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Gestational cytokine concentrations and neurocognitive development at 7 years

Ghassabian, Akhgar; Albert, Paul S; Hornig, Mady; Yeung, Edwina; Cherkerzian, Sara; Goldstein, Risë B; Buka, Stephen L; Goldstein, Jill M; Gilman, Stephen E
Gestational inflammation may contribute to brain abnormalities associated with childhood neuropsychiatric disorders. Limited knowledge exists regarding the associations of maternal cytokine levels during pregnancy with offspring neurocognitive development. We assayed the concentrations of five cytokines (interleukin (IL)-6, IL-1β, IL-8, tumor necrosis factor alpha (TNF-α), and IL-10) up to four times in the 2nd and 3rd trimesters of pregnancy using stored prenatal sera from 1366 participants in the New England Family Study (enrollment 1959-1966). Intelligence (IQ), academic achievement, and neuropsychological functioning of singleton offspring were assessed at age 7 years using standardized tests. We used linear mixed models with random effects to estimate the cumulative exposure to each cytokine during 2nd and 3rd trimesters, and then related cumulative cytokine exposure to a wide range of offspring neurocognitive outcomes. We found that children of women with higher levels of the pro-inflammatory cytokine, TNF-α, in the 2nd and 3rd trimesters had lower IQ (B = -2.51, 99% CI: -4.84,-0.18), higher problem scores in visual-motor maturity (B = 0.12, 99% CI: 0.001,0.24), and lower Draw-a-Person test scores (B = -1.28, 99% CI: -2.49,-0.07). Higher gestational levels of IL-8, another pro-inflammatory molecule, were associated with better Draw-a-Person test scores and tactile finger recognition scores. Other cytokines were not associated with our outcome of interest. The opposing directions of associations observed between TNF-α and IL-8 with childhood outcomes suggest pleiotropic effects of gestational inflammation across the domains of neurocognitive functioning. Although the path to psychopathological disturbances in children is no doubt multifactorial, our findings point to a potential role for immune processes in the neurocognitive development of children.
PMCID:5847536
PMID: 29531226
ISSN: 2158-3188
CID: 2992592

Downstream effects of maternal hypothyroxinemia in early pregnancy: nonverbal IQ and brain morphology in school-age children

Ghassabian, Akhgar; El Marroun, Hanan; Peeters, Robin P; Jaddoe, Vincent W; Hofman, Albert; Verhulst, Frank C; Tiemeier, Henning; White, Tonya
CONTEXT: Although maternal hypothyroxinemia is suggested to be related to various adverse consequences in a child's neurodevelopment, the underlying neurobiology is largely unknown. OBJECTIVE: The objective of the study was to examine the relationship between maternal hypothyroxinemia in early pregnancy and children's nonverbal intelligence quotient (IQ). Furthermore, we explored whether global brain volumes, cortical thickness, and brain surface area differed between children exposed prenatally to hypothyroxinemia and healthy controls. DESIGN AND SETTING: The study included a large population-based prospective birth cohort in The Netherlands. PARTICIPANTS: A total of 3727 mother-child pairs with data on prenatal thyroid function at less than 18 weeks of gestation and nonverbal IQ at 6 years participated in the study. In 652 children, brain imaging was performed at 8 years of age. MAIN MEASURES: Maternal hypothyroxinemia was defined as free T4 in the lowest 5% of the sample, whereas TSH was in the normal range. At 6 years, children's IQ was assessed using a Dutch test battery. Global brain volumetric measures, cortical thickness, and surface area were assessed using high-resolution structural magnetic resonance imaging. RESULTS: The children of mothers with hypothyroxinemia in early pregnancy scored 4.3 points IQ lower than the children of mothers with normal thyroid status (95% confidence interval -6.68, -1.81; P = .001). After adjustment for multiple testing, we did not find any differences in brain volumetric measures, cortical thickness, and surface area between children exposed prenatally to hypothyroxinemia and controls. CONCLUSIONS: Our findings confirm a large adverse effect of maternal hypothyroxinemia on children's nonverbal IQ at school age. However, we found no evidence that maternal hypothyroxinemia is associated with differences in brain morphology in school-age children.
PMID: 24684462
ISSN: 1945-7197
CID: 2117962

