Prenatal substance exposure: Neurobiologic organization at 1 month

Elisabeth Conradt, Stephen J. Sheinkopf, Barry M. Lester, Ed Tronick, Linda L. Lagasse, Seetha Shankaran, Henrietta Bada, Charles R. Bauer, Toni M. Whitaker, Jane A. Hammond

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Objective: To examine the autonomic nervous system and neurobehavioral response to a sustained visual attention challenge in 1-month-old infants with prenatal substance exposure. Study design: We measured heart rate, respiratory sinus arrhythmia, and neurobehavior during sustained visual orientation tasks included in the Neonatal Intensive Care Unit Network Neurobehavioral Scale in 1129 1-month-old infants with prenatal substance exposure. Four groups were compared: infants with prenatal cocaine and opiate exposure, infants with cocaine exposure, infants with opiate exposure, and infants with exposure to other substances (ie, alcohol, marijuana, and tobacco). Results: The infants with prenatal exposure to both cocaine and opiates had the highest heart rates and lowest levels of respiratory sinus arrhythmia during a sustained visual attention challenge compared with the other 3 groups. Infants with prenatal cocaine and opiate exposure had poorer quality of movement and more hypertonicity during the Neonatal Intensive Care Unit Network Neurobehavioral Scale examination. They also had more nonoptimal reflexes and stress/abstinence signs compared with infants with prenatal exposure to cocaine only and those with prenatal exposure to alcohol, tobacco, and marijuana. Conclusion: Problems with arousal regulation were identified in infants with prenatal substance exposure. Autonomic dysregulation has been implicated as a mechanism by which these difficulties occur. Our results suggest that infants with prenatal exposure to both cocaine and opiates have the greatest autonomic response to the challenge of a sustained visual attention task, possibly putting these infants at risk for problems associated with physiologic and behavioral regulation, a necessary prerequisite for early learning.

Original languageEnglish
Pages (from-to)989-994.e1
JournalJournal of Pediatrics
Issue number4
StatePublished - Oct 2013

