Comparison of nasopharyngeal samples for SARS-CoV-2 detection in a paediatric cohort.

AIM: The diagnosis of coronavirus disease 2019 (COVID-19) depends on accurate and rapid testing. Choosing an appropriate sample may impact diagnosis. Naso-oropharyngeal swabs (NOS) are most frequently used, despite several limitations. Since studies suggest nasopharyngeal aspirate (NPA) as a superior alternative in children, we hypothesised collecting both nasopharyngeal swab and aspirate would improve our diagnostic accuracy. METHODS: Observational, longitudinal, prospective study from 7 March to 7 May in a tertiary paediatric hospital in Lisbon. The objective was to compare the rate of detection of SARS-CoV-2 between NOS and NPA samples collected simultaneously. RESULTS: A total of 438 samples collected from 85 patients with confirmed COVID-19. There were 47.7% overall positive specimens - 32% (70/219) positive NOS and 63.5% (139/219) positive NPA. The tests were 67.6% concordant (k = 0.45). 50.3% had positive NPA with negative NOS, while 1.3% had positive NOS with negative NPA. NPA proved to be more sensitive (98.6% with 95% confidence interval 91.2-99.9% vs. 49.6% with 95% confidence interval 41.1-58.2%, P < 0.001). Additionally, the difference between NPA and NOS positive samples was statistically significant across all population groups (age, health condition, clinical presentation, contact with COVID-19 patients or need for hospitalisation), meaning NPA is more sensitive overall. CONCLUSIONS: Nasopharyngeal aspirates had greater sensitivity than naso-oropharyngeal swabs in detecting SARS-CoV-2. Our results suggest paediatric patients would benefit from collecting nasopharyngeal aspirates in hospital settings, whenever feasible, to improve diagnosis of COVID-19.

A qualitative systematic review and thematic synthesis exploring the impacts of clinical academic activity by healthcare professionals outside medicine.

BACKGROUND: There are increasing opportunities for healthcare professionals outside medicine to be involved in and lead clinical research. However, there are few roles within these professions that include time for research. In order to develop such roles, and evaluate effective use of this time, the range of impacts of this clinical academic activity need to be valued and understood by healthcare leaders and managers. To date, these impacts have not been comprehensively explored, but are suggested to extend beyond traditional quantitative impact metrics, such as publications, citations and funding awards. METHODS: Ten databases, four grey literature repositories and a naïve web search engine were systematically searched for articles reporting impacts of clinical academic activity by healthcare professionals outside medicine. Specifically, this did not include the direct impacts of the research findings, rather the impacts of the research activity. All stages of the review were performed by a minimum of two reviewers and reported impacts were categorised qualitatively according to a modified VICTOR (making Visible the ImpaCT Of Research) framework. RESULTS: Of the initial 2704 identified articles, 20 were eligible for inclusion. Identified impacts were mapped to seven themes: impacts for patients; impacts for the service provision and workforce; impacts to research profile, culture and capacity; economic impacts; impacts on staff recruitment and retention; impacts to knowledge exchange; and impacts to the clinical academic. CONCLUSIONS: Several overlapping sub-themes were identified across the main themes. These included the challenges and benefits of balancing clinical and academic roles, the creation and implementation of new evidence, and the development of collaborations and networks. These may be key areas for organisations to explore when looking to support and increase academic activity among healthcare professionals outside medicine. The modified VICTOR tool is a useful starting point for individuals and organisations to record the impact of their research activity. Further work is needed to explore standardised methods of capturing research impact that address the full range of impacts identified in this systematic review and are specific to the context of clinical academics outside medicine.

State-led opioid overdose prevention efforts: Challenges, solutions and lessons learned from the CDC Prevention for States Program (PfS).

