How does Neonatal Abstinence Syndrome impact Neurodevelopment in the long-term?
Neonatal Abstinence Syndrome (NAS) occurs when there is in utero exposure to psychotropic drugs, principally opioids, with symptoms apparent 24 to 72 hours after the child is born. These children are typically hospitalized for at least 5 days, with an average stay between 17-23 days. 1,2,3 The symptoms of NAS can range from mild, such as difficulty sleeping, feeding, or regulating temperature; to severe, including seizures, failure to thrive, respiratory distress, tremors, and increased muscle tone.1,2 Additionally, NAS often causes problems with regulation of the central and autonomic nervous systems as well as the gastrointestinal system. 2,3 Opiate exposure during pregnancy (including Methadone used to treat addiction in the mother) affects the fetus with binge and withdrawal signs and can cause increased rates of fetal death. A number of NAS babies are also premature and/or small for gestational age.2
Estimates vary regarding the percentage of babies exposed to opioids or other substances who will develop NAS, though figures as high as 80% have been cited.1,4 The effect of opium on the developing fetus was first described in 1875, though there was no treatment and the baby often died. In 1903 babies were first treated with morphine, and then the use of methadone was instituted in 1964.5 NAS can be diagnosed by testing the blood and urine of the mom and baby; or the meconium, which is the preferred method and detects substances used up to 5 months prior to testing.4,5 The duration and timing of exposure to substances may impact the severity of NAS and other adverse outcomes. Cumulative use, consumption later in pregnancy in the third trimester, and using non-opioids and alcohol all increase the relative risk of harmful effects to the child.1,2 The Finnegan Neo-Natal Abstinence Scoring Tool is the most common measure to screen for NAS severity. Results of this scale determine utilization of either non-pharmacologic care (decreased stimuli or holding and soothing techniques among others) or pharmacologic intervention in which methadone and/or phenobarbital, buprenorphine, clonidine, tincture of opium, or morphine may be administered. Currently, methadone is the medication that is most commonly used.2,3,4,5 Whether or not medication or non-pharmacologic treatment is the chosen intervention, it is still important to reduce stimuli, use proper handling and positioning, allow demand feedings, and promote breastfeeding.5
The long-term sequelae are not well known compared with the short-term effects of NAS on children.3 Follow-up of neurodevelopmental status is paramount, including in areas such as cognitive development, motor skills, physical growth, and social/emotional status.5 The lasting effects of NAS are difficult to discern, partly because of the influence of other factors such as the environment, other drugs, medical issues, or socioeconomic status.2
Abnormal motor patterns have been observed in infants with NAS, persisting in toddlerhood, and associated with inattention and social struggles. Babies have demonstrated motor delays and deficits in neurobehavioral growth identified on the BSID (Bailey Scale of Infant Development).2 Exposure to opioids in utero causes regulatory issues associated with behavior, emotions, social skills, and attention. It is thought that cognitive deficits may begin in utero, predominantly in poly-drug exposed children, although it has yet to be ascertained that opioid exposure affects cognition. Problems with emotional regulation may be observed later in life when children begin to engage with peers or attend school; however, longitudinal studies have not been done to confirm this theory. It has been hypothesized that epigenetic responses to substances may be triggered in utero, and the effects of exposure may cause problems with neuronal migration and formation of dendrites.6 Drugs, alcohol, or nicotine have teratogenic effects early in the development of the embryo causing structural changes. Further along in development, more nuanced changes can occur in neurotransmitters, brain formation, protein and lipid synthesis, and hormone levels.7
The lingering effects of drug exposure on mental function is most recognizable in areas such as attention, impulsivity, memory, perception and externalizing behaviors.7 Nygaard studied children aged 4.5 to 8.5 years old to determine if attentional, behavioral, and emotional problems were present and increased over time. Results showed that children with drug exposure had significantly more regulatory problems than their non-exposed peers, especially in attention, internalized anxiety and depression, and externalized aggression. There were larger group differences in cognition, and as the children exposed to drugs were further socialized, regulatory problems intensified.6 Oei studied 2236 children born with NAS from 2000-2006 in New South Wales. The findings suggested that NAS was associated with decreased educational attainment as early as 8 or 9 years of age. While it is hard to know why these children perform poorly, opioids have been found to impair thinking in adults who consume drugs after only a few days. The effects may be less obvious in children, though they may be long-lasting due to impaired neuronal pruning, malformation of dendritic connections, or abnormal neurotransmitter levels. Environmental factors are often thought to contribute further to poor learning, although the effects may still be realized when the environment has changed.8
