Early life stress and environmental influences on the neurodevelopment of children with prenatal opioid exposure.
ABSTRACT: Prenatal opioid exposure has reached epidemic proportions. In the last 10 years, there has been a 242% increase in the number of babies born with the drug withdrawal syndrome known as Neonatal Opioid Withdrawal Syndrome (NOWS). Developmental outcome studies of infants with prenatal opioid exposure are limited by methodological issues including small sample sizes and lack of control for confounding variables such as exposure to poverty and maternal psychopathology. Thus, there is a critical gap in the literature that limits our ability to predict short-term effects of opioid exposure. Here we review direct neurotoxic, indirect, and stress-related pathophysiologies of prenatal opioid exposure. We describe the literature on short and long-term neurodevelopmental outcomes of children with prenatal opioid exposure, highlighting sex differences and the role of early life stress. We conclude by prioritizing avenues for future research for this group of underserved women and their children at risk for neurodevelopmental delays.
Project description:BACKGROUND:While use of prescription opioids and medication assisted therapy (MAT) for opioid use disorder in pregnancy, as well as the incidence of neonatal opioid withdrawal syndrome (NOWS) continue to rise, little is known about outcomes for children with NOWS beyond the newborn period. METHODS:We examined 1) prenatal MAT exposure vs. unexposed healthy controls [HC]; and 2) treatment for NOWS and NOWS severity on infant neurodevelopmental and behavioral outcomes at 5-8?months of age in 78 maternal-infant pairs from the ENRICH prospective cohort study. Data were obtained from 3 study visits: prenatal, delivery, and neurodevelopmental evaluation at 5-8?months of age. Neurodevelopmental outcomes included the Bayley Scales of Infant Development [BSID-III], caregiver questionnaires (Parenting Stress Index [PSI-SF], Infant Behavior Questionnaire [IBQ-R], Sensory Profile), and the experimental Still-Face Paradigm (SFP). RESULTS:No differences in the BSID-III, PSI-SF, or IBQ-R scores were observed between MAT and HC groups; however, MAT-exposed and HC infants differed with respect to SFP self-regulation (??=?-18.9; p?=?0.01) and Sensory Profile sensation seeking (OR?=?4.87; 95% CI: 1.55; 15.30) after adjusting for covariates. No significant differences between Treated-for-NOWS vs. not-Treated-for-NOWS were observed. Shorter timing to NOWS treatment initiation was associated with higher Total Stress (??=?-9.08; p?=?0.035), while longer hospitalization was associated with higher Parent-child dysfunctional interaction (p?=?0.018) on PSI-SF. CONCLUSIONS:Our results provide additional evidence of little-to-no effect of MAT and pharmacological treatment of NOWS on infant neurodevelopmental and behavioral outcomes at 5-8?months of age. However, prolonged hospitalization might increase family psychosocial stress and requires further examination.
Project description:Newborns exposed to prenatal opioids often experience intense postnatal withdrawal after cessation of the opioid, called neonatal opioid withdrawal syndrome (NOWS), with limited pre- and postnatal therapeutic options available. In a prior study in pregnant mice we demonstrated that the peripherally selective opioid antagonist, 6?-naltrexol (6BN), is a promising drug candidate for preventive prenatal treatment of NOWS, and a therapeutic mechanism was proposed based on preferential delivery of 6BN to fetal brain with relative exclusion from maternal brain. Here, we have developed methadone (MTD) treated pregnant guinea pigs as a physiologically more suitable model, enabling detection of robust spontaneous neonatal withdrawal. Prenatal MTD significantly aggravates two classic maternal separation stress behaviors in newborn guinea pigs: calling (vocalizing) and searching (locomotion) - natural attachment behaviors thought to be controlled by the endogenous opioid system. In addition, prenatal MTD significantly increases the levels of plasma cortisol in newborns, showing that cessation of MTD at birth engages the hypothalamic-pituitary-adrenal (HPA) axis. We find that co-administration of 6BN with MTD prevents these withdrawal symptoms in newborn pups with extreme potency (ID50 ?0.02 mg/kg), at doses unlikely to induce maternal or fetal withdrawal or to interfere with opioid antinociception based on many prior studies in rodents and non-human primates. Furthermore, we demonstrate a similarly high potency of 6BN in preventing opioid withdrawal in adult guinea pigs (ID50 = 0.01 mg/kg). This high potency appears to run counter to our pharmacokinetic studies showing slow 6BN transit of both the placenta and maternal blood brain barrier in guinea pigs, and calls into question the preferential delivery mechanism. Rather, it suggests a novel receptor mechanism to account for the selectively high potency of 6BN to suppress opioid dependence at all developmental stages, even in adults, as compared to its well-established low potency as a classical opioid antagonist. In conclusion, 6BN is an attractive compound for development of a preventive therapy for NOWS.