Background: The Centers for Disease Control and Prevention's Prevention for States (PfS) program funded 29 state health departments to prevent opioid overdose by implementing evidence-based prevention strategies. The objectives of this analysis were to describe the scope of activities implemented across the four PfS strategies and identify implementation challenges. Methods: PfS recipients submitted annual progress reports (APRs) to state support staff at CDC from 2015 to 2017. APR data were used to calculate the number of required and optional activities implemented under each PfS strategy. APR data were qualitatively analyzed using a systematic content analysis approach to identify key implementation challenges. Results: From 2015 to 2017, PfS recipients implemented 177 activities across four strategies from 2015 to 2017. Cross-cutting implementation challenges were (1) multi-sector collaboration, (2) lack of knowledge and misperceptions about opioid used disorder (OUD) among some partners and local communities and; (3) management and access to opioid data among PfS recipients. Conclusions: PfS recipients implemented an array of prevention interventions to address the opioid overdose crisis and encountered several cross-cutting implementation challenges. Challenges and state driven solutions over the course of implementing PfS led to several lessons learned and actions that CDC enacted to continue to support and expand overdose prevention.

Head circumference and child ADHD symptoms and cognitive functioning: results from a large population-based cohort study.

The aim of this study is to understand the association between prenatal, newborn and postnatal head circumference (HC) and preschool neurodevelopment in a large population-based birth cohort. The INMA project followed 1795 children from 12 weeks of pregnancy to preschool years. HC measurements were carried out prospectively, and following a standardized protocol during pregnancy (12, 20 and 34 weeks), birth, and child ages of 1-1.5 and 4 years old; and z-scores were further estimated. Prenatal head growth was assessed using conditional z-scores between weeks 12-20 and 20-34. Several neuropsychological tests [MSCA (cognition), CPT (attention)] and behavioral rating scales [DSM-IV-ADHD, CAST (autism), CPSCS (social competence)] were carried out during the last follow-up (5 years old). Multivariable models adjusted for family and child characteristics were applied to analyze associations between HC and neurodevelopment. In fully adjusted models, prenatal HC and head growth showed little or no associations with the neurodevelopment outcomes. Independent associations were observed between HC z-scores at birth, 1-1.5 years and 4 years and MSCA global cognitive scores and DSM-IV inattention symptoms. Specifically, z-score at birth was positively associated with general cognitive scores [ß 1.22, 95% confidence interval (CI) 0.59, 1.85], and we observed a protective association with ADHD-DSM-IV total symptoms, mean ratio (MR) 0.85 (0.75, 0.96). Prenatal HC and head growth measurements gave little information about child cognitive abilities and behavior at preschool years. However, HC at birth and early childhood was positively associated with a range of neuropsychological outcomes, including protective associations with ADHD symptoms.

Dietary and Household Sources of Prenatal Exposure to Polybrominated Diphenyl Ethers (PBDEs) in the INMA Birth Cohort (Spain).

This study looked at predictors of exposure to polybrominated diphenyl ethers (PBDEs) with a focus on dietary and household-level factors. Concentrations of BDE-47, -99, -153, and -209 and their sum (∑PBDEs) were measured in cord serum. Spanish women (n = 541) completed two semiquantitative food frequency questionnaires during the first and third trimesters of pregnancy. The daily mean intake (grams) of eggs, dairy products, meat, cereals and pasta, vegetables and pulses, fruits, shellfish and cephalopods, and fish, and the weekly mean intake (servings) of lean, large oily, other oily, and other fish from both questionnaires were averaged. Information on house size, curtains and carpets at home, mattress type, housekeeping frequency, and television use was also collected later in gestation. Multivariate censored regression was used to assess the association between PBDE concentration (log2 transformed) and potential predictors. BDE-47, -99, -209 and ∑PBDE concentrations increased by 13.6%(95% CI:0.0, 29.0%), 21.1%(2.3, 43.5%), 21.7%(0.4, 47.5%) and 11.5%(2.2, 21.7%), respectively, per interquartile range increment in daily intake of shellfish and cephalopods. Fish intake was associated with BDE-99 (20.8%[1.7, 43.4%]). When fish was disaggregated by types, BDE-99 and ∑PBDEs increased by 13.8%(4.0, 24.7%) and 5.7%(0.8, 10.8%), respectively, per 1-serving/week increment in large oily fish intake. BDE-153 was associated with higher housekeeping frequency (35.9%[0.4, 83.9%]) and BDE-209 with foam mattress use (48.9%[5.8, 109.7%]). In conclusion, seafood consumption, higher housekeeping frequency, and foam mattress were associated with prenatal PBDE exposure.

Prenatal Exposure to Polybrominated Flame Retardants and Fetal Growth in the INMA Cohort (Spain).

