Gestational Window Research Articles

Dynamic changes in spatiotemporal transcriptome reveal maternal immune dysregulation of autism spectrum disorder

Maternal immune activation (MIA) during pregnancy is known to be an environmental risk factor for neurodevelopment and autism spectrum disorder (ASD). However, it is unclear at which fetal brain developmental windows and regions MIA induces ASD-related neurodevelopmental transcriptional abnormalities. The non-chasm differentially expressed genes (DEGs) involved in MIA inducing ASD during fetal brain developmental windows were identified by performing the differential expression analysis and comparing the common DEGs among MIA at four different gestational development windows, ASD with multiple brain regions from human patients and mouse models, and human and mouse embryonic brain developmental trajectory. The gene set and functional enrichment analyses were performing to identify MIA dysregulated ASD-related the fetal neurodevelopmental windows and brain regions and function annotations. Additionally, the networks were constructed using Cytoscape for visualization. MIA at E12.5 and E14.5 increased the risk of distinct brain regions for ASD. MIA-driven transcriptional alterations of non-chasm DEGs, during the coincidence brain developmental windows between human and mice, involving ASD-relevant synaptic components, as well as immune- and metabolism-related functions and pathways. Furthermore, a great number of non-chasm brain development-, immune-, and metabolism-related DEGs were overlapped in at least two existing ASD-associated databases, suggesting that the others could be considered as the candidate targets to construct the model mice for explaining the pathological changes of ASD when environmental factors (MIA) and gene mutation effects co-occur. Overall, our search supported that transcriptome-based MIA dysregulated the brain development-, immune-, and metabolism-related non-chasm DEGs at specific embryonic brain developmental window and region, leading to abnormal embryonic neurodevelopment, to induce the increasing risk of ASD.

Epigenome-wide association of neonatal methylation and trimester-specific prenatal PM2.5 exposure.

Background:Exposure to particulate matter with an aerodynamic diameter smaller than 2.5 microns (PM2.5) can affect birth outcomes through physiological pathways such as inflammation. One potential way PM2.5 affects physiology could be through altering DNA methylation (DNAm). Considering that exposures during specific windows of gestation may have unique effects on DNAm, we hypothesized a timing-specific association between PM2.5 exposure during pregnancy and DNAm in the neonatal epithelial-cell epigenome.Methods:After collecting salivary samples from a cohort of 91 neonates, DNAm was assessed at over 850,000 cytosine-guanine dinucleotide (CpG) methylation sites on the epigenome using the MethylationEPIC array. Daily ambient PM2.5 concentrations were estimated based on the mother’s address of primary residence during pregnancy. PM2.5 was averaged over the first two trimesters, separately and combined, and tested for association with DNAm through an epigenome-wide association (EWA) analysis. For each EWA, false discovery rate (FDR)-corrected P < 0.05 constituted a significant finding and every CpG site with uncorrected P < 0.0001 was selected to undergo pathway and network analysis to identify molecular functions enriched by them.Results:Our analysis showed that cg18705808 was associated with the combined average of PM2.5. Pathway and network analysis revealed little similarity between the first two trimesters. Previous studies reported that TMEM184A, the gene regulated by cg18705808, has a putative role in inflammatory pathways.Conclusions:The differences in pathway and network analyses could potentially indicate trimester-specific effects of PM2.5 on DNAm. Further analysis with greater temporal resolution would be valuable to fully characterize the effect of PM2.5 on DNAm and child development.

Trends and characteristics of Tdap vaccination during pregnancy in Ontario, Canada: a retrospective cohort study.

