Critical Time Window Research Articles

Maternal exposure to fine particulate matter and congenital heart defects during preconception and pregnancy period: A cohort-based case-control study in the Taiwan maternal and child health database

BackgroundFew studies have explored the association between maternal exposure to particulate matter with an aerodynamic diameter of ≤2.5 μm (PM2.5) and congenital heart defects occurring before and during pregnancy. We aimed to investigate the association and the critical time windows between the maternal exposure to PM2.5 and congenital heart defects. MethodWe conducted a cohort-based case-control study of 507,960 participants obtained from the Taiwan Maternal and Child Health Database between 2004 and 2015. We applied satellite-based spatiotemporal models with 1-km resolution to calculate the average PM2.5 concentration during preconception and the specific periods of pregnancy. We also performed conditional logistic regression with distributed lag non-linear models (DLNMs) to assess the effects of weekly average PM2.5 on both congenital heart defects and their isolated subtypes, as well as the concentration-response relationships. ResultsIn DLNMs, exposure to PM2.5 (per 10 μg/m3) during weeks 7–12 before conception and weeks 3–9 after conception was associated with congenital heart defects. The strongest association at 12 weeks before conception (odds ratio [OR] = 1.026, 95% confidence intervals [CI]: 1.012–1.040) and 7 weeks after conception (OR = 1.024, 95% CI: 1.012–1.036) for every 10 μg/m3 increase in PM2.5 concentration. In modification analysis, strongest associations were observed for low SES. ConclusionsOur study revealed that exposure to ambient PM2.5 raises the risk of congenital heart defects, particularly among individuals with lower socioeconomic status. Moreover, our findings suggest that preconception exposure to PM2.5 may be a crucial period for the development of congenital heart defects.

Targeting a vulnerable septum-hippocampus cholinergic circuit in a critical time window ameliorates tau-impaired memory consolidation

BackgroundAbnormal tau accumulation and cholinergic degeneration are hallmark pathologies in the brains of patients with Alzheimer’s disease (AD). However, the sensitivity of cholinergic neurons to AD-like tau accumulation and strategies to ameliorate tau-disrupted spatial memory in terms of neural circuits still remain elusive.MethodsTo investigate the effect and mechanism of the cholinergic circuit in Alzheimer's disease-related hippocampal memory, overexpression of human wild-type Tau (hTau) in medial septum (MS)-hippocampus (HP) cholinergic was achieved by specifically injecting pAAV-EF1α-DIO-hTau-eGFP virus into the MS of ChAT-Cre mice. Immunostaining, behavioral analysis and optogenetic activation experiments were used to detect the effect of hTau accumulation on cholinergic neurons and the MS-CA1 cholinergic circuit. Patch-clamp recordings and in vivo local field potential recordings were used to analyze the influence of hTau on the electrical signals of cholinergic neurons and the activity of cholinergic neural circuit networks. Optogenetic activation combined with cholinergic receptor blocker was used to detect the role of cholinergic receptors in spatial memory.ResultsIn the present study, we found that cholinergic neurons with an asymmetric discharge characteristic in the MS-hippocampal CA1 pathway are vulnerable to tau accumulation. In addition to an inhibitory effect on neuronal excitability, theta synchronization between the MS and CA1 subsets was significantly disrupted during memory consolidation after overexpressing hTau in the MS. Photoactivating MS-CA1 cholinergic inputs within a critical 3 h time window during memory consolidation efficiently improved tau-induced spatial memory deficits in a theta rhythm-dependent manner.ConclusionsOur study not only reveals the vulnerability of a novel MS-CA1 cholinergic circuit to AD-like tau accumulation but also provides a rhythm- and time window-dependent strategy to target the MS-CA1 cholinergic circuit, thereby rescuing tau-induced spatial cognitive functions.Graphical

Revealing the importance of prenatal gut microbiome in offspring neurodevelopment in humans.

