Association Between Prenatal Opioid Exposure and Neurodevelopmental Outcomes in Children

Introduction: Several studies have reported increasing prevalence of prescription opioid use among pregnant women. However, little is known regarding the effects of maternal opioid use on neurodevelopmental disorders in early childhood in pregnant women with no evidence of opioid use disorders or drug dependence. Objective: The aim of this study was to quantify the association between prenatal opioid exposure from maternal prescription use and neurodevelopmental outcomes in early childhood. Methods: This retrospective study included pregnant women aged 12–55 years and their live-birth infants born from 2010 to 2012 present in Optum’s deidentified Clinformatics® Data Mart database. Eligible infants born to mothers without opioid use disorders or drug dependence were followed till occurrence of neurodevelopmental disorders, loss to follow-up, or study end (December 31, 2017), whichever came first. Propensity score by fine stratification was applied to adjust for confounding by demographic characteristics, obstetric characteristics, maternal comorbid mental and pain conditions, and measures of burden of illnesses and to obtain adjusted hazard ratios (HR) and 95% confidence intervals (CI). Exposed and unexposed infants were compared on the incidence of neurodevelopmental disorders. Results: Of 24,910 newborns, 7.6% (1899) were prenatally exposed to prescription opioids. Overall, 1562 children were diagnosed with neurodevelopmental disorders, with crude incidence rates of 2.9 per 100 person-years in exposed children versus 2.5 per 100 person-years in unexposed children. After adjustment, we observed no association between fetal opioid exposure and the risk of neurodevelopmental disorders (HR 1.10; 95% CI 0.92–1.32). However, increased risk of neurodevelopmental disorders were observed in children with longer cumulative exposure duration (HR 1.70; 95% CI 1.05–2.96) or high cumulative opioid doses (HR 1.22; 95% CI 1.01–1.54). Conclusion and Relevance: In pregnant women without opioid use disorders or drug dependence, maternal opioid use was not associated with increased risk of neurodevelopmental disorders in early childhood. However, increased risks of early neurodevelopmental disorders were observed in children born to women receiving prescription opioids for longer duration and at higher doses during pregnancy

Neurobehavioral consequences of chronic intrauterine opioid exposure in infants and preschool children: a systematic review and meta-analysis

<b>Background</b><p></p> It is assumed within the accumulated literature that children born of pregnant opioid dependent mothers have impaired neurobehavioral function as a consequence of chronic intrauterine opioid use.<p></p> <b>Methods</b><p></p> Quantitative and systematic review of the literature on the consequences of chronic maternal opioid use during pregnancy on neurobehavioral function of children was conducted using the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We searched Cinahl, EMBASE, PsychINFO and MEDLINE between the periods of January 1995 to January 2012.<p></p> <b>Results</b><p></p> There were only 5 studies out of the 200 identified that quantitatively reported on neurobehavioral function of children after maternal opioid use during pregnancy. All 5 were case control studies with the number of exposed subjects within the studies ranging from 33–143 and 45–85 for the controls. This meta-analysis showed no significant impairments, at a non-conservative significance level of p < 0.05, for cognitive, psychomotor or observed behavioural outcomes for chronic intra-uterine exposed infants and pre-school children compared to non-exposed infants and children. However, all domains suggested a trend to poor outcomes in infants/children of opioid using mothers. The magnitude of all possible effects was small according to Cohen’s benchmark criteria.<p></p> <b>Conclusions</b><p></p> Chronic intra-uterine opioid exposed infants and pre-school children experienced no significant impairment in neurobehavioral outcomes when compared to non-exposed peers, although in all domains there was a trend to poorer outcomes. The findings of this review are limited by the small number of studies analysed, the heterogenous populations and small numbers within the individual studies. Longitudinal studies are needed to determine if any neuropsychological impairments appear after the age of 5 years and to help investigate further the role of environmental risk factors on the effect of ‘core’ phenotypes

Neonatal abstinence syndrome: Pharmacologic strategies for the mother and infant.

Opioid use in pregnancy has increased dramatically over the past decade. Since prenatal opioid use is associated with numerous obstetrical and neonatal complications, this now has become a major public health problem. In particular, in utero opioid exposure can result in neonatal abstinence syndrome (NAS) which is a serious condition characterized by central nervous system hyperirritability and autonomic nervous system dysfunction. The present review seeks to define current practices regarding the approach to the pregnant mother and neonate with prenatal opiate exposure. Although the cornerstone of prenatal management of opioid dependence is opioid maintenance therapy, the ideal agent has yet to be definitively established. Pharmacologic management of NAS is also highly variable and may include an opioid, barbiturate, and/or α-agonist. Genetic factors appear to be associated with the incidence and severity of NAS. Establishing pharmacogenetic risk factors for the development of NAS has the potential for creating opportunities for personalized genomic medicine and novel, individualized therapeutic interventions

Prenatal Opioid Use and Neonatal Abstinence Syndrome: A Review of the Neurophysiological, Neuropsychological, and Behavioral/Emotional/Social Impacts in the Pediatric Population