Our aim was to investigate the relation between PBDEs and fetal growth or newborn anthropometry in a Spanish cohort (2003-2008). PBDE congeners (BDE-47, -99, -153, -154, and -209) were determined in serum of 670 mothers at gestational week 12 and in 534 umbilical cord samples. Abdominal circumference (AC), estimated fetal weight (EFW), femur length (FL), and biparietal diameter (BPD) during gestation were measured by ultrasounds. At birth, weight (BW), head circumference (HC), and length (BL) were also measured. We assessed growth in the intervals between 12-20 and 20-34 weeks of gestation and size at birth by standard deviation (SD)-scores adjusted for constitutional characteristics. We conducted multivariate linear regression analyses between PBDE congeners and their sum (ΣPBDEs) and outcomes. We found statistically significant inverse associations between ΣPBDEs and AC, EFW, and BPD at weeks 20-34 and HC at birth. Regarding congeners, the association was clearer with BDE-99, with inverse associations being found with AC, EFW, and BPD at weeks 20-34, and with BW and HC at delivery. These outcomes decreased between 1.3% and 3.5% for each 2-fold PBDE increase. Concerning matrices, we found statistically significant inverse associations with BPD, HC, and BW when using maternal serum, and for AC and EFW with cord serum. In conclusion, PBDEs may impair fetal growth in late pregnancy and reduce birth size.

Perineuronal net density in schizophrenia: A systematic review of postmortem brain studies.

BACKGROUND: The onset of schizophrenia is concurrent with multiple key processes of brain development, such as the maturation of inhibitory networks. Some of these processes are proposed to depend on the development of perineuronal nets (PNNs), a specialized extracellular matrix structure that surrounds preferentially parvalbumin-containing GABAergic interneurons (PVIs). PNNs are fundamental to the postnatal experience-dependent maturation of inhibitory brain circuits. PNN abnormalities have been proposed as a core pathophysiological finding in SCZ, being linked to widespread consequences on circuit disruptions underlying SCZ symptoms. OBJECTIVE: Here, we systematically evaluate PNN density in postmortem brain studies of subjects with SCZ. METHODS: A systematic search in 3 online databases (PubMed, Embase, and Scopus) and qualitative review analysis of case-control studies reporting on PNN density in the postmortem brain of subjects with SCZ were performed. RESULTS: Results consisted of 7 studies that were included in the final analysis. The specific brain regions investigated in the studies varied, with most attention given to the dorsolateral prefrontal cortex (DLPFC; 3 studies) and amygdala (2 studies). Findings were mostly positive for reduced PNN density in SCZ, with 6 of the 7 studies reporting significant reductions and one reporting a tendency towards reduced PNN density. Overall, tissue processing methodologies were heterogeneous. CONCLUSIONS: Despite few studies, PNN density was consistently reduced in SCZ across different brain regions. These findings support evidence that implicates deficits in PNN density in the pathophysiology of SCZ. However, more studies, preferably using similar methodological approaches as well as replication of findings, are needed.

3D ultrasound-augmented image guidance for surgery of high-grade gliomas - A quantitative analysis focused on the extent of resection.

Background: We have retrospectively reviewed our series of brain tumor patients operated on using 3D IntraOperative UltraSound (IOUS) to report technical advantages and areas of improvement. Methods: Clinical and radiological data of patients with a diagnosis of high-grade glioma IV operated with and without IOUS were retrieved and analyzed. Results: We have found 391 patients operated using IOUS coupled with neuronavigation and 257 using neuronavigation standalone. We have selected a pool of 60 patients with a diagnosis of GlioBlastoma (GB), comparing two equally sized groups operated with and without IOUS, respectively. The average extent of resection (EOR) in the IOUS group was 93%, while in the control group, it was 80%. IOUS was significantly associated with improved EOR (P < 0.0004), even when accounting for other factors affecting EOR. The average overall survival (OS) was 13.4 months, and the average progression-free survival (PFS) was 7.4 months. The Cox proportional hazard model showed an advantage in OS on patients operated using the IOUS. No statistically significant effect was observed on PFS. Conclusion: Intraoperative ultrasound coupled with image guidance is associated with an improved EOR and possibly an improved OS. While we are aware of several limitations related to the present analysis, these data support the routine use of IOUS as a safe and reliable technology. Larger, prospective series with updated IOUS technology are desirable to verify the accuracy of these results.