Project description:Aim: To define a developmental trajectory in infants with neonatal opioid withdrawal syndrome (NOWS) and determine whether the impacted developmental domain varies with the type of antenatal exposure. Methods: We performed a retrospective cohort study of infants treated pharmacologically for NOWS and assessed using a standardized schedule for follow-up visits. We compared outcomes of the study population to published norms using one-sample t-tests. Multivariable models examined associations with exposures in addition to opioids. Results: In our cohort of 285 infants with 9-12-months testing, 164 (55.7%) were seen at 3-4 months, and 125 (44%), at 15-18 months. The majority (58%) had intrauterine drug exposures in addition to opioids. Neurodevelopmental scores of infants with NOWS at 3-4 and 9-12 months were not different from published norms. Cognitive and language scores at 15-18 months were worse than published norms. Male sex, older maternal age, and additional barbiturate or alcohol exposure were associated with worse outcomes. Conclusion: Infants with pharmacologically treated NOWS had development similar to unexposed infants during the 1st year but worse cognitive and language scores during the 2nd year. These data support the need for a prospective follow-up of large cohorts of infants with NOWS, with systematic assessments and an evaluation of contributing factors.
Project description:AIM:To systematically review and meta-analyse studies of neurodevelopmental outcome of children born to mothers prescribed methadone in pregnancy. METHOD:MEDLINE, Embase, and PsycINFO were searched for studies published from 1975 to 2017 reporting neurodevelopmental outcomes in children with prenatal methadone exposure. RESULTS:Forty-one studies were identified (2283 participants). Eight studies were amenable to meta-analysis: at 2 years the Mental Development Index weighted mean difference of children with prenatal methadone exposure compared with unexposed infants was -4.3 (95% confidence interval [CI] -7.24 to -1.63), and the Psychomotor Development Index weighted mean difference was -5.42 (95% CI -10.55 to -0.28). Seven studies reported behavioural scores and six found scores to be lower among methadone-exposed children. Twelve studies reported visual outcomes: nystagmus and strabismus were common; five studies reported visual evoked potentials of which four described abnormalities. Factors that limited the quality of some studies, and introduced risk of bias, included absence of blinding, small sample size, high attrition, uncertainty about polydrug exposure, and lack of comparison group validity. INTERPRETATION:Children born to mothers prescribed methadone in pregnancy are at risk of neurodevelopmental problems but risk of bias limits inference about harm. Research into management of opioid use disorder in pregnancy should include evaluation of childhood neurodevelopmental outcome. WHAT THIS PAPER ADDS:Children born to opioid-dependent mothers prescribed methadone are at risk of neurodevelopmental impairment. Exposed infants have lower Mental Development Index and Psychomotor Development Index scores than unexposed children. Atypical visual evoked potentials, strabismus, and nystagmus have increased prevalence. Estimates of impairment may be biased by intermediate to poor quality evidence.
Project description:Infants with in-utero opioid exposure are most commonly assessed using the Finnegan Neonatal Abstinence Scoring System (FNASS) or a modified version of that tool. Traditionally, the purpose of these tools has been to characterize the extent of withdrawal signs to guide the pharmacologic treatment for infants with neonatal opioid withdrawal syndrome (NOWS). In the past decade however, in response to some of the limitations of the FNASS tool, there has been an increasing emphasis on developing novel assessment tools not based on the FNASS in addition to the promotion of non-pharmacologic treatment options as the first line treatment for infants with opioid exposure. Additionally, several prediction tools that may be useful in determining which patients are at high or low risk for receiving pharmacologic therapy have been developed. In this review, we will evaluate the clinical utility of these novel tools and will consider new avenues for future research.
