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Paracetamol in pregnancy and the risk of wheezing in offspring: A systematic review and meta-analysis
Abstract
There is evidence to suggest that the risk of asthma might be increased with exposure to paracetamol in the intrauterine environment, infancy, later childhood and adult life.
To review the evidence from studies investigating the association between paracetamol use in pregnancy and childhood asthma.
A systematic review and meta-analysis was undertaken of studies reporting the association between paracetamol use in pregnancy and subsequent asthma in childhood. The primary outcome variable was wheeze in the last 12 months. For tabulated raw data, not adjusted for confounders, random effects odds ratios (OR) were pooled by the inverse variance weighted method.
There were six studies identified that were included in the meta-analysis. The age of children studied ranged from 30 to 84 months. The pooled random effects OR for the risk of current wheeze in the children of women who were exposed to any paracetamol during any stage of pregnancy was 1.21 (95% confidence interval 1.02-1.44). Features of the studies variably included an association with paracetamol use during all trimesters of pregnancy and an association with persistent asthma, severe asthma, and with atopy.
The use of paracetamol during pregnancy is associated with an increased risk of childhood asthma. More research is urgently required to determine the impact of paracetamol during pregnancy on the risk of wheezing in offspring so that appropriate public health recommendations can be made.
... Acetaminophen, also known as paracetamol, is the most common over-the-counter pain and fever medication used by pregnant women [1]. Several prospective cohort studies have reported positive associations between prenatal exposure to acetaminophen and asthma development in offspring during childhood [2][3][4]. Acetaminophen can cross the placenta, exposing the fetus during critical periods of development [5,6]. Acetaminophen was suggested to deplete glutathione (GSH) [7], a key antioxidant in the airways, and enhance immune responses that can predispose prenatally acetaminophen-exposed children to asthmatic phenotypes. ...
... In the California Health Interview Survey 2001-2007, asthma prevalence was higher in some ethnic minorities and families living in poverty [9]. Three meta-analyses estimated that maternal use of acetaminophen during pregnancy is associated with an overall 20-40% increased odds of developing asthma in childhood [2][3][4]. However, most evidence has come from Northern and Western European countries [10][11][12][13], and less consistent findings were reported from studies in the U.S. [14][15][16][17]. ...
... In this LA birth cohort, we estimated a 25-39% higher risk for receiving an asthma diagnosis or experiencing asthmatic symptoms among children exposed to acetaminophen prenatally; these risk estimates are consistent with the most recent meta-analytic results [2][3][4]. Our study is one of few to investigate this association in a cohort of mothers and children with diverse ethnicity and socio-economic backgrounds. Some differences were observed by maternal race/ethnicity, specifically larger effect estimates for Black/AA and Asian/Pacific Islander than white children, and null results for Hispanics/Latinx children. ...
Acetaminophen is the most common over-the-counter pain and fever medication used by pregnant women. While European studies suggest acetaminophen exposure in pregnancy could affect childhood asthma development, findings are less consistent in other populations. We evaluated whether maternal prenatal acetaminophen use is associated with childhood asthmatic symptoms (asthma diagnosis, wheeze, dry cough) in a Los Angeles cohort of 1201 singleton births. We estimated risk ratio (RR) and 95% confidence interval (CI) for childhood asthmatic outcomes according to prenatal acetaminophen exposure. Effect modification by maternal race/ethnicity and psychosocial stress during pregnancy was evaluated. The risks for asthma diagnosis (RR = 1.39, 95% CI 0.96, 2.00), wheezing (RR = 1.25, 95% CI 1.01, 1.54) and dry cough (RR =1.35, 95% CI 1.06, 1.73) were higher in children born to mothers who ever used acetaminophen during pregnancy compared with non-users. Black/African American and Asian/Pacific Islander children showed a greater than two-fold risk for asthma diagnosis and wheezing associated with the exposure. High maternal psychosocial stress also modified the exposure-outcome relationships. Acetaminophen exposure during pregnancy was associated with childhood asthmatic symptoms among vulnerable subgroups in this cohort. A larger study that assessed prenatal acetaminophen exposure with other social/environmental stressors and clinically confirmed outcomes is needed.