Applying Next-Generation Sequencing to Track HIV-1 Drug Resistance Mutations Circulating in Portugal.

BACKGROUND: The global scale-up of antiretroviral treatment (ART) offers significant health benefits by suppressing HIV-1 replication and increasing CD4 cell counts. However, incomplete viral suppression poses a potential threat for the emergence of drug resistance mutations (DRMs), limiting ART options, and increasing HIV transmission. OBJECTIVE: We investigated the patterns of transmitted drug resistance (TDR) and acquired drug resistance (ADR) among HIV-1 patients in Portugal. METHODS: Data were obtained from 1050 HIV-1 patient samples submitted for HIV drug resistance (HIVDR) testing from January 2022 to June 2023. Evaluation of DRM affecting viral susceptibility to nucleoside/tide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs) was performed using an NGS technology, the Vela Diagnostics Sentosa SQ HIV-1 Genotyping Assay. RESULTS: About 71% of patients were ART naïve and 29% were experienced. Overall, 20% presented with any DRM. The prevalence of TDR and ADR was 12.6% and 41.1%, respectively. M184V, T215S, and M41L mutations for NRTI, K103N for NNRTI, and M46I/L for PIs were frequent in naïve and treated patients. E138K and R263K mutations against INSTIs were more frequent in naïve than treated patients. TDR and ADR to INSTIs were 0.3% and 7%, respectively. Patients aged 50 or over (OR: 1.81, p = 0.015), originating from Portuguese-speaking African countries (PALOPs) (OR: 1.55, p = 0.050), HIV-1 subtype G (OR: 1.78, p = 0.010), and with CD4 < 200 cells/mm3 (OR: 1.70, p = 0.043) were more likely to present with DRMs, while the males (OR: 0.63, p = 0.003) with a viral load between 4.1 to 5.0 Log10 (OR: 0.55, p = 0.003) or greater than 5.0 Log10 (OR: 0.52, p < 0.001), had lower chances of presenting with DRMs. CONCLUSIONS: We present the first evidence on TDR and ADR to INSTI regimens in followed up patients presenting for healthcare in Portugal. We observed low levels of TDR to INSTIs among ART-naïve and moderate levels in ART-exposed patients. Regimens containing PIs could be an alternative second line in patients with intermediate or high-level drug resistance, especially against second-generation INSTIs (dolutegravir, bictegravir, and cabotegravir).

Determinants of HIV late presentation among men who have sex with men in Portugal (2014-2019): who's being left behind?

Introduction: HIV late presentation (LP) remains excessive in Europe. We aimed to analyze the factors associated with late presentation in the MSM population newly diagnosed with HIV in Portugal between 2014 and 2019. Methods: We included 391 newly HIV-1 diagnosed Men who have Sex with Men (MSM), from the BESTHOPE project, in 17 countrywide Portuguese hospitals. The data included clinical and socio-behavioral questionnaires and the viral genomic sequence obtained in the drug resistance test before starting antiretrovirals (ARVs). HIV-1 subtypes and epidemiological surveillance mutations were determined using different bioinformatics tools. Logistic regression was used to estimate the association between predictor variables and late presentation (LP). Results: The median age was 31 years, 51% had a current income between 501-1,000 euros, 28% were migrants. 21% had never been tested for HIV before diagnosis, with 42.3% of MSM presenting LP. 60% were infected with subtype B strains. In the multivariate regression, increased age at diagnosis, higher income, lower frequency of screening, STI ever diagnosed and higher viral load were associated with LP. Conclusion: Our study suggests that specific subgroups of the MSM population, such older MSM, with higher income and lower HIV testing frequency, are not being targeted by community and clinical screening services. Overall, targeted public health measures should be strengthened toward these subgroups, through strengthened primary care testing, expanded access to PrEP, information and promotion of HIV self-testing and more inclusive and accessible health services.

Maternal smoking during pregnancy and fetal biometry: the INMA Mother and Child Cohort Study.