Project description:Importance:The opioid epidemic increasingly affects pregnant women and developing fetuses, resulting in high rates of neonatal abstinence syndrome. However, longitudinal studies that prospectively observe newborns with neonatal abstinence syndrome or with maternal opioid use and examine their long-term physical and neurodevelopmental outcomes are lacking. Objective:To examine prenatal risk factors associated with maternal opioid use during pregnancy and the short-term and long-term health consequences on their children. Design, Setting, and Participants:This cohort study analyzed data from the Boston Birth Cohort, an urban, low-income, multiethnic cohort that enrolled mother-newborn pairs at birth at Boston Medical Center (Boston, Massachusetts) starting in 1998, and a subset of children were prospectively observed at Boston Medical Center pediatric primary care and subspecialty clinics from birth to age 21 years. Data analysis began in June 2018 and was completed in May 2019. Exposures:In utero opioid exposure was defined as maternal self-reported opioid use and/or clinical diagnosis of neonatal abstinence syndrome. Main Outcomes and Measures:Pregnancy outcomes, postnatal child physical health, and major neurodevelopmental disabilities, documented in maternal and child medical records. Results:This study included 8509 Boston Birth Cohort mother-newborn pairs for prenatal and perinatal analyses. Of those, 3153 children continued to receive pediatric care at Boston Medical Center and were included in assessing postnatal outcomes. Overall, 454 of the 8509 children (5.3%) in the Boston Birth Cohort had in utero opioid exposure. At birth, opioid exposure was associated with higher risks of fetal growth restriction (odds ratio [OR], 1.87; 95% CI, 1.41-2.47) and preterm birth (OR, 1.49; 95% CI, 1.19-1.86). Opioid exposure was associated with increased risks of lack of expected physiological development (OR, 1.80; 95% CI, 1.17-2.79) and conduct disorder/emotional disturbance (OR, 2.13; 95% CI, 1.20-3.77) among preschool-aged children. In school-aged children, opioid exposure was associated with a higher risk of attention-deficit/hyperactivity disorder (OR, 2.55; 95% CI, 1.42-4.57). Conclusions and Relevance:In this sample of urban, high-risk, low-income mother-child pairs, in utero opioid exposure was significantly associated with adverse short-term and long-term outcomes across developmental stages, including higher rates of physical and neurodevelopmental disorders in affected children. Efforts to prevent the opioid epidemic and mitigate its health consequences would benefit from more intergenerational research.
Project description:BACKGROUND:Neurodevelopment is a complex process involving both genetic and environmental factors. Prenatal exposure to lead (Pb) has been associated with lower performance on neurodevelopmental tests. Adverse neurodevelopmental outcomes are more frequent and/or more severe when toxic exposures interact with genetic susceptibility. METHODS:To explore possible loci associated with increased susceptibility to prenatal Pb exposure, we performed a genome-wide gene-environment interaction study (GWIS) in young children from Mexico (n = 390) and Bangladesh (n = 497). Prenatal Pb exposure was estimated by cord blood Pb concentration. Neurodevelopment was assessed using the Bayley Scales of Infant Development. RESULTS:We identified a locus on chromosome 8, containing UNC5D, and demonstrated evidence of its genome-wide significance with mental composite scores (rs9642758, p meta = 4.35 × 10-6). Within this locus, the joint effects of two independent single nucleotide polymorphisms (SNPs, rs9642758 and rs10503970) had a p-value of 4.38 × 10-9 for mental composite scores. Correlating GWIS results with in vitro transcriptomic profiles identified one common gene, SLC1A5, which is involved in synaptic function, neuronal development, and excitotoxicity. Further analysis revealed interconnected interactions that formed a large network of 52 genes enriched with oxidative stress genes and neurodevelopmental genes. CONCLUSIONS:Our findings suggest that certain genetic polymorphisms within/near genes relevant to neurodevelopment might modify the toxic effects of Pb exposure via oxidative stress.
