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Neurodevelopmental Outcomes of Prenatal Preeclampsia Exposure.

ABSTRACT: Preeclampsia is a dangerous hypertensive disorder of pregnancy with known links to negative child health outcomes. Here, we review epidemiological and basic neuroscience work from the past several decades linking prenatal preeclampsia to altered neurodevelopment. This work demonstrates increased rates of neuropsychiatric disorders [e.g., increased autism spectrum disorder, attention deficit hyperactivity disorder (ADHD)] in children of preeclamptic pregnancies, as well as increased rates of cognitive impairments [e.g., decreased intelligence quotient (IQ), academic performance] and neurological disease (e.g., stroke and epilepsy). We also review findings from multiple animal models of preeclampsia. Manipulation of key clinical preeclampsia processes in these models (e.g., placental hypoxia, immune dysfunction, angiogenesis, oxidative stress) causes various disruptions in offspring, including ones in white matter/glia, glucocorticoid receptors, neuroimmune outcomes, cerebrovascular structure, and cognition/behavior. This animal work implicates potentially high-yield targets that may be leveraged in the future for clinical application.

SUBMITTER: Gumusoglu SB

PROVIDER: S-EPMC7170230 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundRecent studies have suggested an association between prenatal paracetamol exposure and adverse neurodevelopmental outcomes in children. However, these findings may be confounded by unmeasured factors related to maternal use of paracetamol and child outcomes.ObjectiveTo examine the association between duration and timing of prenatal paracetamol exposure on parent-reported communication skills, behaviour, and temperament in preschool-aged children, with focus on the role of unmeasured confounding.MethodsWe used data from the Norwegian Mother and Child Cohort Study. Linear and generalised linear models with inverse probability weights and robust standard errors were used to quantify the association between prenatal paracetamol exposure and continuous and categorical outcomes.ResultsOf the 32 934 children included in our study, 8374 (25.4%), 4961 (15.1%), and 1791 (5.4%) were prenatally exposed to paracetamol in one, two, and three trimesters, respectively. Children exposed to paracetamol in two trimesters scored lower on shyness compared with unexposed children (β -0.62, 95% confidence interval [CI] -1.05, -0.19). Children exposed to paracetamol in three trimesters had a moderate increased risk of internalising behaviour problems (relative risk (RR) 1.36, 95% CI 1.02, 1.80) and borderline externalising behaviour problems (RR 1.22, 95% CI 0.93, 1.60) compared with unexposed children. Children exposed to paracetamol in 2nd/3rd trimester scored lower on shyness (β -0.32, 95% CI -0.66, 0.02) compared with unexposed children. Sensitivity analyses indicated that unmeasured confounders play an important role and may potentially bias the effect estimates away from the null.ConclusionsTiming of exposure and short-term use of paracetamol during pregnancy do not seem to pose any substantial risk of the outcomes examined. Although we found an association between paracetamol use in multiple trimesters and lower shyness and greater internalising behaviour in preschool-aged children, we cannot rule out chance or unmeasured confounding as possible explanations for these findings.

Project description:BackgroundDespite the widespread use of caffeine including consumption during pregnancy, the effect of prenatal caffeine exposure on child brain development and behavior is unclear.MethodsTo address this, we used data from the Adolescent Brain and Cognitive Development Study (n = 11,875 children aged 9-11 years from 22 sites across the United States). We explored the associations between prenatal caffeine exposure and various developmental outcomes including birth outcomes, physical health, behavior problems, cognition, substance use and brain structure in children, and evaluated dose effects.ResultsAmong 9,978 children (4,745 females) who had valid data for prenatal caffeine exposure and whose mothers did not use drugs of abuse after knowing of pregnancy, 4,170 (41.79%) had no prenatal caffeine exposure, 2,292 (22.97%) had daily, 1,933 (19.37%) had weekly, and 1,583 (15.86%) had less than weekly exposures. Prenatal caffeine exposure including the widely recommended 'safe' dose was associated with greater externalizing problems, whereas greater BMI and soda consumption were only observed in children with high dose exposures (3+ per day). Notably, the effect size for association of externalizing problems with prenatal caffeine exposure was comparable with that reported for prenatal alcohol (The American Journal of Psychiatry, 177, 2020 and 1060) and prenatal cannabis (JAMA Psychiatry, 78, 2020 and 64) exposures from previous ABCD publications. Additionally, prenatal caffeine exposure was associated with brain structural changes that included greater posterior and lower frontal cortical thickness and altered parietooccipital sulcal depth.ConclusionsThe recommended 'safe' dose of caffeine during pregnancy should be carefully studied to assess whether the behavioral and brain correlates observed here are clinically relevant and determine whether it needs adjustment. Because of the high prevalence of caffeine use in the general population, studies on prenatal exposure to drugs of abuse should include prenatal caffeine use as a covariate.

