STUDY QUESTION:To what extent is perceived stress during preconception and pregnancy associated with miscarriage incidence? SUMMARY ANSWER:Perceived stress during early pregnancy, but not preconception, was associated with higher miscarriage incidence. WHAT IS KNOWN ALREADY:Some studies have found that higher stress levels are associated with miscarriage risk. However, many of these studies were retrospective, focused on occupational stress only, and/or suffered from under-ascertainment of miscarriage. STUDY DESIGN, SIZE, DURATION:Pregnancy Study Online (PRESTO) is an ongoing prospective preconception cohort study that recruited participants during 2013-2025. Eligible participants were females aged 21-45 years, who resided in the USA or Canada and were trying to conceive without fertility treatments. Eligible partners were males aged ≥21 years. PARTICIPANTS/MATERIALS, SETTING, METHODS:We collected data on perceived stress using the 10-item version of the Perceived Stress Scale (PSS-10) during preconception (every 8 weeks) and early pregnancy for female participants and during preconception only for male participants. We identified pregnancies and miscarriages on bimonthly follow-up questionnaires during preconception and additional questionnaires during early and late pregnancy and postpartum. We fit Cox proportional hazards regression models to estimate hazard ratios (HR) and 95% CIs for the effect of preconception PSS-10 scores (n = 11 189 female and 2656 male participants) and early pregnancy PSS-10 scores (n = 8319 female participants) on miscarriage incidence, adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE:About 20% of the pregnancies ended in miscarriage, with the loss occurring at a median of six gestational weeks. Preconception PSS-10 scores in the female or male partner were not appreciably associated with miscarriage incidence. Female PSS-10 scores during gestational weeks 5-8 were strongly associated with higher miscarriage incidence: adjusted HRs for PSS-10 scores of 10-14, 15-19, 20-24, and ≥25 vs <10 in gestational weeks 5-8 were 1.38 (95% CI: 1.07, 1.77), 1.17 (95% CI: 0.89, 1.52), 1.35 (95% CI: 1.00, 1.83), and 2.05 (95% CI: 1.40, 2.99), respectively. In week-specific analyses, an association existed during weeks 4-8 and peaked at week 7. LIMITATIONS, REASONS FOR CAUTION:Our results may be susceptible to reverse causation, unmeasured confounding by nausea and vomiting in pregnancy, and exposure misclassification. WIDER IMPLICATIONS OF THE FINDINGS:Interventions aimed at decreasing stress during early pregnancy may be effective at reducing miscarriage incidence, but confirmation of our results in randomized studies is warranted. STUDY FUNDING/COMPETING INTEREST(S):This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01-HD086742, R01-HD105863). Lauren Wise has received in-kind donations for primary data collection in PRESTO from ChartNeo.com. The other authors have no conflicts to report. TRIAL REGISTRATION NUMBER:N/A.

BACKGROUND:Cannabis use among reproductive-aged individuals is common, yet there are gaps in our understanding of the effect of cannabis use on adverse birth outcomes. OBJECTIVE:To determine the extent to which female and male preconception cannabis use and female early pregnancy cannabis use are associated with the incidence of preterm birth (PTB), small-for-gestational-age birth (SGA), and large-for-gestational-age (LGA) birth. METHODS:We analysed data from Pregnancy Study Online, an internet-based preconception cohort study of couples trying to conceive. Eligible participants were aged 21-45 years (female) and ≥ 21 years (male) and residents of the United States or Canada. We followed 6838 couples who conceived between June 2013 and September 2024. Both partners completed preconception baseline questionnaires; female participants completed preconception follow-up questionnaires every 8 weeks, at early (< 12 weeks) and late pregnancy (~32 weeks), and at 6 months postpartum. Participants self-reported cannabis use during preconception (female and male) and early pregnancy (female only). We ascertained birthweight and gestational age from birth certificates and questionnaires and defined PTB (delivery < 37 gestational weeks) and SGA and LGA (< 10th and > 90th percentiles of birthweight, respectively, for gestational age and sex). We fit Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for potential confounders. RESULTS:Preconception cannabis use was not appreciably associated with PTB (≥ 1 per week vs. non-use: HR 1.06, 95% CI 0.71, 1.57 for females and HR 1.41, 95% CI 0.73, 2.75 for males). Higher frequency of female cannabis use in early pregnancy was associated with an increased incidence of PTB, although results were imprecise (≥ 1 per week vs. non-use: HR 1.87, 95% CI 1.06, 3.29; < 1/week vs. non-use: HR 0.85, 95% CI 0.36, 2.02). Cannabis use in either partner was not associated with the incidence of SGA or LGA. CONCLUSIONS:Our results support the existing evidence that cannabis use during early pregnancy is a risk factor for PTB.