Project description:BACKGROUND:Previous studies suggest that prenatal exposure to phthalates, ubiquitous synthetic chemicals, may adversely affect neurodevelopment. However, data are limited on how phthalates affect cognition, executive function, and behavioral function into adolescence. OBJECTIVE:We aimed to investigate associations of prenatal phthalate exposure with neurodevelopment in childhood and adolescence in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study. METHODS:We examined associations between maternal urinary phthalate metabolite concentrations measured twice during pregnancy and a range of neurodevelopmental outcomes from ages 7 through 16 y in the CHAMACOS birth cohort (n=334). We used age-specific linear regression models and generalized estimating equation models to assess longitudinal effects and examined differences by sex. RESULTS:Phthalate metabolites were detected in 88%-100% of samples, depending on the metabolite. Associations of phthalates with neurodevelopmental outcomes were largely null with some noteworthy patterns. Higher prenatal concentrations of metabolites of low-molecular weight phthalates (?LMW) were associated with more self-reported hyperactivity [?=0.8, 95% confidence interval (CI): 0.1, 1.4 per 2-fold increase in ?LMW phthalates], attention problems (?=1.5, 95% CI: 0.7, 2.2), and anxiety (?=0.9, 95% CI: 0.0, 1.8) at age 16. We observed sex-specific differences for the sums of high-molecular-weight and di(2-ethylhexyl) metabolites and cognitive outcomes (e.g., ? for Full-Scale IQ for boys=-1.9, 95% CI: -4.1, 0.3 and -1.7, 95% CI: -3.8, 0.3, respectively; ? for girls=1.8, 95% CI: 0.1, 3.4 and 1.6, 95% CI: 0.0, 3.2, respectively; p-int=0.01 for both). CONCLUSION:We found predominantly null associations of prenatal phthalates with neurodevelopment in CHAMACOS, and weak associations of ?LMW phthalates with internalizing and externalizing behaviors in adolescence. No previous studies have examined associations of prenatal phthalate exposure with neurodevelopment into adolescence, an important time for manifestations of effects. https://doi.org/10.1289/EHP5165.
Project description:The long-term consequences of perinatal opioid exposure and subsequent development of neonatal opioid withdrawal syndrome is largely unknown and likely dependent on a multitude of factors, including co-morbid drug use, pre- and post-natal care, and individual factors including the maternal-infant relationship and home environment. This review summarizes the current literature from clinical and preclinical studies on perinatal opioid exposure, focusing on the consequences in the offspring. Although a large number of preclinical studies have been conducted examining the impact of prenatal opioid exposure, the models employed are not necessarily representative of clinical use patterns, making it challenging to translate these results to the impacted population. Use of more clinically-relevant models of perinatal opioid exposure are requisite for the development of improved pharmacological and behavioral treatment strategies to improve quality of life for this vulnerable population.
Project description:Increased rates of Zika virus have been identified in economically deprived areas in Brazil at the population level; yet, the implications of the interaction between socioeconomic position and prenatal Zika virus exposure on adverse neurodevelopmental outcomes remains insufficiently evaluated at the individual level. Using data collected between September 2015 and September 2019 from 163 children with qRT-PCR and/or IgM-confirmed prenatal exposure to Zika virus participating in a prospective cohort study in Rio de Janeiro, Brazil (NCT03255369), this study evaluated the relationships of socioeconomic indicators with microcephaly at birth and Bayley-III neurodevelopmental scores during the early life course. Adjusted logistic regression models indicated increased odds of microcephaly in children born to families with lower household income (OR, 95% CI: 3.85, 1.43 to 10.37) and higher household crowding (OR, 95% CI: 1.83, 1.16 to 2.91), while maternal secondary and higher education appeared to have a protective effect for microcephaly compared to primary education (OR, 95% CI: 0.33, 0.11 to 0.98 and 0.10, 0.03 to 0.36, respectively). Consistent with these findings, adjusted linear regression models indicated lower composite language (-10.78, 95% CI: -19.87 to -1.69), motor (-10.45, 95% CI: -19.22 to -1.69), and cognitive (-17.20, 95% CI: -26.13 to -8.28) scores in children whose families participated in the Bolsa Família social protection programme. As such, the results from this investigation further emphasise the detrimental effects of childhood disadvantage on human health and development by providing novel evidence on the link between individual level socioeconomic indicators and microcephaly and delayed early life neurodevelopment following prenatal Zika virus exposure.