A negative impact on neurodevelopmental outcomes in babies with NAS in cognition, language, vision, and attention that affect academic abilities becomes a public health challenge. Mehar et. al conducted a retrospective observational study that sought to evaluate outcomes in children born with NAS at age 2 using the BSID. The researchers found a 4-6 point difference on BSID. While the authors felt this was clinically significant, it was not proof that NAS impacts learning. Animal studies have shown that opioids cause demyelination and alter neurotransmitters, in addition to environmental factors that may impact cognition.9 Yeoh et. al performed a meta-analysis of 26 cohort studies that followed children anywhere from 0-18 years-old to assess the long-term effects of opioids on cognitive and motor function. Their findings demonstrated a difference in cognition from 0 to 6, though too few studies were done to make a determination regarding older children 7-18. Furthermore, children 6 years or younger were found to have significant impairments in motor skills. Even brief drug use by the mother affects brain size and function hindering neurodevelopment. Animal studies have revealed problems with neuronal development (“differentiation, growth, and survival) and “neurotransmitter homeostasis”. Opioid exposure also poses an enhanced risk of growing up in an environment that is not conducive to proper nervous system development. Opioids have been shown to cause cell death in brain cell cultures, and decreased norepinephrine and dopamine transmission across synapses in mice. NAS babies exhibit decreased size of the cerebellum and the basal ganglia placing babies at risk for neurodevelopmental, cognitive, psychomotor, and behavioral problems.10 More NAS children require an assessment for special education and qualify for therapies than non-NAS children. Educational attainment deteriorates as children get older. Research has revealed decreased gray matter volume, impaired synaptic transmission, and white matter changes. Early intervention has proven benefits that last into adulthood.11
Drug exposure does not typically result in fetal malformations, but “functional abnormalities” that are observed later in childhood and into adulthood, such as effects on IQ, speech, and behavior.12 A metanalysis of studies pertaining to neurodevelopmental issues in areas of neuro-behavioral, cognitive, and the psychomotor effects of neonatal exposure to drugs in preschool age children looked at infant and preschool assessments of motor (fine and gross motor skills), communication (expressive and receptive), cognition (problem solving), adaptive skills (dressing eating and toileting), and personal social competence. Data was split into 3 areas: cognitive, psychomotor and behavioral. There was non-significant evidence of the impact of opioid exposure on these 3 domains, although there was a trend toward worse outcomes in infant and preschool age children with drug exposure.13
The American Medical Association (AMA) still has not come to a consensus regarding the long-term effects of opioid exposure. Most opioid exposed children are low birthweight, which in and of itself is a predictor of cognitive function, therefore executive function and socio-emotional function may be compromised by opioids. A study by Nygard found that both exposed and non-exposed children scored within normal range on cognitive scores, although drug exposed children scored significantly worse on most tests, and delays did not improve over time. Even when controlling for other factors, both internal and external, it is difficult to parse out the precise reasons for delays.14
NAS is a collective term for drug exposure in utero and is not a new disease. However, an escalation in cases occurring in this country has brought this condition to the forefront as a public health crisis. This has also heightened concerns regarding the long-term effects in the population. There are likely significant consequences from this epidemic not only in the near term while the child struggles with medical complications in the NICU, but the costs associated with the long-term development of the child, both physically and mentally. Thus far, there is a paucity of studies pertaining to the effects of drug exposure on the developing nervous system in children born with NAS. As we begin to understand more about the effects of drugs on motor, cognitive, and social development, the efficacy of early interventions to remediate or at the very least ameliorate the adverse effects on early childhood development needs to be investigated.
- Desai R, Huybrechts K, Hernandez-Diaz S, et. al. Exposure to prescription opioid analgesics in utero and risk of neonatal abstinence syndrome: Population based cohort study. https://www.bmj.com/content/350/bmj.h2102.long BMJ. 2015. Accessed November 12, 2019.
- Logan B, Brown M, and Hayes M. Neonatal Abstinence Syndrome: Treatment and Pediatric Outcomes. Clin Obstet Gynecol. 2013; 56(1): 186–192.
- McQueen K and Murphy-Oikonen J. Neonatal abstinence Syndrome. N Engl J Med. 2016; 375: 2468-2479.
- Sublett A. Neonatal Abstinence Syndrome. https://nursing.ceconnection.com/ovidfiles/00005721-201303000-00008.pdf Published March 2013. Accessed November 12, 2019.
- Kocherlokato P. Neonatal Abstinence Syndrome. Pediatrics. 2014; 134 (2): 547-561.
- Nygaard E, Slinning K, Moe V, and Walhovd K. Behavior and attention problems in eight year-old children with prenatal opiate and poly-substance exposure: A longitudinal study. PLoS ONE. 2016; 11(6).
- Benke M and Smith V. Prenatal substance abuse: Short and long-term effects on the exposed fetus. Pediatrics. 2013; 131 (3): 1009-1024.
- Oei J, Melhuish E, and Uebel H et al. Neonatal abstinence syndrome and high school performance. Pediatrics. 2016; 139(2).
- Merhar S, McAllister J, Wedig-Stevie K, et al. Retrospective review of neurodevelopmental outcomes in infants treated for neonatal abstinence syndrome. J Perinatol. 2018; 38(5): 587–592.
- Yeoh S, Eastwood J, and Wright I, et. al. Cognitive and motor outcomes of children with prenatal opioid exposure: A systematic review and meta-analysis. JAMA. 2019;2(7).
- Fill A, Miller A, and Wilkinson R, et al. Educational disabilities among children born with neonatal abstinence syndrome. Pediatrics. 2018; 142(3).
- Bada H. Neurodevelopmental outcomes of children with prenatal opiate exposure. https://www.azdhs.gov/documents/prevention/womens-childrens-health/injury-prevention/prescription-drugs/short-and-long-term-outcomes-bada.pdf Accessed November 13, 2019.
- Baldochino A, Arbuckle K. and Petrie D, et. al. Neurobehavioral consequences of chronic intrauterine opioid exposure in infants and preschool children: A systematic review and meta-analysis. BMC Psychiatry. 2014. 14; (104).
- Nygaard E, Slinning K, and Moe V et al. Cognitive function of youths born to mothers with opioid and poly-substance abuse problems during pregnancy. Child Neuropsychology. 2017; 23(2): 159-187.