In February 2018, Canada's National Advisory Committee on Immunization (NACI) recommended tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccination during pregnancy to protect newborns against pertussis infection. We sought to describe pre- and postrecommendation trends in Tdap vaccination coverage among pregnant Ontario residents. Using linked health administrative databases, we conducted a population-based retrospective cohort study of all pregnant individuals who gave birth in Ontario hospitals between April 2012 and March 2020. We described Tdap vaccination patterns in pregnancy for the entire study period and before and after the NACI recommendation. We used log-binomial regression to identify characteristics associated with Tdap vaccination during pregnancy. Among the 991 850 deliveries included, 7.0% of pregnant individuals received the Tdap vaccination during pregnancy. Vaccine coverage increased from 0.4% in 2011/12 to 29.2% in 2019/20. Coverage was highest among individuals who were older, had no previous live births, had adequate prenatal care and received maternity care primarily from a family physician. After adjustment, characteristics associated with lower coverage included younger maternal age, having a multiple birth, residing in a rural location and higher area material deprivation. In 2019/20, 71.0% of vaccinated individuals received the Tdap vaccination during the recommended gestational window (27-32 wk). Stratified analyses of the pre- and postrecommendation cohorts yielded similar findings to the main analyses with a few gradient differences after adjustment. During pregnancy, Tdap vaccination coverage increased substantially in Ontario between 2011/12 and 2019/20, most notably after recommendations for universal Tdap vaccination during pregnancy began in Canada. To further improve vaccine coverage in the obstetric setting, public health strategies should consider tailoring their programs to reach subpopulations with lower vaccine coverage.

Association between fetal abdominal growth trajectories, maternal metabolite signatures early in pregnancy, and childhood growth and adiposity: prospective observational multinational INTERBIO-21st fetal study

Obesity predominantly affects populations in high-income countries and those countries facing epidemiological transition. The risk of childhood obesity is increased among infants who had overweight or obesity at birth, but in low-resource settings one in five infants are born small for gestational age. We aimed to study the relationships between: (1) maternal metabolite signatures; (2) fetal abdominal growth; and (3) postnatal growth, adiposity, and neurodevelopment. In the prospective, multinational, observational INTERBIO-21st fetal study, conducted in maternity units in Pelotas (Brazil), Nairobi (Kenya), Karachi (Pakistan), Soweto (South Africa), Mae Sot (Thailand), and Oxford (UK), we enrolled women (≥18 years, with a BMI of less than 35 kg/m2, natural conception, and a singleton pregnancy) who initiated antenatal care before 14 weeks' gestation. Ultrasound scans were performed every 5±1 weeks until delivery to measure fetal growth and feto-placental blood flow, and we used finite mixture models to derive growth trajectories of abdominal circumference. The infants' health, growth, and development were monitored from birth to age 2 years. Early pregnancy maternal blood and umbilical cord venous blood samples were collected for untargeted metabolomic analysis. From Feb 8, 2012, to Nov 30, 2019, we enrolled 3598 pregnant women and followed up their infants to 2 years of age. We identified four ultrasound-derived trajectories of fetal abdominal circumference growth that accelerated or decelerated within a crucial 20-25 week gestational age window: faltering growth, early accelerating growth, late accelerating growth, and median growth tracking. These distinct phenotypes had matching feto-placental blood flow patterns throughout pregnancy, and different growth, adiposity, vision, and neurodevelopment outcomes in early childhood. There were 709 maternal metabolites with positive effect for the faltering growth phenotype and 54 for the early accelerating growth phenotype; 31 maternal metabolites had a negative effect for the faltering growth phenotype and 76 for the early accelerating growth phenotype. Metabolites associated with the faltering growth phenotype had statistically significant odds ratios close to 1·5 (ie, suggesting upregulation of metabolic pathways of impaired fetal growth). The metabolites had a reciprocal relationship with the early accelerating growth phenotype, with statistically significant odds ratios close to 0.6 (ie, suggesting downregulation of fetal growth acceleration). The maternal metabolite signatures included 5-hydroxy-eicosatetraenoic acid, and 11 phosphatidylcholines linked to oxylipin or saturated fatty acid sidechains. The fungicide, chlorothalonil, was highly abundant in the early accelerating growth phenotype group. Early pregnancy lipid biology associated with fetal abdominal growth trajectories is an indicator of patterns of growth, adiposity, vision, and neurodevelopment up to the age of 2 years. Our findings could contribute to the earlier identification of infants at risk of obesity. Bill & Melinda Gates Foundation.

The developmental impacts of natural selection on human pelvic morphology.