Maternal Mild Thyroid Hormone Insufficiency in Early Pregnancy and Attention-Deficit/Hyperactivity Disorder Symptoms in Children

Modesto, Thiago; Tiemeier, Henning; Peeters, Robin P; Jaddoe, Vincent W V; Hofman, Albert; Verhulst, Frank C; Ghassabian, Akhgar
IMPORTANCE: Maternal thyroid hormone insufficiency during pregnancy can affect children's cognitive development. Nevertheless, the behavioral outcomes of children exposed prenatally to mild thyroid hormone insufficiency are understudied. OBJECTIVE: To examine whether exposure to maternal mild thyroid hormone insufficiency in early pregnancy was related to symptoms of attention-deficit/hyperactivity disorder (ADHD) in children at 8 years of age. DESIGN, SETTING, AND PARTICIPANTS: The study was embedded within the Generation R, a population-based birth cohort in the Netherlands. Children in the Generation R Study are followed up from birth (April 1, 2002, through January 31, 2006) until young adulthood. Of the 4997 eligible mother-child pairs with data on maternal thyroid levels (excluding twins), 3873 pairs of children and caregivers (77.5%) visited the Generation R research center for in-depth assessments and were included in the main analyses. Data collection in Generation R started December 1, 2001 (enrollment of pregnant women), and is ongoing. For this study, we used the data that were collected until January 1, 2014. Data analyses started on January 31 and finished June 30, 2014. MAIN OUTCOMES AND MEASURES: Maternal hypothyroxinemia, characterized by low levels of free thyroxine coexisting with reference thyrotropin levels, and children's symptoms of ADHD. Maternal thyroid hormone levels (thyrotropin, free thyroxine, thyroid peroxidase antibodies) were measured at a mean (SD) of 13.6 (1.9) weeks of gestation. Children's ADHD symptoms were assessed at 8 years of age using the Conners' Parent Rating Scale-Revised Short Form; higher scores indicate more ADHD symptoms (possible range, 0-36). RESULTS: Maternal hypothyroxinemia (n = 127) in early pregnancy was associated with higher scores for ADHD symptoms in children at 8 years of age after adjustments for child and maternal factors (ie, sex, ethnicity, maternal age, maternal educational level, and income) (increase in ADHD scores, 7% [95% CI, 0.3%-15%]). The results remained essentially unchanged when women with elevated levels of thyroid peroxidase antibodies were excluded from the analyses (increase in ADHD scores, 8% [95% CI, 1%-16%]). Additional adjustment for children's IQ or comorbid autistic symptoms attenuated the association (increase in ADHD scores adjusted for autistic symptoms, 7% [95% CI, 1%-15%]; increase in ADHD scores adjusted for IQ, 6% [95% CI, 1%-14%]). CONCLUSIONS AND RELEVANCE: Children exposed to maternal hypothyroxinemia in early pregnancy had more ADHD symptoms, independent of confounders. This finding suggests that intrauterine exposure to insufficient thyroid hormone levels influences neurodevelopment in offspring.
PMID: 26146876
ISSN: 2168-6211
CID: 2117872

Air Pollution Exposure during Pregnancy and Childhood Autistic Traits in Four European Population-Based Cohort Studies: The ESCAPE Project

