Prenatal Paracetamol Exposure and Wheezing in Childhood: Causation or Confounding?
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ABSTRACT: Background
Several studies have reported an increased risk of wheezing in the children of mothers who used paracetamol during pregnancy. We evaluated to what extent this association is explained by confounding.Methods
We investigated the association between maternal paracetamol use in the first and third trimester of pregnancy and ever wheezing or recurrent wheezing/asthma in infants in the NINFEA cohort study. Risks ratios (RR) and 95% confidence intervals (CI) were estimated after adjustment for confounders, including maternal infections and antibiotic use during pregnancy.Results
The prevalence of maternal paracetamol use was 30.6% during the first and 36.7% during the third trimester of pregnancy. The prevalence of ever wheezing and recurrent wheezing/asthma was 16.9% and 5.6%, respectively. After full adjustment, the RR for ever wheezing decreased from 1.25 [1.07-1.47] to 1.10 [0.94-1.30] in the first, and from 1.26 [1.08-1.47] to 1.10 [0.93-1.29] in the third trimester. A similar pattern was observed for recurrent wheezing/asthma. Duration of maternal paracetamol use was not associated with either outcome. Further analyses on paracetamol use for three non-infectious disorders (sciatica, migraine, and headache) revealed no increased risk of wheezing in children.Conclusion
The association between maternal paracetamol use during pregnancy and infant wheezing is mainly, if not completely explained by confounding.
SUBMITTER: Migliore E
PROVIDER: S-EPMC4549146 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
Publications
Prenatal Paracetamol Exposure and Wheezing in Childhood: Causation or Confounding?
Migliore Enrica E Zugna Daniela D Galassi Claudia C Merletti Franco F Gagliardi Luigi L Rasero Laura L Trevisan Morena M Rusconi Franca F Richiardi Lorenzo L
PloS one 20150825 8
<h4>Background</h4>Several studies have reported an increased risk of wheezing in the children of mothers who used paracetamol during pregnancy. We evaluated to what extent this association is explained by confounding.<h4>Methods</h4>We investigated the association between maternal paracetamol use in the first and third trimester of pregnancy and ever wheezing or recurrent wheezing/asthma in infants in the NINFEA cohort study. Risks ratios (RR) and 95% confidence intervals (CI) were estimated af ...[more]
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Project description:AimThe rising prevalence of bronchial asthma has led to world-wide efforts to understand and stem this development. Cross-sectional studies appear to show that early childhood use of antibiotics may be an important contributory factor, with paracetamol as an additional suspected cause. However, mounting evidence, which is reviewed here, points to various confounding factors as the major reasons for these reported associations.MethodsPubMed and EMBASE were systematically searched for studies on associations between antibiotics and/or paracetamol with asthma and/or wheezing, published up to November 2012. A total of 64 pertinent studies were identified, 35 focusing on antibiotics, 19 on paracetamol, and ten addressing both antibiotics and paracetamol, bringing the number of relevant datasets to 74.ResultsNumerous studies were cross-sectional and made no adjustment for the indication of antibiotics or paracetamol; consequently, they were unable to dismiss possible confounding by indication. Where such adjustments could be performed (mostly in longitudinal studies), they substantially weakened or entirely eliminated the association with asthma or asthma surrogates present in the unadjusted data.ConclusionThe weight of evidence of the collected studies in our review strongly suggests that the association of antibiotics with childhood asthma reflects various forms of bias, the most prominent of which is confounding by indication. Recent studies and meta-analyses support the same conclusion for paracetamol. Truly indicated antibiotics should not be withheld from infants or young children for fears they might develop asthma. Likewise, there is no sound reason to replace paracetamol as the preferred pain relief and fever medication in this age group.
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Project description:BackgroundDespite an overall reduction in suicide, educational disparities in suicide have not decreased over the last decade. The mechanisms behind educational disparities in suicide, however, remain unclear: low educational status may increase the risk of suicide ("causation") or low educational status and suicide may share confounders. This paper assesses whether educational disparities in suicide (EDS) are more likely to be due to causation.MethodThe DEMETRIQ study collected and harmonized register-based data on mortality follow-up from forty population censuses from twelve European populations. More than 102,000 suicides were registered over 392 million person-years. Three analyses were carried out. First, we applied an instrumental variable approach that exploits changes in the legislation on compulsory educational age to instrument educational status. Second, we analyzed EDS by age under the hypothesis that increasing EDS over the life cycle supports causation. Finally, we compared EDS in men and women under the assumption that greater EDS in women would support causation.FindingsThe instrumental variable analysis showed no evidence for causation between higher education and suicide, for men or women. The life-cycle analysis showed that the decrease of educational inequalities in suicide between the baseline 1991 period and the 2001 follow-up period was more pronounced and statistically significant in the first three younger age groups. The gender analysis indicated that EDS were systematic and greater in men than in women: the rate ratio of suicide for men with low level of education (RR = 2.51; 95%CI:2.44-2.58) was higher than the rate ratio in women (RR = 1.32; 95CI%:1.26-1.38).InterpretationOverall, there was little support for the causation hypothesis, suggesting that the association between education and suicide is confounded. Educational inequalities in suicide should be addressed in early life by early targeting of groups who struggle to complete their education and display higher risk of mental disorder or of mental health vulnerabilities.