Background:Hypertensive disorders of pregnancy (HDP) are established predictors of long-term cardiovascular disease (CVD), but the short-term postpartum CVD risk by HDP subtype and onset remains unclear. Materials and methods:We linked electronic health records with vital statistics for 755,606 singleton deliveries in Florida (2012-2017) to examine how different subtypes and onset of HDP are associated with CVD within 5 years postpartum. We classified HDP into six subtypes-chronic hypertension, gestational hypertension, mild preeclampsia, severe preeclampsia, eclampsia, and superimposed preeclampsia - and defined onset as early (<34 weeks) or late (≥34 weeks). Seven CVD outcomes (heart failure, ischemic heart disease, cerebrovascular disease/stroke, arrhythmia/cardiac arrest, cardiomyopathy, peripheral vascular disease, and new-onset chronic hypertension) within five years postpartum were identified. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for sociodemographic and clinical covariates. Results:Compared with normotensive pregnancies, superimposed preeclampsia carried the highest risks for stroke (HR 3.39; 95% CI 2.93-3.92), arrhythmia (2.62; 2.25-3.07), and peripheral vascular disease (3.09; 2.67-3.57). Eclampsia showed the strongest associations with heart failure (5.23; 3.70-7.39), ischemic heart disease (3.61; 2.65-4.92), and cardiomyopathy (5.25; 3.37-8.18). Severe preeclampsia was most strongly associated with new hypertension (3.27; 3.10-3.46). Early-onset eclampsia and superimposed preeclampsia showed higher CVD risks than their late-onset counterparts, whereas late-onset gestational hypertension and mild preeclampsia were more strongly associated with new hypertension and cardiomyopathy, respectively. Conclusions:HDP subtypes and onset timing impart distinct CVD risk profiles within five years postpartum.

BACKGROUND:Observational studies suggest an association between severe respiratory syncytial virus (RSV) and asthma, but it is unclear if this relationship is causal or confounded. OBJECTIVES:We investigated this relationship using calendar time at birth as a source of quasi-random variation with respect to individual-level risk factors for severe RSV infection. We similarly examined influenza (another respiratory virus) and rotavirus (a negative control exposure). METHODS:We analysed province-wide linked administrative data for 1,437,731 infants born in Ontario, Canada, from 2002-2013 (which facilitated 5 years of follow-up for asthma). We ascertained whether each infant experienced an RSV, influenza, and/or rotavirus hospitalisation (and the weekly incidences of RSV, influenza, and rotavirus hospitalisation among infants), and whether each child had asthma at 5 years of age. We used regression models to investigate the relationships between: (i) infant ages during the weeks with the highest incidences of RSV, influenza, and rotavirus hospitalisation and paediatric asthma; (ii) weekly incidences of RSV, influenza, and rotavirus hospitalisation and probability of paediatric asthma. RESULTS:We observed the highest odds of asthma among infants aged 13-16 weeks during the RSV peak, 11-13 weeks during the influenza peak, and 16-19 weeks during the rotavirus peak. The relationship between weekly incidence of RSV hospitalisation and probability of paediatric asthma was small in magnitude; we estimated a 3.15 (95% confidence interval -0.07, 6.36) percentage-point change in probability of paediatric asthma per 1 percentage-point change in weekly incidence of RSV hospitalisation among infants (offset by 13 weeks, which was the infant age at RSV peak that conferred maximum crude odds of paediatric asthma). Additionally, an unexpected relationship between rotavirus seasonal variation and asthma emerged. CONCLUSIONS:We found evidence supporting a limited causal role that did not fully explain the relationship between RSV and asthma. Other mechanisms, including seasonal factors, may contribute to previously reported associations.