In utero tobacco exposure has been associated with fetal growth restriction, but uncertainty remains about critical windows of exposure and specific effects on body segments. In the present study, we aimed to examine the association of maternal smoking with fetal biometry in different stages of pregnancy. The study population comprised 2,478 fetuses from a Spanish birth cohort study that was established between 2003 and 2008. Biparietal diameter, femur length, abdominal circumference, and estimated fetal weight were evaluated at 12, 20, and 34 weeks of gestation. Fetal size and growth were assessed by standard deviation scores adjusted by maternal and fetal characteristics. Maternal smoking was assessed using questionnaire and a sample of urinary cotinine at week 32 of gestation. Associations were estimated using multiple regression analysis. Smokers at week 12 of gestation showed decreased fetal growth as reflected by all growth parameters at 20-34 weeks, leading to a reduced fetal size at week 34. The reduction was greatest in femur length, at -9.4% (95% confidence interval -13.4, -5.4) and least in abdominal circumference, at -4.4% (95% CI: -8.7, -0.1). Fetuses of smokers who quit smoking before week 12 showed reduced growth only in femur length (-5.5; 95% CI: -10.1, -0.9). Dose-response curves for smoking versus fetal growth parameters (abscissa: log2 cotinine) were linear for biparietal diameter and femur length.

A Thematic Analysis of Overdose Prevention and Response Efforts in States Experiencing Declines in Rates of Opioid-Involved Overdose Deaths.

OBJECTIVE: To address the opioid overdose epidemic, it is important to understand the broad scope of efforts under way in states, particularly states in which the rate of opioid-involved overdose deaths is declining. The primary objective of this study was to examine core elements of overdose prevention activities in 4 states with a high rate of opioid-involved overdose deaths that experienced a decrease in opioid-involved overdose deaths from 2016 to 2017. METHODS: We identified 5 states experiencing decreases in age-adjusted mortality rates for opioid-involved overdoses from 2016 to 2017 and examined their overdose prevention programs via program narratives developed with collaborators from each state's overdose prevention program. These program narratives used 10 predetermined categories to organize activities: legislative policies; strategic planning; data access, capacity, and dissemination; capacity building; public-facing resources (eg, web-based dashboards); training resources; enhancements and improvements to prescription drug monitoring programs; linkage to care; treatment; and community-focused initiatives. Using qualitative thematic analysis techniques, core elements and context-specific activities emerged. RESULTS: In the predetermined categories of programmatic activities, we identified the following core elements of overdose prevention and response: comprehensive state policies; strategic planning; local engagement; data access, capacity, and dissemination; training of professional audiences (eg, prescribers); treatment infrastructure; and harm reduction. CONCLUSIONS: The identification of core elements and context-specific activities underscores the importance of implementation and adaptation of evidence-based prevention strategies, interdisciplinary partnerships, and collaborations to address opioid overdose. Further evaluation of these state programs and other overdose prevention efforts in states where mortality rates for opioid-involved overdoses declined should focus on impact, optimal timing, and combinations of program activities during the life span of an overdose prevention program.

HIV-1-Transmitted Drug Resistance and Transmission Clusters in Newly Diagnosed Patients in Portugal Between 2014 and 2019.

Objective: To describe and analyze transmitted drug resistance (TDR) between 2014 and 2019 in newly infected patients with HIV-1 in Portugal and to characterize its transmission networks. Methods: Clinical, socioepidemiological, and risk behavior data were collected from 820 newly diagnosed patients in Portugal between September 2014 and December 2019. The sequences obtained from drug resistance testing were used for subtyping, TDR determination, and transmission cluster (TC) analyses. Results: In Portugal, the overall prevalence of TDR between 2014 and 2019 was 11.0%. TDR presented a decreasing trend from 16.7% in 2014 to 9.2% in 2016 (p for-trend = 0.114). Multivariate analysis indicated that TDR was significantly associated with transmission route (MSM presented a lower probability of presenting TDR when compared to heterosexual contact) and with subtype (subtype C presented significantly more TDR when compared to subtype B). TC analysis corroborated that the heterosexual risk group presented a higher proportion of TDR in TCs when compared to MSMs. Among subtype A1, TDR reached 16.6% in heterosexuals, followed by 14.2% in patients infected with subtype B and 9.4% in patients infected with subtype G. Conclusion: Our molecular epidemiology approach indicates that the HIV-1 epidemic in Portugal is changing among risk group populations, with heterosexuals showing increasing levels of HIV-1 transmission and TDR. Prevention measures for this subpopulation should be reinforced.