Evolutionary responses to selection for bipedalism and childbirth have shaped the human pelvis, a structure that differs substantially from that in apes. Morphology related to these factors is present by birth, yet the developmental-genetic mechanisms governing pelvic shape remain largely unknown. Here, we pinpoint and characterize a key gestational window when human-specific pelvic morphology becomes recognizable, as the ilium and the entire pelvis acquire traits essential for human walking and birth. We next use functional genomics to molecularly characterize chondrocytes from different pelvic subelements during this window to reveal their developmental-genetic architectures. We then find notable evidence of ancient selection and genetic constraint on regulatory sequences involved in ilium expansion and growth, findings complemented by our phenotypic analyses showing that variation in iliac traits is reduced in humans compared to African apes. Our datasets provide important resources for musculoskeletal biology and begin to elucidate developmental mechanisms that shape human-specific morphology.

Timing of delivery for placenta accreta spectrum: the Pan-American Society for the Placenta Accreta Spectrum experience

The Society for Maternal-Fetal Medicine recommends cesarean delivery with potential hysterectomy scheduled in the late preterm period between 34 0/7 and 35 6/7 weeks of gestation for prenatally suspected placenta accreta spectrum. We aimed to investigate clinical compliance with the recommended delivery timing window for placenta accreta spectrum and its impact on maternal and neonatal outcomes. We performed a retrospective multicenter review of data from referral centers within the Pan-American Society for Placenta Accreta Spectrum. Patients with placenta accreta spectrum with both antenatal diagnosis and confirmed histopathologic findings were included. We investigated adherence to the Society for Maternal-Fetal Medicine-recommended gestational age window for delivery, and compliance was further stratified by scheduled and unscheduled delivery. We compared the outcomes for patients with scheduled delivery within vs immediately 2 weeks outside the recommended window. Among 744 patients with a prenatal diagnosis of placenta accreta spectrum and placental histopathologic confirmation, 488 (66%) had scheduled delivery. Among all prenatally diagnosed placenta accreta spectrum patients, 252 (39%) delivered within the recommended window of 34 0/7 and 35 6/7 weeks gestation. For the subgroup of patients who underwent scheduled delivery (n=426), 209 (49%) had delivery in this window, 120 (28%) delivered before 34 weeks, and 97 (23%) delivered at or later than 36 weeks. In the patients with scheduled delivery, 27% of placenta accreta spectrum patients with accreta delivered in the 2 weeks immediately after the recommended window (36 0/7-37 6/7 weeks), and 22% of placenta accreta spectrum pregnancies with increta/percreta delivered in the 2 weeks immediately before the recommended delivery (32 0/7-33 6/7 weeks). The maternal outcomes among those who delivered within the recommended range vs those delivering 2 weeks before and after the recommended range were similar, regardless of placenta accreta spectrum severity. Less than half of placenta accreta spectrum patients had scheduled delivery within the recommended gestational age of 34 0/7 to 35 6/7 weeks. The reasons for deviation from recommendations and the risks and benefits of individualized timing of delivery on the basis of risk factors and predicted outcomes warrant further investigation.

The Postnatal Resolution of Developmental Toxicity Induced by Pharmacological Diacylglycerol Acyltransferase 2 (DGAT2) Inhibition During Gestation in Rats.

Ervogastat (PF-06865571) is a small molecule diacylglycerol acyltransferase 2 (DGAT2) inhibitor being developed for the oral treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis. DGAT2 is a key enzyme in triglyceride synthesis in tissues and in regulating energy metabolism. Fertility and developmental toxicity studies with ervogastat were conducted in female rats and rabbits. There were no effects on female rat fertility or rabbit embryo-fetal development. Administration of ervogastat to pregnant rats during organogenesis reduced fetal weight and caused higher incidences of bent bones in fetuses that were shown to resolve by postnatal day 28 and were therefore considered to be transient variations secondary to developmental delay. Extended dosing in rats through the end of gestation and lactation (pre- and post-natal development study) caused impaired skin development, reduced offspring viability, and growth retardation. The spectrum of developmental effects in rats is consistent with the intended pharmacology (altered triglyceride metabolism) and the transient nature of the skeletal findings, along with the late gestational window of sensitivity for the effects on skin barrier development, reduce the concern for potential adverse developmental effects following unintended early gestational exposure to ervogastat in humans where treatment can be discontinued once pregnancy is determined.

Maternal and Neonatal Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Immunoglobulin G Levels After the Pfizer-BioNTech Booster Dose for Coronavirus Disease 2019 (COVID-19) Vaccination During the Second Trimester of Pregnancy.

