagel Nucleodur Polartec ® (150 mm x 2,1 mm, 5 μm) column using 10mM ammonium formiate, 0,2 % formic acid and acetonitrile, 0,1 % formic acid as mobile phases at a flow rate of 0,35 mL/min in a gradient mode. The analytes were identified and quantified by LC-MS/MS on an ABSciex ® QTRAP3200 instrument with a TurboIon-Spray source operating in positive mode. Total time for each chromatograph was 15 min. Correlations were determined between meconium concentrations and 3 parameters: NAS onset, peak NAS score, and total amount of morphine used for NAS treatment. Other illicit substances and drugs which may have an impact on NAS are screened in maternal and newborn urines. Results For MTD mean meconium concentrations were 4200 ng/g, for EDDP 11700 ng/g (with a mean ratio MTD/EDDP = 0.42). EDDP meconium concentration and methadone/EDDP ratio were correlated with the peak NAS score (p=0.034 and p=0.029 respectively), and with the total amount of morphine used for NAS treatment (p=0.020 and p=0.013). There was no correlation with MTD meconium concentrations. Results are unavailable for buprenorphine at this time. Urine drug screens revealed frequently tobacco, opiates, cannabis, cocaine, hydroxyzine and benzodiazepines, confirming drugs of abuse are commonly used in opioid-dependent pregnant women. Conclusion These results show that measurement of meconium concentrations of EDDP and methadone/EDDP ratio may help clinicians to predict the severity of NAS, and so adapt earlier treatment with morphine. These preliminary results must be confirmed on large cohorts, higher than 30 newborns per group, including buprenorphine results.