Perfluoroalkyl substances and immune cell counts in adults from the Mid-Ohio Valley (USA).

BACKGROUND: Although perfluoroalkyl substances (PFASs) may be immunotoxic, evidence for this in humans is scarce. We studied the association between 4 PFASs (perfluorohexane sulfonate [PFHxS], perfluorooctanoic acid [PFOA], perfluorooctane sulfonate [PFOS] and perfluorononanoic acid [PFNA]) and circulating levels of several types of immune cells. METHODS: Serum PFASs and white blood cell types were measured in 42,782 (2005-2006) and 526 (2010) adults from an area with PFOA drinking water contamination in the Mid-Ohio Valley (USA). Additionally, the major lymphocyte subsets were measured in 2010. Ln(cell counts) and percentages of cell counts were regressed on serum PFAS concentrations (ln or percentiles). Adjusted results were expressed as the percentage difference (95% CI) per interquartile range (IQR) increment of each PFAS concentration. RESULTS: Generally positive monotonic associations between total lymphocytes and PFHxS, PFOA, and PFOS were found in both surveys (difference range: 1.12-7.33% for count and 0.36-1.77 for percentage, per PFAS IQR increment), and were stronger for PFHxS. These associations were reflected in lymphocyte subset counts but not percentages, with PFHxS positively and monotonically associated with T, B, and natural killer (NK) cell counts (range: 5.51-8.62%), PFOA and PFOS with some T-cell phenotypes, and PFOS with NK cells (range: 3.12-12.21%), the associations being monotonic in some cases. Neutrophils, particularly percentage (range: -1.74 to -0.36), showed decreasing trends associated with PFASs. Findings were less consistent for monocytes and eosinophils. CONCLUSION: These results suggest an association between PFHxS and, less consistently, for PFOA and PFOS, and total lymphocytes (although the magnitudes of the differences were small). The increase in absolute lymphocyte count appeared to be evenly distributed across lymphocyte subsets since associations with their percentages were not significant.

Prenatal perfluoroalkyl substance exposure and neuropsychological development throughout childhood: The INMA Project.

BACKGROUND: Perfluoroalkyl substances (PFASs) have been related to neurodevelopmental toxicity in animals. However, human studies are inconclusive. OBJECTIVES: To evaluate the association between prenatal PFAS exposure and neuropsychological development during childhood. METHODS: 1240 mother-child pairs from the Spanish INMA Project were analyzed. Perfluorohexanesulfonic acid (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorononanoic acid (PFNA) were measured in first-trimester maternal plasma. Neuropsychological development was assessed at 14 months, 4-5 and 7 years covering four domains: general cognitive, general motor, attention, and working memory. Associations were studied by means of multivariable regression analyses. RESULTS: PFHxS, PFOA, PFOS, and PFNA medians were: 0.6, 2.4, 6.1, and 0.7 ng/mL. Higher PFAS prenatal exposure was associated with worse motor development at 14 months, especially in the case of PFHxS (ß[95%CI]: -1.49[-2.73, -0.24]) and to a lesser extent PFOS (-1.25[-2.62, 0.12]). There was also a marginal positive association between general cognitive development at 4-5 years and PFOS (1.17[-0.10, 2.43]) and PFNA (0.99[-0.13, 2.12]). No clear associations for other neuropsychological outcomes or any sex differences were found. DISCUSSION: This study shows no clear-cut evidence of an association between prenatal PFAS exposure and adverse neuropsychological development in children up to the age of 7 years.

Early Life Exposure to Perfluoroalkyl Substances (PFAS) and ADHD: A Meta-Analysis of Nine European Population-Based Studies.

