Longitudinal cohort studies can provide important evidence about preventable causes of disease, but the success relies heavily on the commitment of their participants, both at recruitment and during ...follow up. Initial participation rates have decreased in recent decades as have willingness to participate in subsequent follow ups. It is important to examine how such selection affects the validity of the results. In this article, we describe the conceptual framework for selection bias due to nonparticipation and loss to follow up in cohort studies, using both a traditional epidemiological approach and directed acyclic graphs. Methods to quantify selection bias are introduced together with analytical strategies to adjust for the bias including controlling for covariates associated with selection, inverse probability weighting and bias analysis. We use several studies conducted in the Danish National Birth Cohort as examples of how to quantify selection bias and also understand the underlying selection mechanisms. Although women who chose to participate in this cohort were typically of higher social status, healthier and with less disease than all those eligible for study, differential selection was modest and the influence of selection bias on several selected exposure–outcome associations was limited. These findings are reassuring and support enrolling a subset of motivated participants who would engage in long‐term follow up rather than prioritize representativeness. Some of the presented methods are applicable even with limited data on nonparticipants and those lost to follow up, and can also be applied to other study designs such as case–control studies and surveys.
Acetaminophen (paracetamol) is the most commonly used medication for pain and fever during pregnancy in many countries. Research data suggest that acetaminophen is a hormone disruptor, and abnormal ...hormonal exposures in pregnancy may influence fetal brain development.
To evaluate whether prenatal exposure to acetaminophen increases the risk for developing attention-deficit/hyperactivity disorder (ADHD)-like behavioral problems or hyperkinetic disorders (HKDs) in children.
We studied 64,322 live-born children and mothers enrolled in the Danish National Birth Cohort during 1996-2002.
Acetaminophen use during pregnancy was assessed prospectively via 3 computer-assisted telephone interviews during pregnancy and 6 months after child birth.
To ascertain outcome information we used (1) parental reports of behavioral problems in children 7 years of age using the Strengths and Difficulties Questionnaire; (2) retrieved HKD diagnoses from the Danish National Hospital Registry or the Danish Psychiatric Central Registry prior to 2011; and (3) identified ADHD prescriptions (mainly Ritalin) for children from the Danish Prescription Registry. We estimated hazard ratios for receiving an HKD diagnosis or using ADHD medications and risk ratios for behavioral problems in children after prenatal exposure to acetaminophen.
More than half of all mothers reported acetaminophen use while pregnant. Children whose mothers used acetaminophen during pregnancy were at higher risk for receiving a hospital diagnosis of HKD (hazard ratio = 1.37; 95% CI, 1.19-1.59), use of ADHD medications (hazard ratio = 1.29; 95% CI, 1.15-1.44), or having ADHD-like behaviors at age 7 years (risk ratio = 1.13; 95% CI, 1.01-1.27). Stronger associations were observed with use in more than 1 trimester during pregnancy, and exposure response trends were found with increasing frequency of acetaminophen use during gestation for all outcomes (ie, HKD diagnosis, ADHD medication use, and ADHD-like behaviors; P trend < .001). Results did not appear to be confounded by maternal inflammation, infection during pregnancy, the mother's mental health problems, or other potential confounders we evaluated.
Maternal acetaminophen use during pregnancy is associated with a higher risk for HKDs and ADHD-like behaviors in children. Because the exposure and outcome are frequent, these results are of public health relevance but further investigations are needed.
Perfluoroalkyl substances (PFASs) are widespread industrial pollutants that are extremely persistent in the environment. A previous study in the Danish National Birth Cohort (DNBC) found prenatal ...perfluorooctanoate (PFOA) exposure was associated with decreased birth weight, but had insufficient statistical power to evaluate adverse birth outcomes. Here, we conducted additional analyses in three samples originating from the DNBC for 3535 mothers and infant pairs to evaluate associations between prenatal PFASs exposures and low birth weight and preterm birth. Maternal plasma concentrations were measured for six types of PFASs in early pregnancy. Several PFASs were associated with a reduction in birth weight and gestational age. We estimated a nearly 2-fold increase in risks of preterm birth for the higher quartiles of PFOA and perflourooctanesulfonate (PFOS) exposure. In spline models, risk of preterm birth was increased for perfluorononanoic acid (PFNA), perfluoroheptane sulfonate (PFHpS) and perfluorodecanoic acid (PFDA) in higher exposure ranges. We also observed some elevated risks for low birth weight but these estimates were less precise. Our findings strengthen the evidence that in-utero PFASs exposures affect fetal growth. Future studies are needed to evaluate whether these associations persist with the decline of PFOA and PFOS in populations and should also investigate newer types of fluorinated compounds introduced more recently.