Land-based military deployers to Afghanistan and/or Southwest Asia (SWA) encountered exposure to high concentrations of respirable particulate matter (PM) from multiple sources, including desert dust, burn pit smoke, and military occupations. Adverse lung health effects following deployment have been noted, including upper and lower respiratory tract symptoms, asthma, and small airway and other abnormalities on lung biopsy. The American Thoracic Society (ATS) convened a workshop in 2018 to review studies assessing postdeployment respiratory health, describe emerging research, and highlight knowledge gaps. Progress on understanding postdeployment health prompted a second ATS workshop to update current knowledge by (1) reviewing new studies linking exposure assessments to symptoms and/or clinical disease; (2) describing the spectrum of lung pathology reported in previously deployed personnel; (3) evaluating current knowledge of long-term health outcomes after deployment; (4) reviewing data from recent experimental models of deployment-related respiratory diseases (DRRDs); and (5) providing recommendations for future research priorities. Workshop participants agreed that there is substantial evidence linking deployment-related exposures to respiratory symptoms, pulmonary diagnoses, and lung pathology. Knowledge gaps include understanding: (1) the extent and mechanisms through which specific exposures result in impaired pulmonary function, small airways disease, and potentially future chronic pulmonary diseases; (2) the contribution of exposure-related foreign material in the lung to clinical and pathologic findings; and (3) the relationship of pathologic findings to respiratory health, especially those involving small airways.

A national-scale fluoridation study addresses policy-relevant exposure levels and provides evidence that adverse neurodevelopmental effects do not result from municipal fluoridation.

The author declares no conflicts of interest.

Open-air burning was a prevalent waste management method at many U.S. military bases during the wars in Afghanistan and Iraq. Past studies of the health impacts of burn pit exposure have relied on exposure assessments that did not account for waste segregation practices introduced in the later years of the wars, such as removing hazardous and medical waste before open burning and the use of incinerators. We developed a refined exposure assessment that accounts for waste management practices on military bases and evaluated the impact of waste segregation and incineration on cardiovascular and respiratory health outcomes among veterans deployed during these conflicts. The study cohort consisted of 459,381 Army and Air Force veterans who were deployed between 2005 and 2011 and received health care through the Veterans Health Administration (VHA) after deployment. The 109 most populated military bases in Afghanistan and Iraq were classified into four waste disposal categories by year: unsegregated, segregated, incineration, and no burning or incineration. Individual exposure was defined as the total number of days spent at bases based on the Department of Defense deployment histories. Health outcomes were determined through VHA healthcare records, from the end of deployment through the end of follow-up in 2020. Logistic regression was performed to investigate the association between deployment to bases with varying waste management practices and the risk of respiratory and cardiovascular diseases. Deployment to bases using burn pits with unsegregated waste was associated with elevated risks of hypertension and asthma, whereas deployment to bases that segregated waste or used incinerators was not. Prolonged deployment (highest duration tertile of > 240 days) to bases with unsegregated waste burning was associated with a 16

INTRODUCTION:Respiratory syncytial virus (RSV) is the leading cause of hospitalization among US infants. Characterizing service utilization during infant RSV hospitalizations may provide important information for prioritizing resources and interventions. OBJECTIVE:The objective of this study was to describe the procedures and services received by infants hospitalized during their first RSV episode in their first RSV season, in addition to what proportion of infants died during this hospitalization. METHODS:In this retrospective observational study, we analyzed three different administrative claims datasets to examine healthcare service utilization during RSV hospitalizations among infants. The study population included infants born between July 2016 and February 2020 who experienced an RSV episode during their first RSV season and had an associated inpatient hospitalization. We stratified infants into three comorbidity groups: healthy term, palivizumab-eligible, and other comorbidities. Outcomes included extracorporeal membrane oxygenation, supplemental oxygen use (in-hospital and post-discharge), mechanical ventilation (invasive and non-invasive), chest imaging, infant mortality, length of inpatient stay, intensive care unit (ICU) admission, and number of days in the ICU. RESULTS:Chest imaging was the most frequently administered procedure during RSV-associated hospitalizations, with approximately 34-38% of infants receiving it. Around one-quarter of infants were admitted to the ICU during their first RSV hospitalization. Median lengths of stay in the hospital were 3-4 days, extending to 4-6 days in the presence of ICU admission. Palivizumab-eligible infants had higher utilization of healthcare services and spent more time in the hospital or ICU compared to healthy infants or those with other comorbidities. CONCLUSIONS:This study provides insights into the utilization of healthcare services during RSV hospitalizations among infants. Understanding service utilization patterns can aid in improved management and resource allocation for infants in the United States, ultimately contributing to better outcomes and reduced healthcare costs overall. However, likely under-ascertainment of ventilation and oxygen-related services in insurance claims remains an impediment to studying these outcomes.