It has been widely recognized that a critical time window for neurodevelopment occurs in early life and the host's gut microbiome plays an important role in neurodevelopment. Following recent demonstrations that the maternal prenatal gut microbiome influences offspring brain development in murine models, we aim to explore whether the critical time window for the association between the gut microbiome and neurodevelopment is prenatal or postnatal for human. Here we leverage a large-scale human study and compare the associations between the gut microbiota and metabolites from mothers during pregnancy and their children with the children's neurodevelopment. Specifically, using multinomial regression integrated in Songbird, we assessed the discriminating power of the maternal prenatal and child gut microbiome for children's neurodevelopment at early life as measured by the Ages & Stages Questionnaires (ASQ). We show that the maternal prenatal gut microbiome is more relevant than the children's gut microbiome to the children's neurodevelopment in the first year of life (maximum Q2=0.212 and 0.096 separately using the taxa at the class level). Moreover, we found that Fusobacteriia is more associated with high fine motor skills in ASQ in the maternal prenatal gut microbiota but become more associated with low fine motor skills in the infant gut microbiota (rank=0.084 and-0.047 separately), suggesting the roles of the same taxa with respect to neurodevelopment can be opposite at the two stages of fetal neurodevelopment. These findings shed light, especially in terms of timing, on potential therapeutic interventions to prevent neurodevelopmental disorders. This work was supported by the National Institutes of Health (grant numbers: R01AI141529, R01HD093761, RF1AG067744, UH3OD023268, U19AI095219, U01HL089856, R01HL141826,K08HL148178, K01HL146980), and the Charles A. King Trust Postdoctoral Fellowship.

Poststress social isolation exerts anxiolytic effects by activating the ventral dentate gyrus

After aversive stress, people either choose to return to their previously familiar social environment or tend to adopt temporary social withdrawal to buffer negative emotions. However, which behavior intervention is more appropriate and when remain elusive. Here, we unexpectedly found that stressed mice experiencing social isolation exhibited less anxiety than those experiencing social contact. Within the first 24 h after returning to their previous social environment, mice experienced acute restraint stress (ARS) displayed low social interest but simultaneously received excessive social disturbance from their cage mates, indicating a critical time window for social isolation to balance the conflict. To screen brain regions that were differentially activated between the poststress social isolation and poststress social contact groups, we performed ΔFosB immunostaining and found that ΔFosB + signals were remarkably increased in the vDG of poststress social isolation group compared with poststress social contact group. There were no significant differences between the two groups in the other anxiety- and social-related brain regions, such as prelimbic cortex, infralimbic cortex, nucleus accumbens, etc. These data indicate that vDG is closely related to the differential phenotypes between the poststress social isolation and poststress social contact groups. Electrophysiological recording, further, revealed a higher activity of vDG in the poststress social isolation group than the poststress social contact group. Chemogenetically inhibiting vDG excitatory neurons within the first 24 h after ARS completely abolished the anxiolytic effects of poststress social isolation, while stimulating vDG excitatory neurons remarkably reduced anxiety-like behaviors in the poststress social contact group. Together, these data suggest that the activity of vDG excitatory neurons is essential and sufficient to govern the anxiolytic effect of poststress social isolation. To the best of our knowledge, this is the first report to uncover a beneficial role of temporal social isolation in acute stress-induced anxiety. In addition to the critical 24-h time window, activation of vDG is crucial for ameliorating anxiety through poststress social isolation.

Cell proliferation and glial cell marker expression in the wall of the third ventricle in the tuberal region of the male mouse hypothalamus during postnatal development.

The third ventricle (3V) wall of the tuberal hypothalamus is composed of two types of cells; specialized ependymoglial cells called tanycytes located ventrally and ependymocytes dorsally, which control the exchanges between the cerebrospinal fluid and the hypothalamic parenchyma. By regulating the dialogue between the brain and the periphery, tanycytes are now recognized as central players in the control of major hypothalamic functions such as energy metabolism and reproduction. While our knowledge of the biology of adult tanycytes is progressing rapidly, our understanding of their development remains very incomplete. To gain insight into the postnatal maturation of the 3V ependymal lining, we conducted a comprehensive immunofluorescent study of the mouse tuberal region at four postnatal ages (postnatal day (P) 0, P4, P10, and P20). We analyzed the expression profile of a panel of tanycyte and ependymocyte markers (vimentin, S100, connexin-43 [Cx43], and glial fibrillary acidic protein [GFAP]) and characterized cell proliferation in the 3V wall using the thymidine analog bromodeoxyuridine. Our results show that most changes in marker expression occur between P4 and P10, with a switch from a 3V mostly lined by radial cells to the emergence of a tanycytic domain ventrally and an ependymocytic domain dorsally, a drop in cell proliferation and increased expression of S100, Cx43, and GFAP that acquire a mature profile at P20. Our study thus identifies the transition between the first and the second postnatal week as a critical time window for the postnatal maturation of the 3V wall ependymal lining.