The opioid epidemic over the past two decades has raised concerns regarding the developmental fetal impact of prenatal opioid use. Research in this area continues to grow, but largely has focused on treatment for neonates experiencing withdrawal symptoms postnatally. Long term clinical implications for this at-risk population have not been studied extensively leaving many gaps in research and highlighting the need for future empirical studies. This literature review will examine the neurophysiological, neuropsychological, and the behavioral/social/emotional impacts on infants, toddlers, and school aged children who were prenatally exposed to opioids with or without the diagnosis of neonatal abstinence syndrome. Providing a deeper understanding of the possible short- and long-term impacts of these children will better inform physicians, clinicians, teachers, and caregivers on the importance of implementing early interventions with children in this at-risk population

The Effects of Perinatal Oxycodone Exposure on Behavioral Outcome in a Rodent Model

Opiate addiction is now a major public health problem. Perinatal insults and exposure to opiates such as morphine in utero are well known to affect development of the hypothalamic–pituitary–adrenal axis of the offspring adversely and are associated with a higher risk of developing neurobehavioral problems. Oxycodone is now one of the most frequently abused pain killers during pregnancy; however, limited data are available regarding whether and how perinatal oxycodone exposure (POE) alters neurobehavioral outcomes of the offspring. We demonstrated that exposure to 0.5 mg/kg/day oxycodone in utero was associated with hyperactivity in adult rats in an open field. No significant effects of POE were detected on isolation-induced ultrasonic vocalizations in the early postnatal period or on learning and memory in the water maze in adult offspring. Our findings are consistent with hyperactivity problems identified in children exposed to opiates in utero

Orbitofrontal cortex and drug use during adolescence : role of prenatal exposure to maternal smoking and BDNF genotype

Context : Prenatal exposure to maternal cigarette smoking (PEMCS) may affect brain development and behavior in adolescent offspring. Objective : To evaluate the involvement of the orbitofrontal cortex (OFC) in mediating the relationship between PEMCS and substance use. Design : Cross-sectional analyses from the Saguenay Youth Study aimed at evaluating the effects of PEMCS on brain development and behavior among adolescents. Nonexposed adolescents were matched with adolescents exposed prenatally to cigarette smoking by maternal educational level. Participants and Setting : A French Canadian founder population of the Saguenay–Lac-Saint-Jean region of Quebec, Canada.The behavioral data set included 597 adolescents (275 sibships; 12-18 years of age), half of whom were exposed in utero to maternal cigarette smoking. Analysis of cortical thickness and genotyping were performed using available data from 314 adolescents. Main Outcome Measures : The likelihood of substance use was assessed with the Diagnostic Interview Schedule for Children Predictive Scales. The number of different drugs tried by each adolescent was assessed using another questionnaire. Thickness of the OFC was estimated from T1-weighted magnetic resonance images using FreeSurfer software. Results : Prenatal exposure to maternal cigarette smoking is associated with an increased likelihood of substance use. Among exposed adolescents, the likelihood of drug experimentation correlates with the degree of OFC thinning. In nonexposed adolescents, the thickness of the OFC increases as a function of the number of drugs tried. The latter effect is moderated by a brain-derived neurotrophic factor (BDNF) genotype (Val66Met). Conclusions : We speculate that PEMCS interferes with the development of the OFC and, in turn, increases the likelihood of drug use among adolescents. In contrast, we suggest that, among nonexposed adolescents, drug experimentation influences the OFC thickness via processes akin to experience-induced plasticity

Prenatal methadone exposure and the developing brain

Opioid use globally is increasing resulting in rising numbers of pregnant women exposing their unborn babies to opioid drugs, with an estimated 30,000 children each year in Europe born to mothers who have used opioids during pregnancy. Methadone is the recommended opioid substitute during pregnancy. Although maternal and perinatal outcomes for pregnant opioid users can be improved by maintenance methadone, there are increasing uncertainties about the safety of methadone on the developing brain and subsequent neurodevelopmental outcomes of children who are exposed prenatally to methadone. Advanced MRI techniques, such as diffusion MRI (dMRI), allow detailed non-invasive investigation of brain microstructure. Imaging biomarkers such as fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) derived from dMRI, are robust markers of white matter development, with FA associated with later neurodevelopmental outcome. Tract-based spatial statistics (TBSS) enables group-wise comparison of dMRI data and has been optimised for the neonatal brain. The aim of this thesis was to test the hypotheses that: (i) systematic review of existing published literature shows that prenatal methadone exposure is associated with altered neurodevelopment, visual development and / or brain tissue injury apparent on imaging; (ii) infants with prenatal methadone exposure have altered brain white matter microstructure when compared with term born unexposed control infants, which is manifest by a reduced FA and increased MD and increased RD; (iii) infants with prenatal methadone exposure have reduced total brain volumes and regional brain volumes when compared with term born unexposed infants. A systematic review of the literature was performed and where amenable data were pooled in random effects meta-analysis. 43 studies were included, 29 reported neurodevelopmental outcomes, 12 reported visual, and 2 reported neuroimaging data. 8 studies were meta-analysed and effect size was expressed as weighted mean difference (WMD) in developmental quotient scores. Childhood neurodevelopment, visual development and behaviour were altered in association with prenatal methadone exposure. Meta-analysis point estimates of cognitive indices (WMD of -4.43, 95% CI -7.24 to -1.63) and motor indices (PDI scores: WMD of -5.42, 95% CI -10.55 to -0.28) in 2 year old children exposed to prenatal methadone were lower than in age matched children with no prenatal drug exposure. Term born methadone-exposed infants were recruited and underwent an MRI scan shortly after birth. These were compared with 20 non-exposed term controls. An optimised Tract-based Spatial Statistics (TBSS) pipeline was used to perform voxel-wise statistical comparison of FA data. Prenatal methadone exposure was associated with microstructural alteration in major white matter tracts which were present at birth and when head circumference was adjusted for; these changes persisted in the anterior and posterior limbs of the internal capsule and the inferior longitudinal fasciculus (p<0.05). In a subgroup of prenatal methadone exposed infants, lower white matter volumes (p = 0.049) and higher cerebrospinal fluid volumes (p = 0.001) were demonstrated when compared to healthy term control infants. This thesis has shown that through systematic review of the literature, there is an association between prenatal methadone exposure and both lower neurodevelopmental scores and visual dysfunction. TBSS showed that prenatal methadone exposure is associated with atypical white matter development compared with unexposed controls. Reduced FA in the white matter skeleton is apparent soon after birth, indicating an association between methadone exposure and brain development in utero; polydrug use among maternal cases limits causal inference. The data do not confirm the safety of methadone for medically assisted treatment of heroin addiction in pregnancy