To evaluate maternal and neonatal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) antibody levels at birth after a third (booster) dose of the Pfizer-BioNTech messenger RNA (Pfizer) coronavirus disease 2019 (COVID-19) vaccine during the second trimester of pregnancy, and compare them with those in women who received two vaccine doses during the second trimester. We conducted a prospective cohort study of women admitted to the delivery ward at a single center who received the third Pfizer COVID-19 vaccine dose (booster group) at 17-30 weeks of pregnancy and who did not have previous SARS-CoV-2 infection. Maternal and neonatal antibody levels were measured on admission for delivery and in the umbilical cord blood after birth. Antibody levels for the booster group were compared with those in a historical control group of pregnant women who received their second vaccine dose (two-dose group) within the same gestational age window. Between October 2021 and February 2022, antibody levels were measured in 121 women and 109 neonates at a mean±SD of 15.3±3.9 weeks after booster vaccination. Neonatal titers measured two times higher than maternal titers, with inverse correlation between maternal and neonatal titers at birth and time interval from third vaccination. The two-dose group included 121 women and 107 neonates, with antibody levels measured at a mean±SD of 14.6±2.6 weeks after the second dose. Median [interquartile range] maternal antibody titers were higher in the booster group (4,485 [2,569-9,702] AU/mL) compared with the two-dose group (1,122 [735-1,872] AU/mL) (P<.001). Furthermore, neonatal antibody titers were higher in the booster group (8,773 [5,143-18,830] AU/mL) compared with the two-dose group (3,280 [2,087-5,754] AU/mL) (P<.001). Maternal and neonatal SARS-CoV-2 IgG antibody titers after second-trimester maternal Pfizer COVID-19 vaccination were significantly higher after the booster dose compared with the two-dose vaccination series. Although there is uncertainty as to whether antibody levels correlate with protection, these data support the importance of booster vaccination during pregnancy to restore maternal and neonatal protection against COVID-19.

HDL, heart disease, and the lung

HDL, heart disease, and the lung

Extreme Heat and Pregnancy Outcomes: A Scoping Review of the Epidemiological Evidence.

Background: Extreme heat caused by climate change is a major public health concern, disproportionately affecting poor and racialized communities. Gestational heat exposure is a well-established teratogen in animal studies, with a growing body of literature suggesting human pregnancies are similarly at risk. Characterization of extreme heat as a pregnancy risk is problematic due to nonstandard definitions of heat waves, and variable study designs. To better focus future research in this area, we conducted a scoping review to assess the effects of extreme heat on pregnancy outcomes. Methods: A scoping review of epidemiological studies investigating gestational heat-exposure and published 2010 and 2020, was conducted with an emphasis on study design, gestational windows of sensitivity, adverse pregnancy outcomes and characterization of environmental temperatures. Results: A sample of 84 studies was identified, predominantly set in high-income countries. Preterm birth, birthweight, congenital anomalies and stillbirth were the most common pregnancy outcome variables. Studies reported race/ethnicity and/or socioeconomic variables, however these were not always emphasized in the analysis. Conclusion: Use of precise temperature data by most studies avoided pitfalls of imprecise, regional definitions of heat waves, however inconsistent study design, and exposure windows are a significant challenge to systematic evaluation of this literature. Despite the high risk of extreme heat events and limited mitigation strategies in the global south, there is a significant gap in the epidemiological literature from these regions. Greater consistency in study design and exposure windows would enhance the rigor of this field.

Maternal Nanomaterial Inhalation Exposure: Critical Gestational Period in the Uterine Microcirculation is Angiotensin II Dependent.