Staging of kidney disease today and tomorrow

Since September 2022, there is a new, German-language glossary for the nomenclature of renal function and renal disease, aligned with international technical terms and KDIGO guidelines for a more precise and uniform description of the facts. Terms such as "renal disease," "renal insufficiency," or "acute renal failure" should be avoided and replaced with "disease" or "functional impairment."The KDIGO guideline recommends in patients with CKD stage G3a, in addition to the determination of serum creatinine, the additional determination of cystatin to confirm the CKD stage. A combination of serum creatinine and cystatin C to estimate GFR without taking into account the so-called race coefficient seems to be more accurate in African Americans than the previous eGFR formulas. However, there is no recommendation on this in international guidelines yet. For Caucasians, the formula does not change.Renal function impairment lasting more than 7 days but less than 3 months is called acute kidney disease (AKD). The AKD stage is the critical time window for therapeutic interventions to reduce the risk of progression in kidney disease.A future, expanded AKI definition incorporating biomarkers will allow patients to be divided into subclasses according to functional and structural limitations, thus mapping the two-dimensionality of AKI. By using artificial intelligence, large amounts of data from clinical parameters, blood and urine samples, histopathological and molecular markers (including proteomics and metabolomics data) can be used integratively for the graduation of CKD and thus contribute significantly to individualized therapy.

Security screening capacity during COVID-19 recovery: simulation study of a domestic airport in Brazil

With the recent COVID-19 pandemic, air travel has suffered a dramatic financial and operational crisis, in which quarantine and social distancing have suddenly become habitual and almost ubiquitous. When such measures are taken, the airport throughput capacity is reduced, something that is missed in the current design guidelines. This capacity temporary shortage can undermine system recovery, demanding proper treatment in the post-pandemic world. However, the capacity loss is offset by demand shortage: the relationship between both will tell if a given infrastructure fits the actual needs. This research acknowledges that social distancing might be an important factor for the planning and operation of airports in the foreseeable future and presents a methodological contribution based on simulation. The security screening queueing area of a busy Brazilian domestic airport was assessed under different combinations of %PHP (i.e., the percentage of peak hour passengers) and social distancing. The results indicate that the existing queueing area cannot withstand pre-pandemic passenger traffic under COVID-19 social distancing procedures. However, the recovery rate was found to be low enough to allow social distancing for the most critical time window. The proposed methodology, discussions, and recommendations can be valuable for a more resilient approach to airport design regarding eventual disruptive events in the future.

Multimodal Approach for Characterizing the Quality of Parent–Child Interaction: A Single Synchronization Source May Not Tell the Whole Story

The interaction between the parent and child is essential for the child's cognitive and emotional development and sets the path for future well-being. These interactions, starting from birth, are necessary for providing the sensory stimulation the child needs in the critical time window of brain development. The characterization of parent-child interactions is traditionally performed by human decoding. This approach is considered the leading and most accurate way of characterizing the quality of these interactions. However, the development of computational tools and especially the concept of parent-child synchronization opened up an additional source of data characterizing these interactions in an objective, less human-labor manner. Such sources include brain-to-brain, voice/speech, eye contact, motor, and heart-rate synchronization. However, can a single source synchronization dataset accurately represent parent-child interaction? Will attending to the same stimulation, often resulting in a higher brain-to-brain synchronization, be considered an interactive condition? In this perspective, we will try to convey a new concept of the child-parent interaction synchronization (CHIPS) matrix, which includes the different sources of signals generated during an interaction. Such a model may assist in explaining the source of interaction alterations in the case of child/parent developmental/emotional or sensory deficits and may open up new ways of assessing interventions and changes in parent-child interactions along development. We will discuss this interaction during one of the parent-child joint activities providing opportunities for interaction, i.e., storytelling.