... 6 It can be prescribed, but is also available as an over-the-counter medication. Some studies [17][18][19] have demonstrated associations between the use of paracetamol antenatally and adverse outcomes for the offspring. Adverse effects reported include an increased incidence of childhood asthma and behavioural problems, 18,19 and a delay in gross motor and communication development in children with long-term antenatal exposure to paracetamol. ...
... Some studies [17][18][19] have demonstrated associations between the use of paracetamol antenatally and adverse outcomes for the offspring. Adverse effects reported include an increased incidence of childhood asthma and behavioural problems, 18,19 and a delay in gross motor and communication development in children with long-term antenatal exposure to paracetamol. 17 The US Food and Drug Administration (FDA) published a safety announcement in 2015 20 addressing the concerns raised by these studies, and stated that all of the studies reviewed had potential limitations in their design and contained conflicting results. ...
... In addition, messages included important advises and recommendations for diabetic patients during pregnancy. All the educational materials were collected from different evidence-based medical resources [14][15][16][17][18][19][20][21][22][23] and were translated to Malay language. The investigators used simple, short sentences with one idea per sentence, and positive sentences rather than negative ones. ...
... A multi-center, multi-country, crosssectional study of children (6-7 and 13-14 years of age) from the International Study of Asthma and Allergy in Childhood (ISAAC) showed that acetaminophen use was associated with an increased risk of present symptoms of allergic rhinitis [96]. The mechanism of this association has not been unified, and the depletion of glutathione-S-transferase in the upper airway mucosa leading to increased oxidative stress, promoting the helper T-helper 2 (Th2) differentiation pathway and immunoglobulin E (IgE)-mediated response is one of the leading hypotheses [97][98][99]. Caballero et al. [100] identified lymphocyte aggregates in a group of paracetamol treated rats and determined that the inflammatory infiltrate was primarily composed of lymphoid aggregates and mast cells, suggesting that chronic exposure to paracetamol in a rat model is associated with the development of rhinitis. Although a clear causal relationship between acetaminophen and AR cannot be established from this study, we suggest that exposure to acetaminophen may be an important putative risk factor for the development of AR. ...
Many potential environmental risk factors, protective factors, and biomarkers of AR have been published, but so far, the strength and consistency of their evidence are unclear. We conducted a comprehensive review of environmental risk, protective factors, and biomarkers for AR to establish the evidence hierarchy. We systematically searched Embase, PubMed, Cochrane Library, and Web of Science electronic database from inception to December 31, 2022. We calculated summary effect estimate (odds ratio (OR), relative risk (RR), hazard ratio (HR), and standardized mean difference (SMD)), 95% confidence interval, random effects p value, I² statistic, 95% prediction interval, small study effects, and excess significance biases, and stratification of the level of evidence. Methodological quality was assessed by AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews 2). We retrieved 4478 articles, of which 43 met the inclusion criteria. The 43 eligible articles identified 31 potential environmental risk factors (10,806,206 total population, two study not reported), 11 potential environmental protective factors (823,883 total population), and 34 potential biomarkers (158,716 total population) for meta-analyses. The credibility of evidence was convincing (class I) for tic disorders (OR = 2.89, 95% CI 2.11–3.95); and highly suggestive (class II) for early-life antibiotic use (OR = 3.73, 95% CI 3.06–4.55), exposure to indoor dampness (OR = 1.49, 95% CI 1.27–1.75), acetaminophen exposure (OR = 1.54, 95% CI 1.41–1.69), childhood acid suppressant use (OR = 1.40, 95% CI 1.23–1.59), exposure to indoor mold (OR = 1.66, 95% CI 1.26–2.18), coronavirus disease 2019 (OR = 0.11, 95% CI 0.06–0.22), and prolonged breastfeeding (OR = 0.72, 95% CI 0.65–0.79). This study is registered in PROSPERO (CRD42022384320).
