Pregnancies exposed to methadone, methadone and other illicit substances, and poly-drugs without methadone: A comparison of fetal neurobehaviors and infant outcomes

https://doi.org/10.1016/j.drugalcdep.2011.10.003Get rights and content

Abstract

Background

It is suspected that there is a continuum of impairment among prenatally drug-exposed infants, such that opioid and/or poly-drug exposure confers the highest risk for adverse neonatal outcomes than other classes of substances or single substance exposures. Suitable control groups are difficult to identify. This study compared fetal neurobehavioral development and infant outcomes in offspring of three groups of pregnant women in drug treatment. Exposure groups include: Methadone + other illicit substances (MM + Poly) and two groups currently abstinent for poly drug exposures: Methadone only (MM/A) and Non-Methadone (NM/A).

Methods

Forty-nine women (19 MM + Poly, 18 MM/A, and 12 NM/A) underwent fetal monitoring at 36 weeks gestation at peak and trough levels of methadone (MM + Poly; MM/A) or at comparable morning and afternoon times (NM/A). Fetal heart rate (FHR), heart rate variability (FHRV) and motor activity (FM) data were collected. Infant measures included birth outcomes and Neonatal Abstinence Syndrome (NAS) assessment.

Results

As compared to the NM/A group, cardiac measures were decreased in methadone-exposed fetuses at peak levels. FHR was significantly more suppressed in the MM + Poly group. FM was significantly lower in the MM/A vs. the NM/A group at both peak and trough, indicative of more persistent exposure effects. The MM + Poly group delivered 1 week earlier and required NAS pharmacological treatment twice as often as the MM/A group.

Conclusions

Results support the notion that poly-drug exposure may potentiate the effects of methadone on the fetus and infant and highlights the need for intensified treatment for methadone-maintained women who abuse other substances.

Introduction

Drug use during pregnancy continues to be a public health concern internationally, but there remains a relative dearth of information regarding the effects of maternal drug use on the developing fetus with its implications for infant functioning. Neonatal dysfunction may be dependent on a host of maternal, fetal and infant factors in addition to the direct toxic effects of illicit drug exposure. These may include genetic vulnerability, epigenetic variation and fetal programming (Salisbury et al., 2009), maternal and infant autonomic functioning (Jansson et al., 2007, Jansson et al., 2010), maternal psychopathology (Tuten et al., 2009), licit exposures including cigarettes (Stroud et al., 2009, Law et al., 2003), alcohol (Cotes et al., 1985) and psychotropic medications (Rampono et al., 2009), maternal stress (Vrekoussis et al., 2010), and socioeconomic class (DiPietro et al., 1998). These factors likely interact in a unique manner within each individual pregnancy and are difficult to identify and quantify. A nearly constant criticism of the extant literature on drug-exposed infants is the failure to include an appropriate control group. Yet, due to the multiple social and biologic confounders inherent in a population of drug-dependent pregnant women, identifying an appropriate control group is difficult. Studies that include only a non-exposed comparison group fail to adequately account for the potential non-drug influences on outcomes that are inherent in the addicted woman's life.

Methadone introduces a unique confound in research on the effects of maternal opioid dependence. While it is clear that methadone maintenance confers significant maternal benefit (Jones et al., 1999), the methadone-exposed fetus shows a number of alterations in neurobehavioral functioning suggestive of lack of well-being. When compared to non-drug exposed controls, methadone-exposed fetuses show diminished reactivity in non-stress testing (Archie et al., 1989, Anyaegbunam et al., 1997, Levine and Rebarber, 1995, Cejtin et al., 1996) and reduced fetal breathing and fetal motor activity (Wouldes et al., 2004) shortly after methadone dosing. Methadone-exposed fetuses exhibit slower and less variable heart rates, fewer heart rate accelerations, less motor activity and attenuated integration between heart rate and motor activity (Jansson et al., 2005). Such measures of fetal neurobehavioral functioning reveal information about the developing fetal nervous system (DiPietro et al., 2001), and predict newborn neurobehaviors (DiPietro et al., 2010), which are associated with medical and behavioral outcomes (Liu et al., 2010, Lester et al., 2009) and as such, indicate the possibility of long term impairment as a result of prenatal methadone exposure. The methadone-exposed infant is at significant risk for NAS (Finnegan, 1991) and displays altered neurobehavioral performance after delivery (Velez et al., 2009). However, studies controlling for sociodemographic, biologic and health factors have generally found no differences in development among methadone- vs. non-exposed controls (Lifschitz et al., 1985, Kaltenbach and Finnegan, 1989).

