Methadone pharmacotherapy is the current standard of care for opioid-dependent pregnant women, yet despite over four decades of research, clinically relevant questions regarding the effects of methadone on neonatal outcomes remain. We evaluated whether quantification of methadone and other opioids, cocaine and nicotine in meconium reflects maternal methadone dose and is related to neonatal outcomes, including NAS.
Contrary to a report by Stolk et al. [37
], meconium methadone and EDDP concentrations were associated neither with maternal daily methadone dose at delivery, nor with total or third trimester cumulative doses. The lack of a maternal dose-meconium concentration relationship is not surprising given that methadone dose is not correlated to plasma levels in pregnant women [34
]. Furthermore, absorption, metabolism and excretion vary between individuals and are altered during pregnancy. Several studies demonstrated more rapid methadone elimination as pregnancy progresses [38
], possibly due to cytochrome P450 enzyme induction [42
]. Additionally, the placenta plays a role in fetal methadone exposure [43
]; transplacental permeability to methadone increases with gestational age, thought to be directly mediated by decreasing placental p-glycoprotein expression later in pregnancy [44
]. Thus, maternal dose and hepatic function, placental maturity, gestational age, fetal liver development and excretion all influence fetal methadone exposure and subsequent disposition in meconium, perhaps contributing to the lack of a direct dose-concentration relationship.
Meconium methadone and EDDP concentrations were investigated as predictors of infant birth parameters and NAS severity; however, no significant relationships were observed. As methadone concentrations were not related to maternal dose or neonatal outcomes, meconium analysis could be limited to qualitative determinations of methadone biomarker presence or absence.
In one specimen, no methadone or EDDP was detected, although the mother received 110 mg daily at delivery, 10,580 mg during study enrollment, and 8700 mg in the third trimester. There is no clear explanation of why this meconium was negative for methadone biomarkers. It is highly unlikely that the woman did not take her prescribed daily dose, as daily methadone administration was directly observed at CAP to discourage drug diversion. Separate aliquots of the meconium specimen were analyzed, and both were negative, excluding potential analytical error. Analyte concentrations are known to change with successive bowel movements [45
], and to fall below detectable limits a few days after birth. The time between birth and meconium collection was not recorded in this study, thus it is possible that several days had passed between birth and specimen collection. Misidentification of the specimen was unlikely, but cannot be ruled out.
An important strength of this research was thrice-weekly urine tests for illicit opiate and cocaine exposure during pregnancy, enabling an objective determination of meconium’s drug detection window; few manuscripts to our knowledge describe urine toxicology results collected during pregnancy. In the present study, we observed some women with high percentages of positive urine tests (up to 73.0% for opiates and 63.3% for cocaine), but also some women with no positive tests; as a result, mean ± SD % positive urine specimens were 11.4 ± 16.7% for opioids and 7.3 ± 12.2% for cocaine. In a study by Fischer et al [13
], methadone-maintained women had, on average, 4 opioid-positive urine specimens during treatment (collected twice weekly from enrollment at gestational weeks 24–29 until delivery); however, it is not clear what the variability was between subjects or what the percentage of positive specimens were. In another study conducted by CAP involving buprenorphine-maintained pregnant women, the percentage of positive urine tests collected throughout pregnancy was as high as 75.0% for opiates [28
Most women had at least one opioid- and/or cocaine-positive urine specimen during gestation, and meconium analysis identified substantial opioid, cocaine and tobacco use. Meconium drug detection windows are thought to begin with meconium formation at about 12–16 weeks gestation, and extend until birth. Our data suggest that the detection window is shorter, with meconium reliably detecting drug use only within the last trimester. In addition to timing, frequency of drug use also was an important factor. For opiates and cocaine, high percentages of positive maternal urine specimens, particularly in the third trimester, were associated with positive neonatal meconium [28
]. Yet in three cases each for opiates and cocaine, meconium specimens were positive without any documented gestational drug use. It is possible that in these cases, maternal urine contained drug, but at concentrations below the testing cutoff or women did not provide urine specimens shortly after drug use. Also, drug exposure identification prior to study entry in the second or sometimes early third trimester was by self-report only. Finally, urine specimens were unavailable when women did not attend treatment daily, although urine tends to remain positive for several days after last use.
We did identify significant differences between children with opioid-positive and opioid-negative meconium, including a nearly two-fold increase in the length of hospitalization and lower cumulative maternal methadone doses, but no difference in need for NAS pharmacotherapeutic intervention. From our data, we cannot definitively attribute these outcomes as a consequence of maternal opioid use. Many of the children with opioid-positive meconium results also were premature, a factor associated with longer hospital stays [47
]. Prematurity and the shorter duration of study enrollment would reduce the cumulative amount of methadone received; notably, mean dose at delivery was not significantly different for meconium opioid-positive or – negative results. Prematurity may also be influencing the NAS data, as NAS in premature infants is characterized by lower NAS scores, less need for medication and shorter hospitalizations for NAS-related problems [48
]. Yet, premature infants are more likely to have other medical problems which cause them to have longer lengths of hospital stay.
No differences were observed for tobacco-exposed and unexposed infants, although only six infants had tobacco-negative meconium. Previous research documented a more severe [49
] and extended NAS [16
] in heavy smokers. We did not observe any trend between NAS maximum score and meconium nicotine biomarker concentrations. As we demonstrated for methadone, it is possible that a clear dose-concentration relationship does not exist for tobacco, which would explain why no correlation between meconium nicotine concentrations and neonatal NAS severity was found. Also, it is possible that neonatal nicotine withdrawal differs qualitatively and/or quantitatively from opioid withdrawal, or that tobacco users in this cohort were moderate to light smokers.
We did not observe significant relationships between maternal methadone dose and infant birth parameters including birth weight, length, head circumference or NAS severity. In this study, a modified Finnegan scale [7
] was used to score NAS manifestation. As with all assessments of NAS, some inter-observer variability is expected, but we sought to minimize subjectivity between evaluators by clearly defining scoring criteria and providing extensive training to our nursing staff. Cumulative maternal methadone dose in the third trimester was correlated with older gestational age at delivery and decreased length of hospital stay for infants. Our data support the Center for Substance Abuse Treatment recommendation that dosing decisions should be based on maternal drug craving and relapse potential [50
]. However, women in our study received methadone doses ≤110 mg/d at delivery; effects of higher methadone doses cannot be extrapolated from our data. Recently, high doses of methadone (>140 mg/d) were associated with an increased need for NAS treatment and longer NAS duration [9
In conclusion, meconium testing is a sensitive measure of prenatal methadone, opioid and cocaine exposure during the third trimester, not the second and third trimester as currently assumed. The presence of non-methadone opioids in meconium was associated with poorer neonatal outcomes, such as longer hospital stay, and may be a useful biomarker of poorer neonatal outcomes.