Only 60-70% of fertilized eggs may result in a live birth, and very early fetal loss mainly goes unnoticed. Outcomes that can only be ascertained in live-born children will be missing for those who ...do not survive till birth. In this article, we illustrate a common bias structure (leading to 'live-birth bias') that arises from studying the effects of prenatal exposure to environmental factors on long-term health outcomes among live births only in pregnancy cohorts. To illustrate this we used prenatal exposure to perfluoroalkyl substances (PFAS) and attention-deficit/hyperactivity disorder (ADHD) in school-aged children as an example. PFAS are persistent organic pollutants that may impact human fecundity and be toxic for neurodevelopment. We simulated several hypothetical scenarios based on characteristics from the Danish National Birth Cohort and found that a weak inverse association may appear even if PFAS do not cause ADHD but have a considerable effect on fetal survival. The magnitude of the negative bias was generally small, and adjusting for common causes of the outcome and fetal loss can reduce the bias. Our example highlights the need to identify the determinants of pregnancy loss and the importance of quantifying bias arising from conditioning on live birth in observational studies.
Paracetamol (N-acetyl-p-aminophenol (APAP), otherwise known as acetaminophen) is the active ingredient in more than 600 medications used to relieve mild to moderate pain and reduce fever. APAP is ...widely used by pregnant women as governmental agencies, including the FDA and EMA, have long considered APAP appropriate for use during pregnancy when used as directed. However, increasing experimental and epidemiological research suggests that prenatal exposure to APAP might alter fetal development, which could increase the risks of some neurodevelopmental, reproductive and urogenital disorders. Here we summarize this evidence and call for precautionary action through a focused research effort and by increasing awareness among health professionals and pregnant women. APAP is an important medication and alternatives for treatment of high fever and severe pain are limited. We recommend that pregnant women should be cautioned at the beginning of pregnancy to: forego APAP unless its use is medically indicated; consult with a physician or pharmacist if they are uncertain whether use is indicated and before using on a long-term basis; and minimize exposure by using the lowest effective dose for the shortest possible time. We suggest specific actions to implement these recommendations. This Consensus Statement reflects our concerns and is currently supported by 91 scientists, clinicians and public health professionals from across the globe.
Prenatal maternal smoking has been associated with attention-deficit/hyperactivity disorder (ADHD) in children, but the causal nature of this association is still under scrutiny. We examined the ...association with maternal smoking and nicotine replacement use during pregnancy, using association with paternal smoking as a marker of potential genetic or social confounding.
We included 84 803 singletons who participated in the Danish National Birth Cohort. Information on parental smoking was reported by the mothers during pregnancy. Children with ADHD were identified from the Danish Psychiatric Central Register, the Danish National Patient Register, and the Register of Medicinal Product Statistics by the International Classification of Diseases, 10th Revision diagnosis or medication. We also used hyperactivity/inattention score of the parent-reported Strengths and Difficulties Questionnaire, included in the 7-year follow-up of the National Birth Cohort.
Maternal and paternal smoking during pregnancy were associated with an elevated risk of ADHD defined by hospital diagnosis, medication, and hyperactivity/inattention score, but the association was stronger for maternal smoking than for paternal smoking. Compared with children born to nonsmoking mothers and smoking fathers, children born of smoking mothers and nonsmoking fathers had a higher risk of ADHD (adjusted hazard ratio = 1.26; 95% confidence interval, 1.03 to 1.53). We also saw a higher risk of ADHD in children of mothers who used nicotine replacement during pregnancy.
Our findings indicate that the association between prenatal maternal smoking and ADHD may overestimate a causal link, but nicotine exposure or related factors may still play a causal role.
•Comprehensive review of research studies on metabolomics of PFAS exposures in humans.•PFAS exposures are associated with disruption of amino acid, energy and lipid metabolism.•Metabolic alterations ...associated with PFAS are implicated in cardiometabolic health.•Research needs include prospective design, standardized reporting, and risk of bias.
To summarize the application of non-targeted metabolomics in epidemiological studies that assessed metabolite and metabolic pathway alterations associated with per- and polyfluoroalkyl substances (PFAS) exposure.