Maternal inhalation exposure to engineered nanomaterials (ENM) has been associated with microvascular dysfunction and adverse cardiovascular responses. Pregnancy requires coordinated vascular adaptation and growththat are imperative for survival. Key events in pregnancy hallmark distinct periods of gestation such as implantation, spiral artery remodeling, placentation, and trophoblast invasion. Angiotensin II (Ang II) is a critical vasoactive mediator responsible for adaptations and is implicated in the pathology of preeclampsia. If perturbations occur during gestation, such as those caused by ENM inhalation exposure, then maternal-fetal health consequences may occur. Our study aimed to identify the period of gestation in which maternal microvascular functional and fetal health are most vulnerable. Additionally, we wanted to determine if Ang II sensitivity and receptor density is altered due to exposure. Dams were exposed to ENM aerosols (nano-titanium dioxide) during three gestational windows: early (EE, gestational day (GD) 2-6), mid (ME, GD 8-12) or late (LE, GD 15-19). Within the EE group dry pup mass decreased by 16.3% and uterine radial artery wall to lumen ratio (WLR) increased by 25.9%. Uterine radial artery response to Ang II sensitivity increased by 40.5% in the EE group. Ang II receptor density was altered in the EE and LE group with decreased levels of AT2R. We conclude that early gestational maternal inhalation exposures resulted in altered vascular anatomy and physiology. Exposure during this time-period results in altered vascular reactivity and changes to uterine radial artery WLR, leading to decreased perfusion to the fetus and resulting in lower pup mass.

Prenatal exposure to PM10 and changes in DNA methylation and telomere length in cord blood

BackgroundAir pollution exposure in pregnancy can cause molecular level alterations that might influence later disease susceptibility. ObjectivesWe investigated DNA methylation (DNAm) and telomere length (TL) in the cord blood in relation to gestational PM10 exposure and explored potential gestational windows of susceptibility. MethodsCord blood epigenome-wide DNAm (N = 384) and TL (N = 500) were measured in children of the Italian birth cohort Piccolipiù, using the Infinium Methylation EPIC BeadChip and qPCR, respectively. PM10 daily exposure levels, based on maternal residential address, were estimated for different gestational periods using models based on satellite data. Epigenome-wide analysis to identify differentially methylated probes (DMPs) and regions (DMRs) was conducted, followed by a pathway analysis and replication analysis in an second Piccolipiù dataset. Distributed lag models (DLMs) using weekly exposures were used to study the association of PM10 exposure across pregnancy with telomere length, as well as with the DMPs that showed robust associations. ResultsGestational PM10 exposure was associated with the DNA methylation of more than 250 unique DMPs, most of them identified in early gestation, and 1 DMR. Out of 151 DMPs available in the replication dataset, ten DMPs showed robust associations: eight were associated with exposure during early gestation and 2 with exposure during the whole pregnancy. These exposure windows were supported by the DLM analysis. The PM10 exposure between 15th and 20th gestational week seem to be associated with shorter telomeres at birth, while exposure between 24th and 29th was associated with longer telomeres. DiscussionThe early pregnancy period is a potential critical window during which PM10 exposure can influence cord blood DNA methylation. The results from the TL analysis were consistent with previous findings and merit further exploration in future studies. The study underlines the importance of considering gestational windows outside of the predefined trimesters that may not always overlap with biologically relevant windows of exposure.

Prenatal Exposure to Air Pollution and Autism Spectrum Disorder: Sensitive Windows of Exposure and Sex Differences.

Background:Studies have shown that air pollution exposures during pregnancy are associated with an increased risk of autism spectrum disorder (ASD) in children, and the risk appears to be greater for boys. However, studies assessing gestational windows of susceptibility have been mostly limited by trimesters.Objective:We identified sensitive windows of exposure to regional air pollution and risk of ASD and examined sex differences in a large birth cohort.Methods:This population-based retrospective cohort study included 294,937 mother–child pairs with singleton deliveries in Kaiser Permanente Southern California (KPSC) hospitals from 2001 to 2014. Children were followed using electronic medical records until clinical ASD diagnosis, non-KPSC membership, death, or 31 December 2019, whichever came first. Weekly mean fine particulate matter [PM with an aerodynamic diameter of ()], nitrogen dioxide (), and ozone () pregnancy exposures were estimated using spatiotemporal prediction models. Cox proportional hazard models with distributed lags were used to estimate weekly pollutant exposure associations with ASD risk for the entire cohort, and separately for boys and for girls. Models were adjusted for child sex (for full cohort), maternal race/ethnicity, maternal age at delivery, parity, maternal education, maternal comorbidities, medical center, census tract median household income, birth year, and season.Results:There were 5,694 ASD diagnoses (4,636 boys, 1,058 girls). Sensitive exposure windows associated with ASD were found early in pregnancy, statistically significant throughout the first two trimesters [1–27 wk of gestation, cumulative [95% confidence interval (CI): 1.06, 1.23] per interquartile range (IQR) () increase]. exposure during 34–37 wk of gestation was associated with increased risk [ (95% CI: 1.01, 1.11) per IQR () increase] but with reduced risk during 20–28 wk of gestation [ (95% CI: 0.89, 0.98)]. No associations were observed with . Sex-stratified early gestational associations were stronger among boys [boys (95% CI: 1.08, 1.26); girls (95% CI: 0.89, 1.26)]. associations in later gestation were observed only in boys [boys (95% CI: 1.04, 1.16); girls (95% CI: 0.84, 1.05)].Conclusions:Exposures to in the first two gestational trimesters were associated with increased ASD risk in children, with stronger associations observed for boys. The role of exposure on ASD risk merits further investigation. https://doi.org/10.1289/EHP9509