INTRODUCTION: To date, the evidence for an association between perfluoroalkyl substances (PFAS) exposure and attention deficit and hyperactivity disorder (ADHD) is inconclusive. OBJECTIVE: We investigated the association between early life exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), and ADHD in a collaborative study including nine European population-based studies, encompassing 4,826 mother-child pairs. METHODS: Concentrations of PFOS and PFOA were measured in maternal serum/plasma during pregnancy, or in breast milk, with different timing of sample collection in each cohort. We used a validated pharmacokinetic model of pregnancy and lactation to estimate concentrations of PFOS and PFOA in children at birth and at 3, 6, 12, and 24 months of age. We classified ADHD using recommended cutoff points for each instrument used to derive symptoms scores. We used multiple imputation for missing covariates, logistic regression to model the association between PFAS exposure and ADHD in each study, and combined all adjusted study-specific effect estimates using random-effects meta-analysis. RESULTS: A total of 399 children were classified as having ADHD, with a prevalence ranging from 2.3% to 7.3% in the studies. Early life exposure to PFOS or PFOA was not associated with ADHD during childhood [odds ratios (ORs) ranging from 0.96 (95% CI: 0.87, 1.06) to 1.02 (95% CI: 0.93, 1.11)]. Results from stratified models suggest potential differential effects of PFAS related to child sex and maternal education. CONCLUSION: We did not identify an increased prevalence of ADHD in association with early life exposure to PFOS and PFOA. However, stratified analyses suggest that there may be an increased prevalence of ADHD in association with PFAS exposure in girls, in children from nulliparous women, and in children from low-educated mothers, all of which warrant further exploration. https://doi.org/10.1289/EHP5444.

First-trimester maternal concentrations of polyfluoroalkyl substances and fetal growth throughout pregnancy.

BACKGROUND: Several studies have investigated the possible association between prenatal exposure to perfluoroalkyl substances (PFASs) and birth anthropometry. However, none has assessed fetal size longitudinally. We studied the possible association between PFASs and fetal biometry. METHODS: In 1230 mother-child pairs of three cohorts from the Spanish INMA-Project, we analyzed perfluorohexanesulfonic acid (PFHxS), perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) in first-trimester maternal plasma (collection: 2003-2008). We measured abdominal circumference (AC), femur length (FL), biparietal diameter (BPD), and estimated fetal weight (EFW) by ultrasounds at 12, 20, and 34 gestational weeks. We conducted multivariable linear regression analyses between log2-transformed (PFASs) and SD-scores of fetal parameters in each cohort and subsequent meta-analysis. We also assessed effect modification by sex and maternal smoking. RESULTS: PFHxS, PFOA, PFOS, and PFNA medians were: 0.58, 2.35, 6.05, and 0.65 ng/mL, respectively. There were no associations for the whole population in any trimester of pregnancy. However, we found an indication that maternal smoking modified the effect in different directions depending on the PFAS. Among smokers (31%), we found negative associations between both PFOA and PFNA and FL or EFW at week 20 (% change ranging between -6.8% and -5.7% per twofold PFAS increase) and positive associations between PFHxS or PFOS and BPD at week 34 (6.8% and 6.3%, respectively). CONCLUSIONS: Results did not suggest an overall association between prenatal PFASs and fetal growth. The results among smokers should be taken with caution and further studies are warranted to elucidate the possible role of smoking in this association.

Exposure to perfluoroalkyl substances and thyroid function in pregnant women and children: A systematic review of epidemiologic studies.

INTRODUCTION: Thyroid hormones (THs) are especially important for brain maturation and development during the fetal period and childhood. Several epidemiological studies have assessed the possible association between exposure to perfluoroalkyl substances (PFAS) and thyroid outcomes during the early stages of life. We aimed to review this evidence. METHODS: We conducted a systematic review in compliance with the PRISMA Statement (search conducted in PubMed and Embase, as well as in the citations of the selected articles). We chose studies if they dealt with thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxin (T4), or thyroid dysfunctions, and perfluorohexane sulfonate (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS) or perfluorononanoic acid (PFNA) measured in the blood of pregnant women and/or children up to 19years old. RESULTS: We included in this review three cross-sectional, one case-control, and six cohort studies (publication: 2011-2015), focusing on prenatal life (n=7), childhood (n=2) or both periods (n=1). We observed a high degree of heterogeneity across studies in terms of sampling time (different gestational weeks, at birth, or childhood), outcomes, adjustment for potential confounders, and statistical approach. We found some evidence of a positive association between PFHxS and PFOS exposure and TSH levels measured in maternal blood, and PFNA and TSH levels measured in the blood of boys aged ≥11years. CONCLUSION: Although there is a small number of studies with comparable data, we found some consistency of a positive association between maternal or teenage male exposure to some PFAS and TSH levels based on the current literature. However, further studies are required to confirm these possible relationships.