Guxens, Monica; Ghassabian, Akhgar; Gong, Tong; Garcia-Esteban, Raquel; Porta, Daniela; Giorgis-Allemand, Lise; Almqvist, Catarina; Aranbarri, Aritz; Beelen, Rob; Badaloni, Chiara; Cesaroni, Giulia; de Nazelle, Audrey; Estarlich, Marisa; Forastiere, Francesco; Forns, Joan; Gehring, Ulrike; Ibarluzea, Jesus; Jaddoe, Vincent W V; Korek, Michal; Lichtenstein, Paul; Nieuwenhuijsen, Mark J; Rebagliato, Marisa; Slama, Remy; Tiemeier, Henning; Verhulst, Frank C; Volk, Heather E; Pershagen, Goran; Brunekreef, Bert; Sunyer, Jordi
BACKGROUND: Prenatal exposure to air pollutants has been suggested as a possible etiologic factor for the occurrence of autism spectrum disorder. OBJECTIVES: We aimed to assess whether prenatal air pollution exposure is associated with childhood autistic traits in the general population. METHODS: Ours was a collaborative study of four European population-based birth/child cohorts-CATSS (Sweden), Generation R (the Netherlands), GASPII (Italy), and INMA (Spain). Nitrogen oxides (NO2, NOx) and particulate matter (PM) with diameters of
PMCID:4710593
PMID: 26068947
ISSN: 1552-9924
CID: 2117882

Infant muscle tone and childhood autistic traits: A longitudinal study in the general population

Serdarevic, Fadila; Ghassabian, Akhgar; van Batenburg-Eddes, Tamara; White, Tonya; Blanken, Laura M E; Jaddoe, Vincent W V; Verhulst, Frank C; Tiemeier, Henning
In a longitudinal population-based study of 2,905 children, we investigated if infants' neuromotor development was associated with autistic traits in childhood. Overall motor development and muscle tone were examined by trained research assistants with an adapted version of Touwen's Neurodevelopmental Examination between ages 2 and 5 months. Tone was assessed in several positions and items were scored as normal, low, or high tone. Parents rated their children's autistic traits with the Social Responsiveness Scale (SRS) and the Pervasive Developmental Problems (PDP) subscale of the Child Behavior Checklist at 6 years. We defined clinical PDP if scores were >98th percentile of the norm population. Diagnosis of autism spectrum disorder (ASD) was clinically confirmed in 30 children. We observed a modest association between overall neuromotor development in infants and autistic traits. Low muscle tone in infancy predicted autistic traits measured by SRS (adjusted beta = 0.05, 95% CI for B: 0.00-0.02, P = 0.01), and PDP (adjusted beta = 0.08, 95% CI for B: 0.04-0.10, P < 0.001). Similar results emerged for the association of low muscle tone and clinical PDP (adjusted OR = 1.36, 95% CI: 1.08-1.72, P = 0.01) at age 6 years. Results remained unchanged if adjusted for child intelligence. There was no association between high muscle tone and SRS or PDP. Exclusion of children with ASD diagnosis did not change the association. This large study showed a prospective association of infant muscle tone with autistic traits in childhood. Our findings suggest that early detection of low muscle tone might be a gateway to improve early diagnosis of ASD. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc.
PMCID:5444969
PMID: 28181411
ISSN: 1939-3806
CID: 2472622

Serum perfluoroalkyl substances in children exposed to the world trade center disaster

Trasande, Leonardo; Koshy, Tony T; Gilbert, Joseph; Burdine, Lauren K; Attina, Teresa M; Ghassabian, Akhgar; Honda, Masato; Marmor, Michael; Chu, Dinh Binh; Han, Xiaoxia; Shao, Yongzhao; Kannan, Kurunthachalam
The World Trade Center (WTC) disaster released large amounts of various chemical substances into the environment, including perfluoroalkyl substances (PFASs). Yet, no studies have examined exposures in children living or attending schools near the disaster site. We measured serum PFASs in WTC Health Registry (WTCHR) respondents who were
PMCID:5328959
PMID: 28104511
ISSN: 1096-0953
CID: 2414042

Demographic and health characteristics associated with fish and n-3 fatty acid supplement intake during pregnancy: results from pregnancy cohorts in the ECHO programme