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Funding Information:
Infants with prenatal exposure to both cocaine and opiates exhibited the most neurobiologic dysregulation on the NNNS assessment at both the behavioral (NNNS) and physiologic (HR and RSA) levels compared with infants with prenatal cocaine or opiate exposure alone or those with prenatal exposure to other substances. To date, the majority of research on infants with prenatal substance exposure has been limited to the effects of a single substance, such as cocaine or opiates, while controlling for the effects of other substances. 16 A small body of research, however, suggests that infants with both cocaine and opiate exposure may be at greater risk for poor developmental outcomes. 8,17 Infants with prenatal exposure to cocaine 1,8 and opiates 18 are at risk for difficulties with modulating arousal and attention, and subsequent problems with emotion regulation 1,19 and learning 20 by middle childhood. The mechanisms by which infants with prenatal cocaine and opiate exposure may be at risk for these negative outcomes remain unknown, however. A promising avenue of research involves physiologic aspects of regulatory systems. Physiologic systems subserving attention and arousal, specifically HR and RSA, have previously been studied in infants with prenatal cocaine or opiate exposure, because HR and RSA are involved in the control of visual attention 14 and arousal regulation. 6 Previous studies of HR and RSA in infants with prenatal cocaine or opiate exposure have yielded mixed results. In 1 study, infants with prenatal exposure to both cocaine and opiate exhibited higher HR and lower RSA at baseline 21 compared with infants with opiate exposure only; however, that study did not covary the effects of demographic and medical variables, which might have confounded the results. In addition, baseline levels of HR or RSA are typically not used to index arousal regulation and excitability. A better index is RSA during a challenge. 6 In other studies, infants with prenatal cocaine exposure typically do not exhibit RSA responses to challenges compared with nonexposed controls 22-24 ; however, these studies did not include infants with opiate exposure and did not adequately control for the effects of other substances. To date, there are only 2 published studies of RSA in children with prenatal opiate exposure. One study found no RSA reactivity during an attention-demanding task in 7- to 12-year-old boys with prenatal opiate exposure, 18 whereas the other study found greater RSA reactivity in opiate- and alcohol-exposed 7- to 12-year-olds compared with controls. 25 The inconsistent findings reported so far might be related to differences in age at assessment of RSA reactivity, lack of adequate control for the effects of polysubstance exposure, or exclusion of participants who were exposed to both cocaine and opiates. The tasks used to assess RSA reactivity also might not have been sufficiently potent to tax the participants' attention systems. We used a visual attention task that is analogous to visual exploration, a necessary prerequisite for object exploration and subsequent early learning, and attention-demanding tasks have commonly been used to elicit RSA and HR responses. 6 Our results may be used to help identify infants who may need additional support in learning how to self-regulate in the context of interacting with attention-demanding stimuli. In addition, they point to a possible mechanism by which infants with prenatal cocaine and opiate exposure exhibit difficulties with attention and arousal modulation. In typically developing infants, HR increases and RSA decreases in response to attention- demanding stimuli. 12,14 Moderate decreases in RSA are characteristic of focused attention and self-regulation, 13,14 given that parasympathetic withdrawal provides the activation required to respond to attention demands. Thus, one interpretation of our findings could be simply that the cocaine- and opiate-exposed infants in our cohort required more parasympathetic withdrawal to mount a response to the demands of attention stimulation. Although cocaine and opiates have different mechanisms of action, both drugs affect the reward circuitry in the brain, specifically the ventral tegmental area and extended amygdala, regions rich in monoamines that are involved in reactivity to stress and regulation. 26 The combined impact of cocaine and opiate exposure could require that these infants use greater neurobiologic resources to meet environmental demands, thereby further taxing an already stressed central nervous system. 27,28 A second possible interpretation of our findings is that the greater decreases in RSA in infants with prenatal exposure to both cocaine and opiates reflect a stress response. 6 Sympathetic arousal is part of the “flight or fight” reaction, which also includes activation of the hypothalamic-pituitary-adrenal axis release of cortisol. Thus, we suggest that the increased HR response observed in the infants exposed to both cocaine and opiates could indicate increased sympathetic activity as part of a stress response. These infants might have been demonstrating an acute response to stress, rather than the ability to respond to the demands of attention stimulation. According to the framework of allostatic load, 29 repeated activation of physiologic systems results in increased likelihood of psychological and medical morbidity, owing to “wear and tear” on these systems. Over time, the autonomic nervous system may become overly stressed, increasing the risk of autonomic dysregulation in response to even mild attention-demanding stimuli. Prenatal substance exposure also can alter physiologic stress response systems through epigenetic mechanisms that increase fetal exposure to maternal cortisol, affecting physiologic and neurobehavioral stress reactivity in the infant. 30 Epigenetic changes in placental genes that regulate fetal exposure to maternal cortisol have been related to newborn neurobehavior on the NNNS, including attention 31 and quality of movement. 