Pregnancies exposed to methadone, methadone and other illicit substances, and poly-drugs without methadone: A comparison of fetal neurobehaviors and infant outcomes
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.
References (39)
- et al.
Cross-correlation of fetal cardiac and somatic activity as an indicator of antenatal neural development
Am. J. Obstet. Gynecol.
(2001) - et al.
Pregnancy and addiction: a comprehensive care model
J. Subst. Abuse Treat.
(1996) - et al.
Fetal response to maternal methadone administration
Am. J. Obstet. Gynecol.
(2005) - et al.
Infant autonomic functioning and neonatal abstinence syndrome
Drug Alcohol Depend.
(2010) - et al.
Urine drug screening: a practical guide for clinicians
May Clin. Proc.
(2008) - et al.
Fetal effects of psychoactive drugs
Clin. Perinatol.
(2009) - et al.
Maternal smoking during pregnancy and newborn neurobehavior: effects at 10 to 27 days
Pediatrics
(2009) - et al.
The effect of methadone treatment on the quantity and quality of human fetal movement
Neurotoxicol. Teratol.
(2004) - et al.
Assessment of fetal well-being in methadone-maintained pregnancies: abnormal stress tests
Gynecol. Obstet. Invest.
(1997) - et al.
The effects of methadone treatment on the reactivity of the non-stress test
Obstet. Gynecol.
(1989)
Effect of methadone on the biophysical profile
J. Reprod. Med.
Polydrug- and methadone-addicted newborns: a continuum of impairment?
Pediatrics
Neonatal neuroalcoholism: clinical experimental research. Behavioral characteristics as correlates of maternal alcohol use during gestation
Alcohol. Clin. Exp. Res.
Most prominent symptoms of withdrawal in polydrug-exposed infants
Tenn. Nurse
Fetal neurobehavioral development: associations with socioeconomic class and fetal sex
Dev. Psychobiol.
Prenatal antecedents of newborn neurologic maturation
Child Dev.
Treatment issues for opioid-dependent women during the perinatal period
J. Psychoactive Drugs
Drug exposed infants and their mothers: facts, myths and needs
Soc. Work Health Care
Two new rating scales for opiate withdrawal
Am. J. Drug Alcohol Abuse
Cited by (70)
Guideline No. 443b: Opioid Use Throughout Women's Lifespan: Opioid Use in Pregnancy and Breastfeeding
2023, Journal of Obstetrics and Gynaecology CanadaDirective clinique n<sup>o</sup> 443b: Opioïdes aux différentes étapes de la vie des femmes: Grossesse et allaitement
2023, Journal of Obstetrics and Gynaecology CanadaIntrauterine Drug Exposure: Fetal and Postnatal Effects
2023, Avery's Diseases of the NewbornBuprenorphine X-waiver exemption – beyond the basics for the obstetrical provider
2021, American Journal of Obstetrics and Gynecology MFMImproving translational relevance: The need for combined exposure models for studying prenatal adversity
2021, Brain, Behavior, and Immunity - HealthSupporting mother-infant dyads impacted by prenatal substance exposure
2021, Children and Youth Services Review