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Project description:BackgroundRecent studies have suggested an association between prenatal paracetamol exposure and adverse neurodevelopmental outcomes in children. However, these findings may be confounded by unmeasured factors related to maternal use of paracetamol and child outcomes.ObjectiveTo examine the association between duration and timing of prenatal paracetamol exposure on parent-reported communication skills, behaviour, and temperament in preschool-aged children, with focus on the role of unmeasured confounding.MethodsWe used data from the Norwegian Mother and Child Cohort Study. Linear and generalised linear models with inverse probability weights and robust standard errors were used to quantify the association between prenatal paracetamol exposure and continuous and categorical outcomes.ResultsOf the 32 934 children included in our study, 8374 (25.4%), 4961 (15.1%), and 1791 (5.4%) were prenatally exposed to paracetamol in one, two, and three trimesters, respectively. Children exposed to paracetamol in two trimesters scored lower on shyness compared with unexposed children (β -0.62, 95% confidence interval [CI] -1.05, -0.19). Children exposed to paracetamol in three trimesters had a moderate increased risk of internalising behaviour problems (relative risk (RR) 1.36, 95% CI 1.02, 1.80) and borderline externalising behaviour problems (RR 1.22, 95% CI 0.93, 1.60) compared with unexposed children. Children exposed to paracetamol in 2nd/3rd trimester scored lower on shyness (β -0.32, 95% CI -0.66, 0.02) compared with unexposed children. Sensitivity analyses indicated that unmeasured confounders play an important role and may potentially bias the effect estimates away from the null.ConclusionsTiming of exposure and short-term use of paracetamol during pregnancy do not seem to pose any substantial risk of the outcomes examined. Although we found an association between paracetamol use in multiple trimesters and lower shyness and greater internalising behaviour in preschool-aged children, we cannot rule out chance or unmeasured confounding as possible explanations for these findings.
| S-EPMC8285062 | biostudies-literature
Project description:Study questionWhat is the relationship between maternal paracetamol intake during the masculinisation programming window (MPW, 8-14 weeks of gestation) and male infant anogenital distance (AGD), a biomarker for androgen action during the MPW?Summary answerIntrauterine paracetamol exposure during 8-14 weeks of gestation is associated with shorter AGD from birth to 24 months of age.What is already knownThe increasing prevalence of male reproductive disorders may reflect environmental influences on foetal testicular development during the MPW. Animal and human xenograft studies have demonstrated that paracetamol reduces foetal testicular testosterone production, consistent with reported epidemiological associations between prenatal paracetamol exposure and cryptorchidism.Study design, size, durationProspective cohort study (Cambridge Baby Growth Study), with recruitment of pregnant women at ~12 post-menstrual weeks of gestation from a single UK maternity unit between 2001 and 2009, and 24 months of infant follow-up. Of 2229 recruited women, 1640 continued with the infancy study after delivery, of whom 676 delivered male infants and completed a medicine consumption questionnaire.Participants/materials, setting, methodMothers self-reported medicine consumption during pregnancy by a questionnaire administered during the perinatal period. Infant AGD (measured from 2006 onwards), penile length and testicular descent were assessed at 0, 3, 12, 18 and 24 months of age, and age-specific Z scores were calculated. Associations between paracetamol intake during three gestational periods (<8 weeks, 8-14 weeks and >14 weeks) and these outcomes were tested by linear mixed models. Two hundred and twenty-five (33%) of six hundred and eighty-one male infants were exposed to paracetamol during pregnancy, of whom sixty-eight were reported to be exposed during 8-14 weeks. AGD measurements were available for 434 male infants.Main results and the role of chanceParacetamol exposure during 8-14 weeks of gestation, but not any other period, was associated with shorter AGD (by 0.27 SD, 95% CI 0.06-0.48, P = 0.014) from birth to 24 months of age. This reduction was independent of body size. Paracetamol exposure was not related to penile length or testicular descent.Limitations, reasons for cautionConfounding by other drugs or endocrine-disrupting chemicals cannot be discounted. The cohort was not fully representative of pregnant women in the UK, particularly in terms of maternal ethnicity and smoking prevalence. There is likely to have been misclassification of paracetamol exposure due to recall error.Wider implications of the findingsOur observational findings support experimental evidence that intrauterine paracetamol exposure during the MPW may adversely affect male reproductive development.Study funding/competing interestsThis work was supported by a European Union Framework V programme, the World Cancer Research Fund International, the Medical Research Council (UK), the Newlife Foundation for Disabled Children, the Evelyn Trust, the Mothercare Group Foundation, Mead Johnson Nutrition, and the National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre. The authors declare no conflict of interest.