Oken, Emily; Musci, Rashelle J; Westlake, Matthew; Gachigi, Kennedy; Aschner, Judy L; Barnes, Kathrine L; Bastain, Theresa M; Buss, Claudia; Camargo, Carlos A; Cordero, Jose F; Dabelea, Dana; Dunlop, Anne L; Ghassabian, Akhgar; Hipwell, Alison E; Hockett, Christine W; Karagas, Margaret R; Lugo-Candelas, Claudia; Margolis, Amy E; O'Connor, Thomas G; Shuster, Coral L; Straughen, Jennifer K; Lyall, Kristen; ,
OBJECTIVE: DESIGN/METHODS:Pooled pregnancy cohort studies. SETTING/METHODS:Cohorts participating in the Environmental influences on Child Health Outcomes (ECHO) consortium with births from 1999 to 2020. PARTICIPANTS/METHODS:A total of 10 800 pregnant women in twenty-three cohorts with food frequency data on fish consumption; 12 646 from thirty-five cohorts with information on supplement use. RESULTS:. never). CONCLUSIONS:-3 supplement use was uncommon, even among those who did not consume fish.
PMID: 38410088
ISSN: 1475-2727
CID: 5644262

Beyond traffic jam alleviation: evaluating the health and health equity impacts of New York City's congestion pricing plan

Ghassabian, Akhgar; Titus, Andrea R; Conderino, Sarah; Azan, Alexander; Weinberger, Rachel; Thorpe, Lorna E
New York City (NYC) is slated to be the first jurisdiction in the USA to implement a cordon-based congestion tax, which will be levied on vehicles entering its Central Business District. Several cities around the world, for example, London and Stockholm, have had similar cordon-based pricing programmes, defined as road pricing that charges drivers a fee for entering a specified area (typically a congested urban centre). In addition to reducing congestion and creating revenue, projections suggest the NYC congestion pricing plan may yield meaningful traffic-related air quality improvements that could result in health benefits. NYC is a large city with high air pollution and substantial racial/ethnic and socioeconomic health inequities. The distinct geography and meteorological conditions of the city also suggest that the policy's impact on air quality may extend beyond the NYC metropolitan area. As such, the potential breadth, directionality and magnitude of health impacts on communities who might be heavily affected by the nation's first congestion pricing plan should be empirically investigated. We briefly review evaluation studies of other cordon-based congestion pricing policies and argue that implementation of this policy provides an excellent opportunity to employ a quasi-experimental study design to evaluate the policy's impacts on air quality and health outcomes across population subgroups using a health equity lens. We discuss why real-time evaluations of the NYC congestion pricing plan can potentially help optimise benefits for communities historically negatively affected by traffic-related air pollution. Assessing intended and unintended impacts on health equity is key to achieving these goals.
PMID: 38195634
ISSN: 1470-2738
CID: 5624072

Maternal self-reported polycystic ovary syndrome with offspring and maternal cardiometabolic outcomes