INTRODUCTION:Five million US Veterans had possible exposure to open burn pits used for waste disposal through service in Iraq (2003-2011) and Afghanistan (2001-2014). Burn pits generate toxic exposures that may be associated with adverse health outcomes. We examined all-cause and cause-specific mortality in relation to deployment to bases with open burn pits. METHODS:We analysed a cohort of 474 634 Veterans who received some healthcare from the Veterans Health Administration, linked to Department of Defense deployment records to identify assignments to bases with burn pits. In multivariable logistic regression models, we assessed the association between duration of deployment to bases with burn pits and all-cause mortality and cause-specific mortality from the six most common causes among this population of Veterans. RESULTS:Duration of deployment to bases with burn pits was modestly related to all-cause mortality, with adjusted ORs of 1.07 (95% CI 0.99 to 1.15), 1.08 (95% CI 1.00 to 1.16) and 1.16 (95% CI 1.06 to 1.27) across tertiles, but not associated with mortality due to cancer, heart disease or chronic liver disease/cirrhosis. Positive associations were also found for unintentional injuries, suicide and stroke. DISCUSSION:These data are suggestive of an association between duration of deployment to bases with burn pits and overall mortality, but not from cancer or heart disease. Unexpected associations with injury and suicide call for a more detailed evaluation. Conclusions are restricted by the broad aggregations of causes of death, a limited number of deaths in this relatively young cohort and the lack of more detailed information on exposure to burn pits.

BACKGROUND:Respiratory syncytial virus (RSV) is the leading cause of infant hospitalization in the United States. Understanding healthcare utilization associated with medically attended (MA) RSV lower respiratory tract infection (LRTI) might inform research priorities aimed at reducing RSV-associated pediatric morbidity. We described healthcare utilization during acute MA RSV LRTI episodes within a geographically diverse cohort of infants in the United States. METHODS:We created retrospective cohorts of infants born in the United States from July 1, 2016 through February 29, 2020 in each of three de-identified insurance claims datasets: Merative MarketScan Commercial Claims and Encounters, Multi-State MarketScan Medicaid, and Optum's de-identified Clinformatics ® Data Mart. We identified infants' first MA RSV LRTI diagnosis during their first RSV season and followed them for 7 subsequent days to record outpatient, emergency department, and inpatient hospital utilization. We calculated the number of outpatient visits, emergency department visits, and inpatient hospital stays occurring during this acute episode and estimated the proportion of episodes involving ≥ 2 visits to a given healthcare setting. RESULTS:In the CCAE database, we identified 25,409 acute MA RSV LRTI episodes under the specific RSV definition and 69,068 under the sensitive definition. In the MDCD database, these totals were 67,357 and 170,744, while in the CDM database, they were 12,402 and 31,363, respectively. Across data sources, 34%-69% of infants' first acute MA RSV LRTI episodes involve 2 or more visits to a healthcare setting within 7 days. The percentage of episodes involving at least 2 visits ranged from 34-62% among healthy term infants, 38-65% for Palivizumab-eligible infants, and 38-69% for infants with other comorbidities. CONCLUSIONS:Within a week of their first MA RSV LRTI diagnosis, infants frequently experience at least 2 visits to one or more healthcare settings, regardless of their comorbidity profile. The percentage of MA RSV LRTI episodes involving at least 2 visits to a healthcare setting may vary by insurance claims database, even between commercial payers.