Pediatrics

CONTEXTOpioid use and abuse have increased dramatically in recent years, particularly among women.OBJECTIVESWe conducted a systematic review to evaluate the association between prenatal opioid use and congenital malformations.DATA SOURCESWe searched Medline and Embase for studies published from 1946 to 2016 and reviewed reference lists to identify additional relevant studies.STUDY SELECTIONWe included studies that were full-text journal articles and reported the results of original epidemiologic research on prenatal opioid exposure and congenital malformations. We assessed study eligibility in multiple phases using a standardized, duplicate review process.DATA EXTRACTIONData on study characteristics, opioid exposure, timing of exposure during pregnancy, congenital malformations (collectively or as individual subtypes), length of follow-up, and main findings were extracted from eligible studies.RESULTSOf the 68 studies that met our inclusion criteria, 46 had an unexposed comparison group; of those, 30 performed statistical tests to measure associations between maternal opioid use during pregnancy and congenital malformations. Seventeen of these (10 of 12 case-control and 7 of 18 cohort studies) documented statistically significant positive associations. Among the case-control studies, associations with oral clefts and ventricular septal defects/atrial septal defects were the most frequently reported specific malformations. Among the cohort studies, clubfoot was the most frequently reported specific malformation.LIMITATIONSVariabilities in study design, poor study quality, and weaknesses with outcome and exposure measurement.CONCLUSIONSUncertainty remains regarding the teratogenicity of opioids; a careful assessment of risks and benefits is warranted when considering opioid treatment for women of reproductive age.CC999999/Intramural CDC HHS/United States2018-06-01T00:00:00Z28562278PMC556145

In utero and Postnatal Oxycodone Exposure: Implications for Intergenerational Effects

Prescription opioid abuse during and after pregnancy is a rising public health concern. Adding a layer of complexity is the role of heredity in the overall development of these exposed offspring. The present work uses a preclinical rat model mimicking oxycodone (oxy) exposure in utero (IUO) and postnatally (PNO) to investigate comparative and intergenerational effects in the two different exposure groups. To understand the direct effects of IUO and PNO exposure on the F1 generation, we employed a systems biology approach encompassing proton magnetic resonance spectroscopy (1H-MRS), electrophysiology RNA-sequencing, and pain assessment to elucidate molecular and behavioral changes in these offspring. 1H-MRS studies revealed significant changes in brain metabolites that were corroborated with changes in synaptic currents. RNA-sequencing of the prefrontal cortex further revealed alterations in the expression of key genes associated with synaptic transmission, neurodevelopment, mood disorders, and addiction. Von Frey testing showed lower pain thresholds in both oxy-exposed groups. Further, because addictive drugs produce significant and persistent changes in the synapse, we investigated the synaptic vesicle (SV) contents of the PNO and IUO groups. To that end, we found that the expression levels of key SV proteins associated with functional pathways and neurological disease were altered in oxy-exposed groups. While our earlier studies characterized the effects PNO and IUO exposure have on the F1 generation, we next sought to compare the overall development between F1 offspring and their progeny, the F2 generation. We observed significant differences in phenotypic attributes of both generations in each treatment group, and RNA-sequencing of the nucleus accumbens revealed alterations in the expression of key synaptic genes in both generations. Post-validation of these genes using RT-PCR highlighted the differential expression of several neuropeptides associated with the hypocretin system, a system recently implicated in addiction. Further, behavior studies revealed anxiety-like behaviors and social deficits in both treatment groups that persisted into the F2 generation. Collectively, our studies reveal a new line of investigation on the potential risks associated with oxy use during and after pregnancy, specifically the disruption of neurodevelopment and the intergenerational impact on behavior