Factors influencing perinatal outcomes in women with preterm preeclampsia: A secondary analysis of the PHOENIX trial.

This secondary analysis of the PHOENIX trial (evaluating planned delivery against expectant management in late preterm preeclampsia) demonstrates that in women who started induction of labour, 63% of women delivered vaginally (56% at 34weeks' gestation). Compared to expectant management, planned delivery was associated with higher rates of neonatal unit admission for prematurity (but lower proportions of small-for-gestational age infants); length of neonatal unit stay and neonatal morbidity (including respiratory support) were similar across both intervention groups at all gestational windows. Neonatal unit admission was increased by earlier gestation at delivery, development of severe preeclampsia, and being small-for-gestational age.

Prenatal exposure to PM10 and changes in DNA methylation and telomere length in cord blood

BACKGROUND AND AIM: Air pollution exposure in pregnancy can cause molecular level alterations associated with later disease susceptibility. We aimed to investigate changes in two molecular marker types, DNA methylation and telomere length, in cord blood in relation to gestational PM10 exposure and to explore potential gestational windows of susceptibility. METHODS: Cord blood epigenome-wide DNA methylation (N=384) and telomere length (N=500) were measured in children of the Italian birth cohort Piccolipiù using the Infinium Methylation EPIC BeadChip (Illumina) and qPCR, respectively. PM10 exposure levels were estimated for different gestational periods based on maternal residential address, using advanced methods based on satellite data. Lag distributed models using weekly exposures were used to further confirm the identified exposure windows. RESULTS:PM10 exposure during the first gestational weeks was associated with DNA methylation of more than 100 unique CpGs, mapped to genes with relevant functions in cell replication, differentiation and response to environmental stressors. We were able to test half of the CpGs in an independent sample from the same cohort and six CpGs showed robust associations. PM10 exposure during mid and later pregnancy was associated with shorter and longer telomeres, respectively. CONCLUSIONS:The first weeks of pregnancy seems to be a particularly important PM10 exposure window for DNA methylation that should be accounted for in future analyses, while exposure to PM10 in mid and late pregnancy might be important for telomere length. DNA methylation and telomere length are fundamental regulators of cellular processes during early life, and their alterations could have major implications for later disease susceptibility. KEYWORDS: Environmental epidemiology, Particulate matter, Epigenomics, Telomere length

Prenatal air pollution exposure and adverse birth outcomes: windows of susceptibility and socio-economic inequalities

BACKGROUND AND AIM: Air pollution exposure has been associated with adverse birth outcomes. However, few studies have investigated potential gestational windows of susceptibility. Further, the extent to which this association differs across socioeconomic status (SES) is underexplored. Therefore, the aim of this study is to investigate windows of susceptibility and explore potential social inequalities in the association between prenatal air pollution exposure and adverse birth outcomes. METHODS: We used a Spanish national-wide birth registry study which includes all newborns born between 2009 and 2010 (n=353,750) and whose mothers resided in the peninsula or the Balearic Islands. Maternal exposures to particulate matter with an aerodynamic diameter of 10 µm (PM10), 2.5 µm (PM2.5), and 2.5-10µm (PMcoarse) were estimated at the residential address throughout pregnancy on a daily basis using spatiotemporal land use machine-learning models. Birth outcomes (i.e., birth weight, gestational age, prematurity, and small or large for gestational age) and SES characteristics of the parents (i.e., education, occupation, ethnicity, area-level deprivation index) were obtained from the registry. Confounder adjusted associations between pollutant concentrations and birth outcomes, windows of susceptibility, and SES disparities were examined using regression models. RESULTS:Higher air pollution concentrations were associated with lower birth weight and increased prematurity [e.g., 20 gram decrease in birth weight (95%CI -25.3, -15.2) per each 10μg/m3 increase in PM10]. Results revealed that exposure during the third trimester were driving these associations and that effect on birth weight and prematurity was greater in magnitude for children from low SES families. Air pollution exposure was not associated with being small or large for gestational age. CONCLUSIONS:Exposure to air pollution during pregnancy was associated with adverse birth outcomes, with the third trimester of pregnancy being the most susceptible window. A pattern of social inequality was observed in this association, with a greater impact on newborns from families with fewer resources. KEYWORDS: Air pollution, birth outcomes, socio-economic inequalities, windows of susceptibility, pregnancy