Background:Cold temperatures are associated with increased risk for cardiovascular and respiratory disease mortality. Due to limited temperature regulation in prisons, incarcerated populations may be particularly vulnerable to cold-related mortality.Methods:We analyzed mortality data in US prisons from 2001 to 2019. Using a case-crossover approach, we estimated the association of a 10 degrees F decrease in cold temperature and extreme cold (days below the 10th percentile) with the risk of total mortality and deaths from heart disease, respiratory disease, and suicide. We assessed effect modification by personal, facility, and regional characteristics.Results:There were 18,578 deaths during cold months. The majority were male (96%) and housed in a state-operated prison (96%). We found a delayed association with mortality peaking 3 days after and remaining positive until 6 days after cold exposure. A 10 degrees F decrease in temperature averaged over 6 days was associated with a 5.1% (95% confidence interval [CI]: 2.1%, 8.0%) increase in total mortality. The 10-day cumulative effect of an extreme cold day was associated with an 11% (95% CI: 2.2%, 20%) increase in total mortality and a 55% (95% CI: 11%, 114%) increase in suicides. We found the greatest increase in total mortality for prisons built before 1980, located in the South or West, and operating as a dedicated medical facility.Conclusions:Cold temperatures were associated with an increased risk of mortality in prisons, with marked increases in suicides. This study contributes to the growing evidence that the physical environment of prisons affects the health of the incarcerated population.

Hill’s list of considerations for assessing causality, proposed 60 years ago, became a landmark in the interpretation of epidemiologic evidence. However, it has been and continues to be misused as a list of causal criteria to be scored and summed, despite causal inference being unattainable through the application of this or any other algorithm. Recognizing the distinction between statistical associations and causal effects was a key contribution of Hill. While he identified several clues for distinguishing between causal and non-causal associations, causal inference in epidemiology has become much more explicit and effective. Rather than relying on Hill’s indirect hints of potential bias by considering strength of association or dose-response gradients, newer methods such as quantitative bias analysis directly assess confounding and other candidate biases that compete with causal explanations, leading to more informed inferences. Similarly, the interpretation of consistency depends on variation in methods across studies; triangulation may be used to search for informative inconsistencies, strengthening causal inference. Most importantly, a causal connection is not a categorical property bestowed upon an association based on Hill’s considerations or any other checklist. Causal inference is an inherently indirect process, with the inference gradually crystallizing by withstanding challenges from competing theories in which other explanations, including random error or biases, are found not to account for the measured association.

ImportanceMany veterans who served in Afghanistan and Iraq during Operations Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) were deployed to military bases with open burn pits and exposed to their emissions, with limited understanding of the long-term health consequences.ObjectiveTo determine the association between deployment to military bases where open burn pits were used for waste disposal and the subsequent risk of developing respiratory and cardiovascular diseases.Design, Setting, and ParticipantsThis retrospective observational cohort study used Veterans Health Administration medical records and declassified deployment records from the Department of Defense to assess Army and Air Force veterans who were deployed between 2001 and 2011 and subsequently received health care from the Veterans Health Administration, with follow-up through December 2020. Data were analyzed from January 2023 through February 2024.ExposureDuration of deployment to military bases with open burn pits.Main Outcomes and MeasuresDiagnosis of asthma, chronic obstructive pulmonary disease, interstitial lung disease, hypertension, myocardial infarction, congestive heart failure, ischemic stroke, and hemorrhagic stroke.ResultsThe study population included 459 381 OEF and OIF veterans (mean [SD] age, 31.6 [8.7] years; 399 754 [87.0%] male). Median (IQR) follow-up from end of deployment was 10.9 (9.4-12.7) years. For every 100 days of deployment to bases with burn pits, veterans experienced increased adjusted odds for asthma (adjusted odds ratio [aOR], 1.01; 95% CI, 1.01-1.02), chronic obstructive pulmonary disease (aOR, 1.04; 95% CI, 1.02-1.07), hypertension (aOR, 1.02; 95% CI, 1.02-1.03), and ischemic stroke (aOR, 1.06; 95% CI, 0.97-1.14). Odds of interstitial lung disease, myocardial infarction, congestive heart failure, or hemorrhagic stroke were not increased. Results based on tertiles of duration of burn pit exposures were consistent with those from the continuous exposure measures.Conclusions and RelevanceIn this cohort study, prolonged deployment to military bases with open burn pits was associated with increased risk of developing asthma, COPD, and hypertension. The results also point to a possible increased risk in ischemic stroke. The novel ability to use integrated data on deployment and health outcomes provides a model for additional studies of the health impact of environmental exposures during military service.