A smart risk-responding polymer membrane for safer batteries.

Safety concerns related to the abuse operation and thermal runaway are impeding the large-scale employment of high-energy-density rechargeable lithium batteries. Here, we report that by incorporating phosphorus-contained functional groups into a hydrocarbon-based polymer, a smart risk-responding polymer is prepared for effective mitigation of battery thermal runaway. At room temperature, the polymer is (electro)chemically compatible with electrodes, ensuring the stable battery operation. Upon thermal accumulation, the phosphorus-containing radicals spontaneously dissociate from the polymer skeleton and scavenge hydrogen and hydroxyl radicals to terminate the exothermic chain reaction, suppressing thermal generation at an early stage. With the smart risk-responding strategy, we demonstrate extending the time before thermal runaway for a 1.8-Ah Li-ion pouch cell by 100% (~9hours) compared with common cells, creating a critical time window for safety management. The temperature-triggered automatic safety-responding strategy will improve high-energy-density battery tolerance against thermal abuse risk and pave the way to safer rechargeable batteries.

Long-run exposure to low-dose radiation reduces cognitive performance

This paper examines the effect of long-run exposure to low-dose radiation on cognitive performance. We focus on the fallout from the Chernobyl accident, which increased the level of ground radiation in large parts of Europe. To identify a causal effect, we exploit unexpected rainfall patterns in a critical time window after the disaster as well as the trajectory of the radioactive plume, which determine local fallout but have no plausible direct effect on test scores. Based on geo-coded survey data from Germany, we show that people exposed to higher radiation perform significantly worse in standardized cognitive tests 25 years later. An increase in initial exposure by one standard deviation reduces cognitive test scores by around 5% of a standard deviation.

Early prenatal exposure to air pollutants and congenital heart disease: a nested case-control study

Congenital heart disease (CHD) is one of the most common congenital malformations in humans. Inconsistent results emerged in the existed studies on associations between air pollution and congenital heart disease. The purpose of this study was to evaluate the association of gestational exposure to air pollutants with congenital heart disease, and to explore the critical exposure windows for congenital heart disease. The nested case-control study collected birth records and the following health data in Tianjin Women and Children's Health Center, China. All of the cases of congenital heart disease from 2013 to 2015 were selected matching five healthy controls for each case. Inverse distance weighting was used to estimate individual exposure based on daily air pollution data. Furthermore, the conditional logistic regression with distributed lag non-linear model was performed to identify the association between gestational exposure to air pollution and congenital heart disease. A total of 8,748 mother-infant pairs were entered into the analysis, of which 1,458 infants suffered from congenital heart disease. For each 10 µg/m3 increase of gestational exposure to PM2.5, the ORs (95% confidence interval, 95%CI) ranged from 1.008 (1.001-1.016) to 1.013 (1.001-1.024) during the 1st-2nd gestation weeks. Similar weak but increased risks of congenital heart disease were associated with O3 exposure during the 1st week and SO2 exposure during 6th-7th weeks in the first trimester, while no significant findings for other air pollutants. This study highlighted that gestational exposure to PM2.5, O3, and SO2 had lag effects on congenital heart disease. Our results support potential benefits for pregnancy women to the mitigation of air pollution exposure in the early stage, especially when a critical exposure time window of air pollutants may precede heart development.

Trimester-specific associations of maternal dietary patterns with preterm birth: China Medical University birth cohort study.

The trimester-specific associations of maternal dietary patterns with preterm birth (PTB) are unclear. In a prospective prebirth cohort study, we aimed to examine the critical time window of maternal prenatal dietary patterns and the risk of PTB. We assessed prenatal dietary intake among 1500 pregnant women with validated food frequency questionnaires during the 1st, 2nd and 3rd trimester, respectively. We used logistic regression models and generalized estimating equation models to examine the trimester-specific associations and longitudinal associations between maternal dietary patterns in relation to risk of PTB and PTB subtypes. The incidence rate of PTB was 11.9% (179 out of 1500 pregnant women) in the present study. We observed that maternal adherence to a fish-seafood pattern in the 1st trimester was associated with higher risk of PTB [tertile 3 (T3) vs. tertile 1 (T1): OR = 2.29, 95% CI: 1.32-3.96] and iatrogenic preterm birth (IPTB) (T3 vs. T1: OR = 2.26, 95% CI: 1.21-4.20), while a fish-seafood pattern in the 2nd trimester was associated with lower risk of PTB (T3 vs. T1: OR = 0.49, 95% CI: 0.25-0.93). Maternal adherence to a dairy-egg pattern in the 2nd or 3rd trimester was associated with higher risks of PTB and IPTB. No dietary patterns were associated with spontaneous preterm birth. Our findings provide new evidence that specific dietary patterns during different trimesters may have different and even inverse health effects on pregnant women. This supports the necessity of guiding the maternal diet according to different periods of pregnancy to prevent PTB.