Eleven human studies published before April 1st, 2021 were identified through database searches (PubMed, Dimensions, Web of Science Core Collection, Embase, Scopus), and citation chaining (Citationchaser). The sample sizes of these studies ranged from 40 to 965, involving children and adolescents (n = 3), non-pregnant adults (n = 5), or pregnant women (n = 3). High-resolution liquid chromatography–mass spectrometry was the primary analytical platform to measure both PFAS and metabolome. PFAS were measured in either plasma (n = 6) or serum (n = 5), while metabolomic profiles were assessed using plasma (n = 6), serum (n = 4), or urine (n = 1). Four types of PFAS (perfluorooctane sulfonate(n = 11), perfluorooctanoic acid (n = 10), perfluorohexane sulfonate (n = 9), perfluorononanoic acid (n = 5)) and PFAS mixtures (n = 7) were the most studied. We found that alterations to tryptophan metabolism and the urea cycle were most reported PFAS-associated metabolomic signatures. Numerous lipid metabolites were also suggested to be associated with PFAS exposure, especially key metabolites in glycerophospholipid metabolism which is critical for biological membrane functions, and fatty acids and carnitines which are relevant to the energy supply pathway of fatty acid oxidation. Other important metabolome changes reported included the tricarboxylic acid (TCA) cycle regarding energy generation, and purine and pyrimidine metabolism in cellular energy systems.
There is growing interest in using non-targeted metabolomics to study the human physiological changes associated with PFAS exposure. Multiple PFAS were reported to be associated with alterations in amino acid and lipid metabolism, but these results are driven by one predominant type of pathway analysis thus require further confirmation. Standardizing research methods and reporting are recommended to facilitate result comparison. Future studies should consider potential differences in study methodology, use of prospective design, and influence from confounding bias and measurement errors.
Abstract
Outdoor air pollution has been linked to poor sleep health, but limited studies have investigated the relationship between solid cooking fuels and sleep health in adults. Therefore, we ...analyzed data from the China Health and Retirement Survey (CHARLS), a national survey of about 17,000 residents aged over 45. Participants were restricted to those who participated in CHARLS 2011, 2013 and 2015 (n = 8,668). Sleep health was indicated by self-reported average sleep hours at night and the numbers of unrested days/week in CHARLS 2015. We analyzed cooking fuel types reported and assessed the duration of solid fuels usage as consistent (indicated use in all three surveys or 6 + years) or inconsistent use (indicated use in one or two surveys or 1–4 years). We found consistent use of solid fuels was associated with a shorter sleep duration (OR = 1.17 95% CI 1.01, 1.35 for ≤ 6 h vs. 7–9 h/day) and higher frequencies of feeling unrested (OR = 1.32 95% CI 1.12, 1.55 for ≥ 5 days/week vs. none) compared with cleaner fuels use. The associations for inconsistent solid fuels use and sleep health were in the similar direction but smaller in magnitude. Further research is needed to confirm our findings and evaluate the exposure impact of specific fuel types to inform intervention strategies.
Maternal exposure to traffic-related air pollution during pregnancy has been shown to increase the risk of adverse birth outcomes and neurodevelopmental disorders. By utilizing high-resolution ...metabolomics (HRM), we investigated perturbations of the maternal serum metabolome in response to traffic-related air pollution to identify biological mechanisms.
We retrieved stored mid-pregnancy serum samples from 160 mothers who lived in the Central Valley of California known for high air particulate levels. We estimated prenatal traffic-related air pollution exposure (carbon monoxide, nitric oxides, and particulate matter <2.5 μm) during first-trimester using the California Line Source Dispersion Model, version 4 (CALINE4) based on residential addresses recorded at birth. We used liquid chromatography-high resolution mass spectrometry to obtain untargeted metabolic profiles and partial least squares discriminant analysis (PLS-DA) to select metabolic features associated with air pollution exposure. Pathway analyses were employed to identify biologic pathways related to air pollution exposure. As potential confounders we included maternal age, maternal race/ethnicity, and maternal education.
In total we extracted 4038 and 4957 metabolic features from maternal serum samples in hydrophilic interaction (HILIC) chromatography (positive ion mode) and C18 (negative ion mode) columns, respectively. After controlling for confounding factors, PLS-DA (Variable Importance in Projection (VIP) ≥2) yielded 181 and 251 metabolic features (HILIC and C18, respectively) that discriminated between the high (n = 98) and low exposed (n = 62). Pathway enrichment analysis for discriminatory features associated with air pollution indicated that in maternal serum oxidative stress and inflammation related pathways were altered, including linoleate, leukotriene, and prostaglandin pathways.
The metabolomic features and pathways we found to be associated with air pollution exposure suggest that maternal exposure during pregnancy induces oxidative stress and inflammation pathways previously implicated in pregnancy complications and adverse outcomes.
•High-resolution metabolomics detected metabolic signals associated with air pollution in maternal mid-pregnancy serum.•High levels of air pollution in early pregnancy affected oxidative stress and inflammatory activities.•Metabolism derived markers pointed to mechanisms in which air pollution may cause adverse pregnancy and birth outcomes.
PDF