Prenatal Exposure to Air Pollution and Autism Spectrum Disorder: Sensitive Windows of Exposure and Sex Differences

BACKGROUND AND AIM: Emerging animal and human data demonstrate sexual dimorphism in the developmental neurotoxicity of PM2.5 exposure. However, little is known about the sensitive gestational windows of prenatal PM2.5 exposure associated with increased ASD risk. METHODS: This population-based retrospective birth cohort study included 294,937 mother-child pairs with singleton deliveries in Kaiser Permanente Southern California (KPSC) hospitals between 2001 and 2014. Children were followed using electronic medical records (EMR) until a clinical diagnosis of ASD, non-KPSC membership, death, or December 31, 2019, whichever came first. Weekly mean PM2.5, NO2, and O3 exposures during pregnancy were estimated using spatiotemporal (1km x 1km) prediction models. Cox proportional-hazard models with distributed lags were used to estimate the independent associations between weekly pollutant exposures with ASD risk, separately for boys and girls. RESULTS:5,694 children (4,636 boys, 1,058 girls) had ASD diagnosis. Significant sensitive windows of exposure associated with PM2.5 exposure were found throughout the first two trimesters [1-27 weeks, cumulative HR=1.20 (95%CI=1.09–1.32) per 10 µg/m3 increase], adjusting for maternal race/ethnicity, maternal age at delivery, parity, maternal education, maternal comorbidities, medical center, median household income, birth year, and season. The cumulative hazard ratio (HR) during the entire pregnancy was 1.24 per 10 µg/m3 increase in PM2.5 (95%CI=1.10 –1.39). O3 exposure during 34-37 gestational weeks was also associated with increased ASD risk [cumulative HR=1.03 (1.01–1.06) per 10 ppb increase]. No associations were observed with NO2. When stratified by sex, early gestational (1-28 weeks) associations of PM2.5 were stronger for boys [cumulative HR=1.23 (1.10 –1.36) for boys and 1.10 (0.81 –1.38) for girls]; O3 associations in later gestation (33-37 weeks) were observed only in boys [boys=1.05 (1.02 –1.08); girls= 0.97 (0.9 –1.03)]. CONCLUSIONS:Exposures to higher levels of PM2.5 in the first two trimesters and O3 in the late 3rd trimester was associated with increased ASD risk, especially among boys. KEYWORDS: Autism Spectrum Disorder, Air Pollution, Sex Differences, Sensitive Windows

Placental histopathology in preterm birth with confirmed maternal infection: A systematic literature review.

Four in five neonatal deaths of preterm births occur in low and middle income countries and placental histopathology examination can help clarify the pathogenesis. Infection is known to play a significant role in preterm birth. The aim of this systematic review is to explore the association between placental histopathological abnormality and preterm birth in the presence of confirmed infection. PubMed/Medline, Scopus, Web of Science and Embase were searched using the keywords related to preterm birth, placental histopathology and infection. Titles and abstracts were screened and the full texts of eligible articles were reviewed to extract and summarise data. Of 1529 articles, only 23 studies (13 bacterial, 6 viral and 4 parasitic) were included, and they used 7 different gestational age windows, and 20 different histopathological classification systems, precluding data pooling. Despite this, histopathological chorioamnionitis, and funisitis (when examined) were commonly observed in preterm birth complicated by confirmed bacterial or viral, but not parasitic, infection. The presence of malaria parasites but not pigment in placenta was reported to increase the risk of PTB, but this finding was inconclusive. One in three studies were conducted in low and middle income countries. An array of: definitions of preterm birth subgroups, histological classification systems, histopathologic abnormalities and diagnostic methods to identify infections were reported in this systematic review. Commitment to using standardised terminology and classification of histopathological abnormalities associated with infections is needed to identify causality and potential treatment of preterm birth. Studies on preterm birth needs to occur in high burden countries and control for clinical characteristics (maternal, fetal, labor, and placental) that may have an impact on placental histopathological abnormalities.