Objective This study aimed to evaluate whether transient fetal growth restriction (FGR) that resolves prior to delivery confers a similar risk of neonatal morbidity as uncomplicated FGR that persists at term. Study Design This is a secondary analysis of a medical record abstraction study of singleton live-born pregnancies delivered at a tertiary care center between 2002 and 2013. Patients with fetuses that had either persistent or transient FGR and delivered at 38 weeks or later were included. Patients with abnormal umbilical artery Doppler studies were excluded. Persistent FGR was defined as estimated fetal weight (EFW) <10th percentile by gestational age from diagnosis through delivery. Transient FGR was defined as EFW <10th percentile on at least one ultrasound, but not on the last ultrasound prior to delivery. The primary outcome was a composite of neonatal morbidity: neonatal intensive care unit admission, Apgar's score <7 at 5 minutes, neonatal resuscitation, arterial cord pH <7.1, respiratory distress syndrome, transient tachypnea of the newborn, hypoglycemia, sepsis, or death. Baseline characteristics and obstetric and neonatal outcomes were compared using Wilcoxon's rank-sum and Fisher's exact test. Log binomial regression was used to adjust for confounders. Results Of 777 patients studied, 686 (88%) had persistent FGR and 91 (12%) had transient FGR. Patients with transient FGR were more likely to have a higher body mass index, gestational diabetes, diagnosed with FGR earlier in pregnancy, have spontaneous labor, and deliver at later gestational ages. There was no difference in the composite neonatal outcome (relative risk = 1.03, 95% confidence interval [CI] 0.72, 1.47) for transient versus persistent FGR after adjusting for confounders (adjusted relative risk = 0.79, 95% CI 0.54, 1.17). There were no differences in cesarean delivery or delivery complications between groups. Conclusion Neonates born at term after transient FGR do not appear to have differences in composite morbidity compared with those where uncomplicated FGR persists at term. Key Points

ObjectiveOligohydramnios (defined as amnioticfluid volume<5cm or deepestvertical pocket<2cm) is regarded as an ominousfinding on prenatal ultrasound.Amnioticfluid, however, is not static, and to date, there have been no studiescomparing perinatal outcomes in patients who are diagnosed with oligohydramniosthat resolves and those who have persistent oligohydramnios.Study DesignThis is a secondary analysis of a National Institutes of Health-fundedretrospective cohort study of singleton gestations delivered at a tertiary care hospitalbetween 2002 and 2013 with mild hypertensive disorders and/or fetal growthrestriction (FGR). Maternal characteristics, delivery, and neonatal information were abstracted by trained research nurses. Patients with a diagnosis of oligohydramnioswere identified, and those with resolved versus persistent oligohydramnios at the timeof delivery were compared. The primary outcome was a composite of neonatalresuscitation at delivery: administration of oxygen, bag-mask ventilation, continuouspositive airway pressure, intubation, chest compression, or cardiac medication admin-istration. Secondary outcomes included FGR, timing, and mode of delivery.Results Of 527 women meeting study criteria, 42had oligohydramnios that resolvedprior to delivery, whereas 485 had persistent oligohydramnios. There were nosignificant differences in patient demographics between groups. The gestationalage at diagnosis was significantly lower for patients with resolved versus persistentoligohydramnios (median: 33.0 [interquartile range, IQR: 29.1-35.9] vs. 38.0 [IQR 36.4-39.3],p<0.001). There was not a substantial difference in rate of neonatalresuscitation (41 vs. 32%,p<1/4>0.31). Patients with resolved oligohydramnios were more likely to have developed FGR than those with persistent oligohydramnios (55 vs. 36%,p<0.02). There were no significant differences for gestational age at delivery, birthweight, or neonatal intensive care unit admission.ConclusionPatients whose oligohydramnios resolved were diagnosed earlier yet hadsimilar rates of neonatal resuscitation but higher rates of FGR than those who hadpersistent oligohydramnios.