Growth Response of Red Oaks to Climatic Conditions in the Lower Mississippi Alluvial Valley: Implications for Bottomland Hardwood Restoration with a Changing Climate

Bottomland hardwood forests (BHFs) offer a wide range of ecosystem services that are of high environmental and socioeconomic value. Yet, nearly 70% of BHFs in the southern United States have been lost during the past 100 years primarily due to land use change including agricultural expansion, calling for restoration efforts. We estimated the statistical relationship of the annual radial growth rate of three red oak species with climatic conditions and tree age using the tree ring data collected from a BHF plantation in the Arkansas Delta region. These species were Cherry bark oak (Quercus pagoda), Shumard oak (Quercus shumardii), and Nuttall oak (Quercus texana). The destructive sampling method was employed to obtain tree growth data and the cross-dating method was used for tree age determination. A log-linear regression model was estimated to uncover the statistical relationship between annual tree ring growth rate and climatic conditions. We identified the most critical time windows of climate variables that affect the growth of these trees. We found that the average temperature in October of the previous year and the minimum temperature between December of the previous year and January of the current year were positively associated with the radial growth rate in the current year although the maximum temperature from January to August and total precipitation from April to July of the current year were negatively correlated with the growth rate. Compared to Cherry bark and Shumard oaks, Nuttall oak was less sensitive to a rise in the minimum temperature between December and January. The projected climate change is likely to create slightly more favorable overall climatic conditions for these oak species in the region. Our findings suggest that these three red oak species are well suited for the study region for restoring BHFs, especially with a changing climate.

Tracking the path of predator recognition in a predator-naive population of the pond snail

Abstract Organisms evolve adaptive strategies to adjust to rapidly changing environmental stressors. Predation pressure is one of the strongest selective forces and organisms respond to predatory threats via innate and learned responses. We utilized a natural, experimental set-up, where two lakes Stoney and Margo in Canada containing natural populations of the prey Lymnaea stagnalis differed in the presence and absence of an invasive, predatory Northern crayfish, Faxonius virilis. We exploited the contrast in the predation backgrounds of the snail populations from the two lakes to test, 1) predator recognition in predator-experienced snails is innate, (2) predator-naive snails learn to detect a novel invasive predator, and 3) learning about a novel predator gets transmitted to the successive generations. We quantified predator fear memory formation using a higher-order learning paradigm called configural learning. We found that 1) predator recognition in predator-experienced snails is innate, 2) predator-naive snails learned to recognize the novel predator even after a brief exposure to predator cues highlighting the role of learning in combating invasive predators and the critical time-window during development that accounts for predator recognition, and 3) the learning and predator detection mechanism in predator-naive snails are not transmitted to successive generations. The population variation observed in the predator-detection mechanism may be due to the past and current experience of predators in one population over the other. We find an interesting study system to address how fear learning occurs and prospective future directions to understand the mechanism of innate fear recognition from a learned fear recognition.

Variation in breeding phenology in response to climate change in two passerine species

Increasingly warmer springs have caused phenological shifts in both plants and animals. In birds, it is well established that mean laying date has advanced to match the earlier food peak. We know less about changes in the distribution of egg-laying dates within a population and the environmental variables that determine this variation. This could be an important component of how populations respond to climate change. We, therefore, used laying date and environmental data from 39 years (1983–2021) to determine how climate change affected laying date variation in blue tits (Cyanistes caeruleus) and marsh tits (Poecile palustris), two sympatric passerines with different life histories. Both species advanced mean laying date (0.19–0.24 days per year) and mean laying date showed a negative relationship with maximum spring temperature in both blue and marsh tits. In springs with no clear temperature increase during the critical time window (the time-window in which mean laying date was most sensitive to temperature) start of breeding in blue tits was distributed over a longer part of the season. However, there was no such pattern in marsh tits. Our findings suggest that temperature change, and not necessarily absolute temperature, can shape the variation in breeding phenology in a species-specific manner, possibly linked to variation in life-history strategies. This is an important consideration when predicting how climate change affects timing of breeding within a population.