Optimising the Timing of whooping cough Immunisation in MUMs: a randomised controlled trial investigating the timing of pertussis vaccination in pregnancy (OpTIMUM): a protocol paper

Background: Pertussis is a highly infectious respiratory illness caused by the bacteria Bordetella pertussis. A resurgence of pertussis, even in countries with good vaccine coverage, has led to an increase in infant deaths. In response to this, many countries have introduced pertussis vaccination in pregnancy. This strategy is effective at preventing infant disease, but there remains uncertainty about what gestational timing is best to ensure maximal protection of the infant. These uncertainties are the rationale for this randomised controlled trial and a sub-study investigating pertussis-specific antibody in breastmilk. Protocol: We will recruit 354 pregnant women and will randomise them to receive their pertussis vaccination in one of three gestational age windows: ≤23+6, 24-27+6 and 28-31+6 weeks of gestation. Vaccination will be with Boostrix-IPV® and participants will be asked to complete a symptom diary for seven days following vaccination. Blood sampling will be performed prior to vaccination, two weeks following vaccination and at the time of delivery. A cord blood sample will be collected at delivery and a blood sample collected from the infant 4-10 weeks after completion of the primary immunisations. Individuals participating in the breastmilk sub-study will provide a sample of colostrum within 48 hours of delivery and samples of breastmilk at two weeks and around five-six months. Blood samples will be analysed using enzyme linked immunosorbent assay (ELISA) techniques for pertussis toxin, filamentous haemagglutinin and pertactin. A subset of serum samples will also be analysed using a functional assay. Colostrum and breastmilk samples will be analysed using functional assays. Discussion: Although pertussis vaccination has been shown to be safe and effective in pregnancy there remains debate about the optimal timing for the administration during pregnancy. This study will investigate antibody responses in serum and breastmilk when vaccination is performed in three different time periods. Clinicaltrials.gov registration: NCT03908164 (09/04/2019)

Perinatal exposure to tetracycline contributes to lasting developmental effects on offspring

BackgroundFor more than 30 years, the tetracycline on/off system of inducible gene expression has been leveraged to study disease mechanisms across many research areas, especially that of metabolism and neuroscience. This system requires acute or chronic exposure to tetracycline derivatives, such as doxycycline, to manipulate gene expression in a temporal and tissue-specific manner, with exposure often being restricted to gestational and early developmental windows. Despite evidence showing that early life antibiotic exposure has adverse effects on gut microbiota, metabolism, physiology, immunity and behavior, little is known regarding the lasting impact of doxycycline treatment on relevant outcomes in experimental offspring.ResultsTo examine the hypothesis that early life doxycycline exposure produces effects on offspring growth, behavior, and gut microbiota, we employed the most commonly used method for tetracycline on/off system by administering a low dose of doxycycline (0.5 mg/ml) in the drinking water to C57Bl/6J and C57BL/6J:129S1/SvImJ dams from embryonic day 15.5 to postnatal day 28. Developmental exposure to low dose doxycycline resulted in significant alterations to growth trajectories and body weight in both strains, which persisted beyond cessation of doxycycline exposure. Developmental doxycycline exposure influenced offspring bacterial community assembly in a temporal and sex-specific manner. Further, gut microbiota composition failed to recover by adulthood, suggesting a lasting imprint of developmental antibiotic exposure.ConclusionsOur results demonstrated that early life doxycycline exposure shifts the homeostatic baseline of prior exposed animals that may subsequently impact responses to experimental manipulations. These results highlight the gut microbiota as an important factor to consider in systems requiring methods of chronic antibiotic administration during pregnancy and critical periods of postnatal development.