... The occurrence of various pharmaceuticals in water causes a range of health impacts to humans and animals. For instance, antibiotics such as sulfamethoxazole induce genetic mutations and chronic effects even at low concentrations [13,14], while analgesics such as paracetamol increase the risk of kidney cancer, liver damage, and asthma [15,16]. Overall, adverse effects of pharmaceuticals include the disruption of the endocrine system, and induction of antimicrobial resistance in environmental systems [17]. ...
Pharmaceuticals in the concentration range of hundreds of ng/L to μg/L occur in wastewater and end up in surface water, groundwater and agricultural land where they cause various health risks. These pollutants are classified as emerging and cannot be efficiently removed by conventional wastewater treatment processes. The use of nano-enabled photocatalysts in the removal of pharmaceuticals in aquatic systems has recently received research attention owing to their enhanced properties and effectiveness. The industrial scale application of photocatalytic technology is still limited. A comprehensive review on the removal of pharmaceuticals from real wastewater using the photocatalysts is therefore necessary. This paper reviews literature on the occurrence, fate, and nano-sized photocatalytic removal strategies of pharmaceuticals from wastewater. Modifications of nano-enabled photocatalysts through doping, deposition on various supports, and introducing magnetic character to enhance their photocatalytic efficiency and recyclability were discussed. The synthetic routes of photocatalysts influence the physical and chemical properties which can either enhance or inhibit their effectiveness. The benefits of photocatalytic degradation include easy recycling as they exhibit excellent stability, and can be used for several cycles. Going forward, research should focus on: (1) elucidation of photodegradation mechanisms, (2) real wastewater treatment at industrial scale to remove multiple pharmaceutical compounds, (3) regeneration, and disposal particularly towards large scale application, (4) life cycle assessment of the photocatalysts from synthesis to application, (5) lowering the cost and improving photodegradation efficiency, and (6) investigating the toxicity of intermediates to the photocatalyst and the environment.
... In their work, OR = 1.19, 95% CI: 1.12 to 1.27. In turn, Eyers et al. [36] showed increased risk of recurrent wheeze in the children of women who were exposed to paracetamol during pregnancy. In their study, OR was 1.21, 95% CI: 1.24 to 1.44. ...
The aim of the report was to evaluate whether in utero exposure to paracetamol is associated with risk towards developing respiratory disorders such as asthma and wheeze after birth. MEDLINE (PubMed), EMBASE and Cochrane Library databases were searched for articles published in English to December 2021. The study involved 330,550 women. We then calculated the summary risk estimates and 95% CIs and plotted forest plots using random effect models (DerSimonian–Laird method) and fixed effect models. We also performed a systematic review of the chosen articles and a meta-analysis of studies based on the guidelines outlined in the PRISMA statement. Accordingly, maternal exposure to paracetamol during pregnancy was associated with a significant increased risk of asthma: crude OR = 1.34, 95% CI: 1.22 to 1.48, p < 0.001; and significant increased risk of wheeze: crude OR = 1.31, 95% CI: 1.12 to 1.54, p < 0.002. Results of our study confirmed that maternal paracetamol use in pregnancy is associated with an enhanced risk of asthma and wheezing in their children. We believe paracetamol should be used with caution by pregnant women, and at the lowest effective dose, and for the shortest duration. Long-term use or the use of high doses should be limited to the indications recommended by a physician and with the mother-to-be under constant supervision.
... No ha sido posible hasta ahora determinar si es causa de asma, o simplemente la evidencia de asociación se debe a su uso frecuente en infecciones respiratorias o por síntomas que pueden solaparse con los del asma (125). Varios estudios de cohortes, y algunos meta-análisis de los mismos, han atribuido una relación positiva al uso de paracetamol durante el embarazo y el asma infantil (29,(126)(127)(128). Esa asociación que parecía clara en la mayoría de los estudios realizados se debate ahora, ya que se piensa que hay factores como asma materna o infecciones respiratorias en la madre que actúan como factores de confusión y no se han tenido en cuenta apropiadamente (129)(130)(131). ...