Use of Methotrexate in Girls and Women of Childbearing Age, Occurrence of Methotrexate-Exposed Pregnancies and Their Outcomes in Germany: A Claims Data Analysis

Methotrexate should be withdrawn before pregnancy because of its teratogenic potential. We aimed to describe the use of methotrexate in women of childbearing age in Germany and the occurrence and outcomes of pregnancies exposed to methotrexate. Using the German Pharmacoepidemiological Research Database (GePaRD,covering ~ 20% of the German population), we determined the age-specific and age-standardized prevalence of methotrexate use for each year between 2004 and 2019 among women aged 13-49 years (cross-sectional analyses). In a cohort analysis, we assessed the number and outcomes of pregnancies exposed to methotrexate in the critical time window. Exposure was defined as a dispensation overlapping with the onset of pregnancy or a dispensation in the first 8 weeks of pregnancy. For children born from exposed pregnancies, the mother's and children's data were linked and the occurrence of malformations was assessed by reviewing all available data of these children. The age-standardized prevalence of methotrexate use per 1000 females increased from 1.5 in 2004 to 2.3 in 2019, i.e., by 52%. Overall, we identified 184 pregnancies exposed to methotrexate. Of these, 53% ended in a live birth (21% preterm) and 11% in an induced abortion. Among 81 live-born children linked to their mothers, five children (6%) had relevant malformations including congenital heart defects and musculoskeletal malformations. In Germany, the use of methotrexate in women of childbearing age has substantially increased since 2004. Despite the known teratogenic effect, there was a considerable number of exposed pregnancies. Also, malformations likely associated with methotrexate and thus avoidable were observed.

Writing Development in DHH Students: A Bimodal Bilingual Approach.

This article describes the lexical and syntactic development of written narratives in 24 deaf and hard-of-hearing (DHH) students aged between 8 and 18 and takes into account how their varying linguistic backgrounds may predict their written performance. All participants use spoken Swedish, but the study also considers their proficiency in Swedish Sign language, which ranged from zero to fluent. Their narrative texts were analyzed in regard to syntax and lexicon, which demonstrated a strong developmental trend in which increased age predicted more complex texts. Age of acquisition did not predict any writing outcome, which is suggested to occur because all participants were exposed to language early, that is, within the critical time window for language acquisition. Sign language proficiency showed a tendency to predict adjective density and number of clauses, which encourages future research in this area, especially since this connection argues for the benefits of early access to a language and the positive relationship between sign language proficiency and writing.

Gestational bisphenol A exposure advances puberty onset in female offspring: Critical time window identification

Increasing evidence shows that the early onset of puberty in female offspring may be caused by maternal prenatal exposure to bisphenol A (BPA) during pregnancy; however, the critical time window of maternal prenatal BPA exposure remains unknown. Here, we identify the critical time window of gestational BPA exposure that induces early onset of puberty in female offspring. Pregnant CD-1 mice were gavaged with BPA (8 mg/kg) daily during the early gestational stage (GD1–GD6), middle gestational stage (GD7–GD12) or late gestational stage (GD13–GD18). We show that maternal BPA exposure during the early and middle gestational stages could advance the vaginal opening time and increase the serum levels of kisspeptin-10 and GnRH in the female offspring at PND 34. Mechanistically, maternal BPA exposure during early and middle gestation could significantly increase CpG island methylation in the Eed gene promoters but reduce the mRNA expression of Eed in the hypothalamus tissues of the female offspring. In conclusion, the critical period of maternal BPA exposure-induced early onset of puberty in female offspring is early and middle gestation; this BPA-induced early onset of puberty might be partly attributed to epigenetic programming of the Eed gene in the hypothalamus. This study provides important insights regarding the relationship and the mechanisms between BPA and offspring pubertal development.