Prenatal exposure to perfluoroalkyl substances and birth outcomes in a Spanish birth cohort.

BACKGROUND: Prenatal perfluorooctanoate (PFOA) exposure has been associated with reduced birth weight but maternal glomerular filtration rate (GFR) may attenuate this association. Further, this association remains unclear for other perfluoroalkyl substances (PFAS), such as perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), and perfluorononanoate (PFNA). We estimated associations between prenatal PFAS exposure and birth outcomes, and the influence of GFR, in a Spanish birth cohort. METHODS: We measured PFHxS, PFOS, PFOA, and PFNA in 1st-trimester maternal plasma (years: 2003-2008) in 1202 mother-child pairs. Continuous birth outcomes included standardized weight, length, head circumference, and gestational age. Binary outcomes included low birth weight (LBW), small-for-gestational-age, and preterm birth. We calculated maternal GFR from plasma-creatinine measurements in the 1st-trimester of pregnancy (n=765) using the Cockcroft-Gault formula. We used mixed-effects linear and logistic models with region of residence as random effect and adjustment for maternal age, parity, pre-pregnancy BMI, and fish intake during pregnancy. RESULTS: Newborns in this study weighted on average 3263g and had a median gestational age of 39.8weeks. The most abundant PFAS were PFOS and PFOA (median: 6.05 and 2.35ng/mL, respectively). Overall, PFAS concentrations were not significantly associated to birth outcomes. PFOA, PFHxS, and PFNA showed weak, non-statistically significant associations with reduced birth weights ranging from 8.6g to 10.3g per doubling of exposure. Higher PFOS exposure was associated with an OR of 1.90 (95% CI: 0.98, 3.68) for LBW (similar in births-at-term) in boys. Maternal GFR did not confound the associations. CONCLUSIONS: In this study, PFAS showed little association with birth outcomes. Higher PFHxS, PFOA, and PFNA concentrations were non-significantly associated with reduced birth weight. The association between PFOS and LBW seemed to be sex-specific. Finally, maternal GFR measured early during pregnancy had little influence on the estimated associations.

Prenatal Exposure to NO2 and Ultrasound Measures of Fetal Growth in the Spanish INMA Cohort.

BACKGROUND: Air pollution exposure during pregnancy has been associated with impaired fetal growth. However, few studies have measured fetal biometry longitudinally, remaining unclear as to whether there are windows of special vulnerability. OBJECTIVE: The aim was to investigate the impact of nitrogen dioxide (NO2) exposure on fetal and neonatal biometry in the Spanish INMA study. METHODS: Biparietal diameter (BPD), femur length (FL), abdominal circumference (AC), and estimated fetal weight (EFW) were evaluated for up to 2,478 fetuses in each trimester of pregnancy. Size at 12, 20, and 34 weeks of gestation and growth between these points, as well as anthropometry at birth, were assessed by SD scores derived using cohort-specific growth curves. Temporally adjusted land-use regression was used to estimate exposure to NO2 at home addresses for up to 2,415 fetuses. Associations were investigated by linear regression in each cohort and subsequent meta-analysis. RESULTS: A 10-µg/m(3) increase in average exposure to NO2 during weeks 0-12 was associated with reduced growth at weeks 0-12 in AC (-2.1%; 95% CI: -3.7, -0.6) and EFW (-1.6%; 95% CI: -3.0, -0.3). The same exposure was inversely associated with reduced growth at weeks 20-34 in BPD (-2.6%; 95% CI: -3.9, -1.2), AC (-1.8%; 95% CI: -3.3, -0.2), and EFW (-2.1%; 95% CI: -3.7, -0.2). A less consistent pattern of association was observed for FL. The negative association of this exposure with BPD and EFW was significantly stronger in smoking versus nonsmoking mothers. CONCLUSIONS: Maternal exposure to NO2 in early pregnancy was associated with reduced fetal growth based on ultrasound measures of growth during pregnancy and measures of size at birth.