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Project description:BackgroundRetinoblastoma is a rare tumor of the retina, most commonly found in young children. Due to the rarity of this childhood cancer, few studies have been able to examine prenatal pesticide exposure as a risk factor.ObjectiveTo examine the relationship between childhood retinoblastoma and prenatal exposure to pesticides through residential proximity to agricultural pesticide applications.MethodsWe conducted a population-based case-control study using cases aged 5 and younger identified from the California Cancer Registry, and controls randomly selected from California birth certificates. Frequency matching cases to controls by age resulted in 221 cases of unilateral retinoblastoma and 114 cases of bilateral retinoblastoma, totaling 335 cases and 123,166 controls. Based on addresses from birth certificates we employed Pesticide Use Reports and land use information within a geographic information system approach to individually assess exposures to specific pesticides within 4000 m of the residence reported on birth certificates. The associations between retinoblastoma (all types combined and stratified by laterality) and individual pesticides were expressed as odds ratios estimates obtained from unconditional logistic regression models including a single pesticide, and from a hierarchical logistic regression model including all pesticides.ResultsWe found that exposures to acephate (OR: 1.70, 95% CI: 1.20, 2.41) and bromacil (OR: 1.87, 95% CI: 1.07, 3.26) were associated with increased risk for unilateral retinoblastoma. In addition to acephate, we found that pymetrozine (OR: 1.45, 95% CI: 1.00, 2.08) and kresoxim-methyl (OR: 1.60, 95% CI: 1.00, 2.56) were associated with retinoblastoma (all types combined).ConclusionOur findings suggest that certain types of prenatal ambient pesticide exposure from residing near agricultural fields may play a role in the development of childhood retinoblastoma.
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2013-12-31 | E-GEOD-35222 | biostudies-arrayexpress
Project description:Introduction: Assessments on whether prenatal antibiotic exposure and mode of delivery increase the risk of wheezing in infants and toddlers are inconsistent. Our goal is to evaluate the association between prenatal antibiotic use and Cesarean section with three subtypes of wheezing in infancy.Methods: An ongoing prospective three generations cohort study provides data on prenatal antibiotic use and mode of delivery. Respective questionnaire data was used to distinguish three subtypes of wheezing: any wheezing, infectious wheezing, and noninfectious wheezing. Repeated measurements of wheezing at 3, 6, and 12 months were analyzed using generalized estimation equations. Latent transition analysis assessed patterns of infant wheezing development in the first year of life.Results: The prevalence of any wheezing was highest at 12 months (40.1%). The prevalence of infectious wheezing was higher (3 months 23.8%, 6 months 33.5%, 12 months 38.5%) than of noninfectious wheezing (3 months 13.0%, 6 months 14.0%, 12 months 11.1%). About 11-13% of children had both infectious and noninfectious wheezing at 3, 6, and 12 months (3 months 10.7%, 6 months 13.9%, 12 months 13.1%). Children born via Cesarean section have approximately a 70-80% increase in the risk of any wheezing (RR = 1.83, 95% CI 1.29-2.60) and of infectious wheezing (RR = 1.72, 95% CI 1.18-2.50).Conclusions: Analyses of infectious and noninfectious wheezing subtypes suggests that children born by Cesarean sections may be more susceptible to infectious wheezing, warranting investigations into microbial factors of infectious wheezing. No significant associations were found between prenatal antibiotic exposure and wheezing types.