Investigating drug safety in pregnancy based on the German Pharmacoepidemiological Research Database (GePaRD): A proof-of-concept analysis on the association between valproate and spina bifida.

Large health-care databases are increasingly used for research on drug utilization and safety in pregnancy. For the German Pharmacoepidemiological Research Database (GePaRD), covering ~20% of the German population, algorithms have been developed to identify pregnancies, to estimate their date of onset and to link mothers to their babies. Using this methodology, we aimed to conduct a proof-of-concept analysis on the known association between valproate (VPA) exposure in early pregnancy and spina bifida in the exposed child. We identified all pregnancies in GePaRD between 2006 and 2016 in women aged 12 to 50 years. To each VPA dispensation of these women, an exposure period was assigned, based on the dispensation date and the number of defined daily doses in the dispensed package. A pregnancy was classified as exposed to VPA in the critical time window if this exposure period overlapped with the first 55 days of pregnancy. Risk ratios were calculated for spina bifida in live births and induced abortions comparing VPA-exposed ones to all pregnancies. Overall, we identified 1 271 384 pregnancies fulfilling the inclusion criteria. Of these, 668 pregnancies (0.053%) were classified as exposed to VPA in the critical time window regarding spina bifida. An induced abortion accompanied by a diagnosis of spina bifida was observed in one of the VPA-exposed pregnancies (0.15%) and in 154 of all pregnancies (0.012%), yielding a risk ratio of 12.4 (95% confidence interval [CI]: 1.7-88.2). Out of 775 875 pregnancies ending in a live birth, 366 (0.047%) were classified as VPA exposed. A diagnosis of spina bifida was coded in 3 of 366 VPA-exposed live births (0.82%) and in 260 of all live births (0.03%), yielding a relative risk of 24.5 (95% CI: 7.9-76.0). Our proof-of-concept analysis based on GePaRD showed a strong association between intrauterine exposure to VPA and occurrence of spina bifida. The results are plausible and consistent with the literature, supporting the suitability of GePaRD and the developed algorithms to conduct studies on drug safety in pregnancy.

Preconceptional, prenatal, and postnatal exposure to home environmental factors and childhood otitis media

BackgroundOtitis media (OM) is a common pediatric infectious disease worldwide. Increasing evidence have associated indoor environment with OM, yet the role of home environmental factor(s) exposure during which critical window(s) on childhood OM are unclear. ObjectiveTo examine the association between indoor environmental factors exposure and childhood OM, to identify main indoor factor(s) and key window(s). MethodsA retrospective cohort study involving 8689 preschoolers aged 3–6 was performed in Changsha, China. The data about each child's health outcome and home environments was obtained through a standard questionnaire. Exposure timing windows included 1 year before pregnancy, pregnancy, first year of life, and past year. Multiple logistic regression models were used to analyze the association between indoor environmental factors and childhood OM. ResultsWe found that exposure to mold/damp stains and mold/damp clothes or bedding during preconceptional, prenatal, and postnatal periods was consistently associated with childhood OM, with ORs ranged from 1.25 (1.02–1.54) to 1.38 (1.13–1.68). Past year was identified as a critical time window for mold/damp stains exposure in relation to OM risk. We further found that exposures to new furniture during pregnancy and environmental tobacco smoke (ETS) and grandparental smoking during first year were significantly associated with an increase in childhood OM, with ORs (95% CI) = 1.28 (1.00–1.64), 1.20 (1.01–1.42), and 1.21 (1.00–1.48). Moreover, current exposure to total plants especially for non-flowering plants significantly increased OM risk, with ORs (95% CI) = 1.23 (1.05–1.44) and 1.25 (1.06–1.46). The association between early life exposure to indoor environmental factors and OM was stronger among children living near traffic roads. Outdoor air pollution and temperature could modify the effect of indoor environmental exposure on childhood OM. Our sensitivity analysis indicated that some subgroups were more susceptible to OM risk of indoor exposure. ConclusionOur findings suggest that exposure to home environmental factors played an important role in childhood OM, and the association can be interacted by outdoor air pollution and temperature.