Despite the accumulating body of evidence that methadone affects neurodevelopmental functioning in the fetus and infant, the effects of maternal poly-drug use in addition to, or in the absence of methadone are generally unknown. The multiple risk model associates the likelihood of infant morbidity with the number of maternal risk factors; maternal chemical use represents one such factor (Gustavvson, 1992). According to this model, there is a continuum of impairment in drug-exposed neonates such that infants exposed to multiple substances have poorer neonatal outcomes than infants exposed to single drugs, with opioid-exposed infants, as a result of their propensity to display significant NAS, having the poorest outcomes overall. Despite the fact that poly-drug use is more common than single-drug use, there is scant information on poly-drug effects on the infant (Lester et al., 2004). One large prospective longitudinal study found that effects of multiple drugs can be detected even at low thresholds in poly-drug exposed 1-month-old infants using neurobehavioral tests that are differentially sensitive to drug effects (Lester et al., 2002). In addition, opioid-exposed infants have been found to have poorer state control and reduced interactive behaviors than multiple-drug, non-opioid-exposed infants, who in turn have poorer neurobehavioral outcomes than non-drug-exposed control infants (Chasnoff et al., 1982). Therefore, a useful set of comparisons would be to compare a group of opioid-dependent women who abstained from other illicit drugs during methadone maintenance, opioid-dependent women who received methadone but continued to abuse other illicit substances, and women who used illicit substances during early gestation but did not receive methadone maintenance.

This study compared fetal neurobehaviors and neonatal outcomes among three such groups. We hypothesized that there would be a continuum of effects indicative of fetal neurological development such that non-methadone, other drug abstinent group fetuses would have the most mature patterns of fetal neurobehavioral functioning, followed by methadone only-exposed fetuses, who in turn would display indicators of more optimal neurobehavioral functioning than those fetuses exposed to both methadone plus poly-drugs. We additionally hypothesized that early infant functioning would parallel the fetal findings, with methadone and poly-drug exposed infants exhibiting more Neonatal Abstinence Syndrome (NAS) symptomatology, which is a reflection of dysregulation neurobehavioral functioning.

Section snippets

Participants

Participants were pregnant women enrolled in a comprehensive urban drug treatment center that treats pregnant and post-partum women and their children. The program is described elsewhere (Jansson et al., 1996). Inclusion criteria included singleton pregnancies with normal fetal growth and absence of anomalies as indentified by an obstetrical sonogram and negative serum quad screening. For women receiving methadone maintenance, inclusion criteria also included single daily dosing, as split as

Maternal characteristics

Maternal characteristics are presented in Table 1. The groups did not differ on age, parity, or education level. There were significantly more non-Hispanic-White women in the MM + Poly group and more African-American women in the NM/A group. Most women (82%) smoked cigarettes and there was a trend (p < .10) level difference among groups in the number of cigarettes reported smoked per day, with the least reported smoking in the NM/A group. However, CO levels at the time of fetal testing did not

Conclusion

The original hypothesis of a continuum of impairment, such that maternal poly-drug use during pregnancy can potentiate effects of methadone exposure on the developing fetus and newborn infant, was partially supported. Infants in the MM + Poly group delivered nearly 1 week earlier and were twice as likely to receive treatment for NAS than the MM/A group, despite the fact that the maternal dose in each group was equivalent. Although all infants were delivered at term, there is increasing evidence

Role of funding source

This research was supported by NIH/NIDA RO1DA019934 (Jansson).

Contributors

All authors have materially contributed to this research, and have approved the final manuscript. Lauren Jansson, MD conceptualized and designed the study, obtained funding, and participated in data collection, analysis and manuscript preparation. Janet DiPietro, PhD participated in study design, oversaw fetal data collection and analysis, and participated in manuscript preparation. Andrea Elko PA-C performed subject recruitment and data collection. Erica Williams participated in subject

Conflict of interest

The authors report no conflicts of interest.

Acknowledgement

The authors wish to thank Kristin Voegtline for her assistance in aspects of data analysis.

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