Project description:PurposeAlthough abstinence is recommended in pregnancy, many pregnancies are exposed to alcohol. Observational studies of the effects of low to moderate prenatal alcohol exposure (PAE) and neurodevelopmental outcomes have yielded inconsistent results, with some studies finding an increased risk of adverse neurobehavioral and cognitive outcomes, and other studies finding no changes or reduced risk of the same outcomes. The purpose of this narrative review is to summarize these inconsistencies and apply a methodological framework to discuss how different parameters contribute to the findings. The authors also provide recommendations on how to advance future research in this area.Search methodsThe PubMed, Web of Science, and Embase databases were searched, along with reference lists of selected systematic reviews and meta-analyses. Search terms used were (infant or child or children or adolescent or offspring) AND (low or light or mild or moderate or low-to-moderate) AND (drinking or alcohol or drinks) AND (pregnancy or prenatal or fetal) AND (neurodevelopment or behavioral or psychological or cognitive or developmental) NOT (mice or rat or fish or animal) NOT (meta-analysis or review). Peer-reviewed original research studies were included if they analyzed associations between an exposure defined and characterized as low/light or moderate PAE with offspring neurodevelopmental outcomes. Animal studies, studies that did not provide clear cutoff points to classify PAE categories, studies lacking an abstinence control group, and studies that did not present a multivariable-adjusted measure of association were excluded.Search resultsThe searches identified 2,422 papers, with 36 papers meeting eligibility criteria. These studies were carried out across nine countries and included samples ranging from approximately 500 to 40,000 participants. Cognitive, academic, socioemotional, and behavioral outcomes were assessed from infancy through age 19.Discussion and conclusionWhen the findings from the selected articles were summarized by geographic region, exposure definition, or neurodevelopmental outcome, no consistent observations or patterns emerged between low to moderate PAE and offspring outcomes. Although some studies found positive (i.e., beneficial) associations between low to moderate PAE and outcomes (primarily outcomes related to cognition) and others found negative (i.e., detrimental) associations (primarily for behavioral outcomes), most findings were null (i.e., showed no effect of PAE). The heterogeneity in study results is likely due to methodological issues, including residual confounding, effect measure modification, and exposure misclassification that make synthesis of studies difficult. Alternative study designs, including longitudinal trajectory analysis, sibling design, negative controls, and instrumental variable analyses, may reduce biases and are discussed. To date, the consequences of light to moderate levels of PAE on neurodevelopment remain unresolved; studies that advance methodological rigor will be important contributions to the field.

Project description:IntroductionSeveral 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.ObjectiveThe aim of this study was to quantify the association between prenatal opioid exposure from maternal prescription use and neurodevelopmental outcomes in early childhood.MethodsThis 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.ResultsOf 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 relevanceIn 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.