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Project description:Iron overload due to environmental or genetic causes have been associated diabetes. We hypothesized that prenatal iron exposure is associated with higher risk of childhood type 1 diabetes. In the Norwegian Mother and Child cohort study (n?=?94,209 pregnancies, n?=?373 developed type 1 diabetes) the incidence of type 1 diabetes was higher in children exposed to maternal iron supplementation than unexposed (36.8/100,000/year compared to 28.6/100,000/year, adjusted hazard ratio 1.33, 95%CI: 1.06-1.67). Cord plasma biomarkers of high iron status were non-significantly associated with higher risk of type 1 diabetes (ferritin OR?=?1.05 [95%CI: 0.99-1.13] per 50?mg/L increase; soluble transferrin receptor: OR?=?0.91 [95%CI: 0.81-1.01] per 0.5?mg/L increase). Maternal but not fetal HFE genotypes causing high/intermediate iron stores were associated with offspring diabetes (odds ratio: 1.45, 95%CI: 1.04, 2.02). Maternal anaemia or non-iron dietary supplements did not significantly predict type 1 diabetes. Perinatal iron exposures were not associated with cord blood DNA genome-wide methylation, but fetal HFE genotype was associated with differential fetal methylation near HFE. Maternal cytokines in mid-pregnancy of the pro-inflammatory M1 pathway differed by maternal iron supplements and HFE genotype. Our results suggest that exposure to iron during pregnancy may be a risk factor for type 1 diabetes in the offspring.
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Project description:Background: How prenatal smoke exposure affects DNA methylation leading to atopic disorders remains to be addressed. Epigenetic biomarkers informative of prenatal smoke exposure and atopic disorders are wanting. Since most children suffering from atopic dermatitis (AD) continue to develop asthma later in life, we explored whether prenatal smoke exposure e induces DNA methylation and searched for predictive epigenetic biomarkers for smoke related atopic disorders. Methods: Methylation differences associated with smoke exposure were screened by Illumina methylation panel for children from the Taiwan birth panel study cohort initially. Information about development of atopic dermatitis (AD) and risk factors were collected. Cord blood cotinine levels were measured to represent prenatal smoke exposure. CpG loci that demonstrated a statistically significant difference in methylation were validated by methylation-dependent fragment separation (MDFS). Differential methylation in three genes (TSLP, GSTT1, and CYB5R3) was identified through the screen and their functions were investigated. Results: Among these, only thymic stromal lymphopoietin (TSLP) gene displayed significant difference in promoter methylation percentage after being validated by MDFS (p=0.029). TSLP gene was further investigated in a larger sample of 92 children from the cohort. Methylation status of the TSLP 5′-CpG island (CGI) was found to be significantly associated with prenatal smoke exposure (OR=3.59, 95%CI=1.49-8.64; cotinine level 0.10 ng/ml, sensitivity= 77%; specificity = 61%) and with AD (OR=4.77, 95%CI=1.47-15.53). The degree of TSLP 5′CGI methylation inversely correlated with TSLP protein expression levels (per unit: β=－6.69 ng/ml; 95% CIs, －12.80~－0.59; p=0.032). Conclusions: The effect of prenatal tobacco smoke exposure on the risk for AD may be mediated through DNA methylation. Cord blood methylated TSLP 5′CGI may be a potential epigenetic biomarker for environmentally-related atopic disorders.
2013-12-31 | GSE35222 | GEO
Project description:Triptan medications are serotonin agonists used to treat migraine, a chronic pain condition highly prevalent in women of reproductive age. Data on the safety of triptans during pregnancy are scant. We sought to quantify the association of prenatal triptan exposure on neurodevelopment in 3-year-old children.Using data from the Norwegian Mother and Child Cohort Study, we used propensity score matching to examine associations between prenatal triptan exposure and psychomotor function, communication, and temperament. We used an external validation study to perform propensity calibration to adjust effect estimates for confounders unmeasured in the main study (migraine severity, type, and maternal attitudes towards medication use).We identified 4204 women who reported migraine headache at baseline, of which 375 (8.9%) reported using a triptan greater than or equal to once during pregnancy. Children with prenatal triptan exposure had 1.37-fold greater unadjusted odds of fine motor problems (95% confidence interval (CI): 1.06-1.77), which decreased after propensity score matching (odds ratio (OR): 1.29, 95%CI 0.97-1.73) and was further attenuated after calibration (OR: 1.25, 95%CI 0.89-1.74). We observed no increased risk for gross motor or communication problems, and no differences in temperament. Adjustment for migraine severity using propensity score calibration had a moderate impact on effect estimates, with percent changes ranging from 2.4% to 50%.Prenatal triptan exposure was not associated with psychomotor function, communication problems, or temperament in 3-year-old children. Adjustment for migraine severity reduced effect estimates and should be considered in future studies of the safety of triptans during pregnancy. Copyright © 2015 John Wiley & Sons, Ltd.
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