32 Our findings of increased HR and RSA responses on the NNNS during an attention-demanding task, along with poorer quality of movements and greater hypertonicity, in infants with prenatal exposure to both cocaine and opiates are consistent with the interpretation that these infants were exhibiting a stress response. Further research is needed to determine whether this response may be impacted by epigenetic processes. Our results do not preclude the possibility that exposure to drugs other than cocaine and opiates have teratogenic effects. This study has some limitations. The inclusion of a comparison group of nonexposed infants with no prenatal substance exposure might have helped clarify our findings. For instance, we would have been able to determine whether infants with prenatal cocaine and opiate exposure exhibited significantly greater HR and lower RSA than unexposed infants. However, the fact that these differences were observed among groups of infants, all with some form of prenatal exposure to substances, argues for the robust effects found in this study. Although prenatal exposure to alcohol, marijuana, or tobacco did not meet the criteria for inclusion as covariates, there were some intergroup differences in exposure to these other substances. However, because our criteria for inclusion of covariates were well established in the literature and defined a priori, we believe that our comparison groups are appropriate. The first month of life represents a particularly vulnerable time for infants, characterized by high levels of cortisol secretion as the infant becomes more physiologically and behaviorally organized. Infants with prenatal exposure to both cocaine and opiates may be a more susceptible group, given their high levels of sympathetic and parasympathetic responses to a sustained visual attention challenge along with greater motor disorganization. Considering the autonomic nervous system's role in maintaining coordination of attention and arousal, our results suggest that early difficulties with regulation of arousal, exacerbated by the increased likelihood of being reared in an adverse environment, may make cocaine- and opiate-exposed infants more vulnerable to difficulties with arousal regulation. An important developmental objective for such infants is to coordinate biological and behavioral attention systems, with the goal of maintaining a calm state while visually inspecting new stimuli. This ability is also a necessary prerequisite for early learning. The impaired biobehavioral regulation seen in infants with prenatal cocaine and opiate exposure suggests that these infants may be at increased risk for problems with regulation later in development, owing in part to the heightened physiologic responses identifiable by age 1 month. Our findings underscore the importance of including physiologic measures in addition to behavioral assessments to identify infants at need of extra support and interventions. The ability to differentiate infants demonstrating a stress response from those showing the expected response to environmental demands could have implications for preventive intervention, for example, to combat the well-known long-term effects of chronic stress or allostatic load. 29,33 In clinical practice, our group uses the NNNS to help guide the management of infants in the hospital. For example, some infants with prenatal substance exposure benefit from soothing strategies and proprioceptive interventions to support motor organization. These interventions include containment, use of a pacifier, neutral warmth, and infant massage, preferably by the parent. 34 The goal is to capitalize on the malleability of the infant's neurobiologic stress response to support sensitive caregiving experiences and ultimately promote positive adaptation. We are indebted to our medical and nursing colleagues and to the infants and their parents who participated in this study. Appendix 1 The following individuals and federal funding grants contributed to this study and, in addition to the authors, are members of the Maternal Lifestyle Study: Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rosemary Higgins, PhD. Brown University, Warren Alpert Medical School Women & Infants Hospital of Rhode Island (U10 HD27904, N01 HD23159): Cynthia Miller-Loncar, PhD, Jean Twomey, PhD, Laura Dietz, MA, Melissa Kupchak, RN. National Institute on Drug Abuse: Vincent L. Smeriglio, PhD, Nicolette Borek, PhD. RTI International (U10 HD36790): W. Kenneth Poole, PhD, Abhik Das, PhD, Debra Fleischmann, BS. University of Miami Holtz Children's Hospital (GCRC M01 RR16587, U10 HD21397): Ann L. Graziotti, MSN, ARNP, Tonya Barriere-Perez, MSW, Janine Closius, BS, Diedre Gallop, MSW, Edgar Garcia, RN ARNP, Susan Gauthier, BA, Wendy Griffin, RN, Elizabeth Jacque, RN, Jennifer Lewis; Daniel A. Messinger, PhD, Yamille Valdez. University of Tennessee (U10 HD42638): Charlotte Bursi, MSSW, Deloris Lee, MSSW, Lillie Hughey, MSSW. Wayne State University Hutzel Women's Hospital and Children's Hospital of Michigan (U10 HD21385): Eunice Woldt, RN, MSN, Jay Ann Nelson, BSN, Catherine Bartholomay, BA, Lisa Sulkowski, BS, Nicole Walker, BA. Appendix 2 Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network and an interinstitution agreement with the National Institute on Drug Abuse (NIDA) through cooperative agreements ( U10-DA-024117-01 , U10-HD-21385 [to S.S.], I10-DA-024128-06 , U10-HD-2786 [to H.B.], U10-DA-024119-01 , U10-HD-27904 [to B.L.], U10-DA-024118-01 , and U10-HD-21397 [to C.B.]), NICHD contract ( N01-HD-2-3159 , to B.L.), and a National Research Service Award from the National Institute on Drug Abuse ( F32DA032175 , to E.C.). Support for the Maternal Lifestyle Study was provided by the National Institutes of Health through the NIDA and the NICHD, with supplemental funding from the National Institute of Mental Health ; the Administration on Children, Youth, and Families ; and the Center for Substance Abuse and Treatment , US Department of Health and Human Services . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIDA, NICHD, or National Institutes of Health. The authors declare no conflicts of interest. Table I Demographic characteristics by exposure group Other substance exposure (n = 466) Cocaine exposure (n = 546) Opiate exposure (n = 57) Cocaine and opiate exposure (n = 60) P value Maternal age, years, mean ± SD 26.9 ± 5.8 30.2 ± 4.8 29.7 ± 7.2 32.0 ± 5.6 <.001 Birth weight, g, mean ± SD 2762.5 ± 812.5 2561.1 ± 739.7 2849.8 ± 820.8 2392.5 ± 806.8 <.001 PMA, weeks, mean ± SD 40.8 ± 3.7 40.1 ± 4.0 41.2 ± 3.6 40.0 ± 4.4 .02 Low socioeconomic status (continuous), % 55.9 61.4 56.6 61.1 .35 Male sex, % 52.4 53.1 61.4 35 .22 Race, % <.001 Caucasian 17.4 12.5 43.9 38.3 African American 75.1 80.0 45.6 55.0 Hispanic 6.0 6.4 7.0 5.0 Other 1.5 1.1 3.5 1.7 Prenatal alcohol exposure, % 77.0 75.1 36.8 58.3 <.001 Prenatal tobacco exposure, % 44.4 82.8 59.6 91.7 <.001 Prenatal marijuana exposure, % 15.2 41.0 12.3 36.7 <.001

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health


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