Project description:Higher prenatal ambient air pollution exposure has been associated with impaired neurodevelopment in preschoolers and school-aged children. The purpose of this study was to explore the relationships between prenatal ambient air pollution exposure and neurodevelopment during infancy. This study examined 161 Latino mother-infant pairs from the Southern California Mother's Milk Study. Exposure assessments included prenatal nitrogen dioxide (NO2) and particulate matter smaller than 2.5 and 10 microns in diameter (PM2.5 and PM10, respectively). The pregnancy period was also examined as three windows, early, mid, and late, which describe the first, middle, and last three months of pregnancy. Infant neurodevelopmental outcomes at 2 years of age were measured using the Bayley-III Scales of Infant and Toddler Development. Multivariable linear models and distributed lag linear models (DLM) were used to examine relationships between prenatal exposures and neurodevelopmental scores, adjusting for socioeconomic status, breastfeeding frequency, time of delivery, pre-pregnancy body mass index, and infant birthweight and sex. Higher prenatal exposure to PM10 and PM2.5 was negatively associated with composite cognitive score (β = -2.01 [-3.89, -0.13] and β = -1.97 [-3.83, -0.10], respectively). In addition, higher average prenatal exposure to PM10 was negatively associated with composite motor (β = -2.35 [-3.95, -0.74]), scaled motor (β = -0.77 [-1.30, -0.24]), gross motor (β = -0.37 [-0.70, -0.04]), fine motor (β = -0.40 [-0.71, -0.09]), composite language (β = -1.87 [-3.52, -0.22]), scaled language (β = -0.61 [-1.18, -0.05]) and expressive communication scaled scores (β = -0.36 [-0.66, -0.05]). DLMs showed that higher prenatal air pollution exposure during mid and late pregnancy was inversely associated with motor, cognitive, and communication language scores. Higher exposure to air pollutants during pregnancy, particularly in the mid and late prenatal periods, was inversely associated with scaled and composite motor, cognitive, and language scores at 2 years. These results indicate that prenatal ambient air pollution may negatively impact neurodevelopment in early life.

Project description:BackgroundLamotrigine has become one of the most commonly prescribed antiseizure medications (ASM) in epileptic women during pregnancy and therefore requires regular updates regarding its safety. The aim of this study was to estimate the association between in utero exposure to lamotrigine monotherapy and the occurrence of neurodevelopmental outcomes.MethodsAll comparative studies assessing the occurrence of neurodevelopmental outcomes after epilepsy-indicated lamotrigine monotherapy exposure during pregnancy were searched. First, references were identified through a snowballing approach, then, through electronic databases (Medline and Embase) from 2015 to June 2022. One investigator evaluated study eligibility and extracted data and a second independent investigator reviewed the meta-analysis (MA). A systematic review and random-effects model approach were performed using a collaborative WEB-based meta-analysis platform (metaPreg.org) with a registered protocol (osf.io/u4gva).ResultsOverall, 18 studies were included. For outcomes reported by at least 4 studies, the pooled odds ratios and 95% confidence interval obtained with the number of exposed (N1) and unexposed children (N0) included were: neurodevelopmental disorders as a whole 0.84 [0.66;1.06] (N1 = 5,271; N0 = 22,230); language disorders or delay 1.16 [0.67;2.00] (N1 = 313; N0 = 506); diagnosis or risk of ASD 0.97 [0.61;1.53] (N1 = at least 5,262; N0 = 33,313); diagnosis or risk of ADHD 1.14 [0.75;1.72] (N1 = at least 113; N0 = 11,530) and psychomotor developmental disorders or delay 2.68 [1.29-5.56] (N1 = 163; N0 = 220). The MA of cognitive outcomes included less than 4 studies and retrieved a significant association for infants exposed to lamotrigine younger than 3 years old but not in the older age groups.ConclusionPrenatal exposure to lamotrigine monotherapy is not found to be statistically associated with neurodevelopmental disorders as a whole, language disorders or delay, diagnosis or risk of ASD and diagnosis or risk of ADHD. However, the MA found an increased risk of psychomotor developmental disorders or delay and cognitive developmental delay in less than 3 years old children. Nevertheless, these findings were based exclusively on observational studies presenting biases and on a limited number of included children. More studies should assess neurodevelopmental outcomes in children prenatally exposed to lamotrigine.

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Neurodevelopmental Outcomes of Prenatal Preeclampsia Exposure.

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