Polinski, K J; Robinson, S L; Putnick, D L; Sundaram, R; Ghassabian, A; Joseph, P; Gomez-Lobo, V; Bell, E M; Yeung, E H
STUDY QUESTION/OBJECTIVE:Do children born to mothers with polycystic ovary syndrome (PCOS) have an adverse cardiometabolic profile including arterial stiffness at 9 years of age compared to other children? SUMMARY ANSWER/CONCLUSIONS:Children of mothers with PCOS did not have differing cardiometabolic outcomes than children without exposure. WHAT IS KNOWN ALREADY/BACKGROUND:While women with PCOS themselves have higher risk of cardiometabolic conditions such as obesity and diabetes, the evidence on intergenerational impact is unclear. Given in utero sequalae of PCOS (e.g. hyperandrogenism, insulin resistance), the increased risk could be to both boys and girls. STUDY DESIGN, SIZE, DURATION/METHODS:The Upstate KIDS cohort is a population-based birth cohort established in 2008-2010 to prospectively study the impact of infertility treatment on children's health. After ∼10 years of follow-up, 446 mothers and their 556 children attended clinical visits to measure blood pressure (BP), heart rate, arterial stiffness by pulse wave velocity (PWV), mean arterial pressure, lipids, high-sensitivity C-reactive protein (hsCRP), hemoglobin A1c (HbA1c), and anthropometrics. PARTICIPANTS/MATERIALS, SETTING, METHODS/METHODS:Women self-reported ever diagnoses of PCOS ∼4 months after delivery of their children in 2008-2010. Linear regression models applying generalized estimating equations to account for correlation within twins were used to examine associations with each childhood cardiometabolic outcome. MAIN RESULTS AND THE ROLE OF CHANCE/RESULTS:In this cohort with women oversampled on infertility treatment, ∼14% of women reported a PCOS diagnosis (n = 61). We observed similarities in BP, heart rate, PWV, lipids, hsCRP, HbA1c, and anthropometry (P-values >0.05) among children born to mothers with and without PCOS. Associations did not differ by child sex. LIMITATIONS, REASONS FOR CAUTION/CONCLUSIONS:The sample size of women with PCOS precluded further separation of subgroups (e.g. by hirsutism). The population-based approach relied on self-reported diagnosis of maternal PCOS even though self-report has been found to be valid. Participants were predominantly non-Hispanic White and a high proportion were using fertility treatment due to the original design. Differences in cardiometabolic health may be apparent later in age, such as after puberty. WIDER IMPLICATIONS OF THE FINDINGS/CONCLUSIONS:Our results provide some reassurance that cardiometabolic factors do not differ in children of women with and without self-reported PCOS during pregnancy. STUDY FUNDING/COMPETING INTEREST(S)/BACKGROUND:Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States (contracts #HHSN275201200005C, #HHSN267200700019C, #HHSN275201400013C, #HHSN275201300026I/27500004, #HHSN275201300023I/27500017). The authors have no conflicts of interest. REGISTRATION NUMBER/BACKGROUND:NCT03106493.
PMCID:10767861
PMID: 37935839
ISSN: 1460-2350
CID: 5628172

Associations of Organophosphate Ester Flame Retardant Exposures during Pregnancy with Gestational Duration and Fetal Growth: The Environmental influences on Child Health Outcomes (ECHO) Program

Oh, Jiwon; Buckley, Jessie P; Li, Xuan; Gachigi, Kennedy K; Kannan, Kurunthachalam; Lyu, Wenjie; Ames, Jennifer L; Barrett, Emily S; Bastain, Theresa M; Breton, Carrie V; Buss, Claudia; Croen, Lisa A; Dunlop, Anne L; Ferrara, Assiamira; Ghassabian, Akhgar; Herbstman, Julie B; Hernandez-Castro, Ixel; Hertz-Picciotto, Irva; Kahn, Linda G; Karagas, Margaret R; Kuiper, Jordan R; McEvoy, Cindy T; Meeker, John D; Morello-Frosch, Rachel; Padula, Amy M; Romano, Megan E; Sathyanarayana, Sheela; Schantz, Susan; Schmidt, Rebecca J; Simhan, Hyagriv; Starling, Anne P; Tylavsky, Frances A; Volk, Heather E; Woodruff, Tracey J; Zhu, Yeyi; Bennett, Deborah H; ,
BACKGROUND/UNASSIGNED:Widespread exposure to organophosphate ester (OPE) flame retardants with potential reproductive toxicity raises concern regarding the impacts of gestational exposure on birth outcomes. Previous studies of prenatal OPE exposure and birth outcomes had limited sample sizes, with inconclusive results. OBJECTIVES/UNASSIGNED:We conducted a collaborative analysis of associations between gestational OPE exposures and adverse birth outcomes and tested whether associations were modified by sex. METHODS/UNASSIGNED: RESULTS/UNASSIGNED: DISCUSSION/UNASSIGNED:In the largest study to date, we find gestational exposures to several OPEs are associated with earlier timing of birth, especially among female neonates, or with greater fetal growth. https://doi.org/10.1289/EHP13182.
PMCID:10805613
PMID: 38262621
ISSN: 1552-9924
CID: 5624892