Estudio Global Asthma Network en niños de 6-7 años de la provincia de Salamanca Salamanca, en el que se evalua la prevalencia de asma en 2388 niños, y los posibles factores de riesgo/proteccion, presentacion clínica, tratamientos...
Global Asthma Network study in Salamanca of 6-7 years old children from Salamanca province in Spain, with 2388 questionnaires collected where asthma prevalence, symptoms, treatments, and possible risk/protection factors are evaluated.
... 722 Frequent use of paracetamol by pregnant women has been associated with asthma in their children. 723 There is no evidence that vaccinations increase the risk of a child developing asthma. ...
Hintergrund: Die chronische Rhinosinusitis mit Nasenpolypen (CRSwNP) ist eine multifaktorielle entzündliche Erkrankung der paranasalen Schleimhäute, der als Endotyp meistens eine Typ-2-Inflammation zugrunde liegt. Mittlerweile sind drei Antikörper (Dupilumab, Omalizumab und Mepolizumab) für die Therapie der schweren CRSwNP zugelassen. Eine Dokumentation der Erkrankungsschwere im Behandlungsverlauf ist unverzichtbar.
Methoden: In einer Literaturrecherche in Medline, Pubmed sowie den nationalen und internationalen Studien- und Leitlinienregistern und der Cochrane Library wurde die Immunologie der CRSwNP analysiert und die Evidenz zur Wirkung von Dupilumab, Omalizumab und Mepolizumab bei dieser Erkrankung ermittelt. Hieraus wurden drei Positionspapiere durch unsere Autorengruppe erstellt, die Grundlage dieser zusammenfassenden Übersichtsarbeit sind.
Ergebnisse: Basierend auf den Angaben aus der internationalen Literatur werden von einem Expertengremium Empfehlungen für die Anwendung von Dupilumab, Omalizumab und Mepolizumab bei CRSwNP im deutschen Gesundheitssystem gegeben.
Schlussfolgerung: Dupilumab, Omalizumab und Mepolizumab sind zugelassen für Patienten ab 18 Jahren mit schwerer CRSwNP als Zusatztherapie zu intranasalen Glukokortikosteroiden (INCS), wenn, bei Dupilumab und Mepolizumab, durch eine Therapie mit systemischen Glukokortikosteroiden und/oder chirurgischem Eingriff keine ausreichende Krankheitskontrolle erzielt werden kann. Eine Therapie mit Omalizumab ist angezeigt, wenn eine Therapie mit INCS keine suffiziente Kontrolle der Erkrankung ergibt. Es werden dezidierte Empfehlungen zur Dokumentation der Anwendung im Deutschen Gesundheitssystem gegeben, die auf den hierzu bereits publizierten Positionspapieren unserer Autorengruppe basieren.
Zitierweise: Klimek L, Förster-Ruhrmann U, Beule AG, Chaker AM, Hagemann J, Klimek F, Casper I, Huppertz T, Hoffmann TK, Dazert S, Deitmer T, Olze H, Strieth S, Wrede H, Schlenter W, Welkoborsky H-J, Wollenberg B, Bergmann C, Cuevas M, Beutner C, Gröger M, Becker S. Indicating biologics for chronic rhinosinusitis with nasal polyps (CRSwNP): Recommendations by German Allergy and ORL-societies AeDA and DGHNO for Dupilumab, Omalizumab and Mepolizumab. Allergo J Int 2022;31:149-60
https://doi.org/10.1007/s40629-022-00220-x
... Environmental exposures in utero or in early life that are associated with increased risk of developing asthma include tobacco smoke [15,16], vitamin D insufficiency [17], paracetamol [16,18,19], broad-spectrum antibiotics [16,20,21], allergens [22][23][24], obesity [16,25,26], air pollution [16,[27][28][29][30] and childhood respiratory infections [16,31]. Dietary factors [32][33][34], certain bacterial exposures [35][36][37], helminth infection [38] and microbiome diversity [39,40] may be protective. ...
Asthma is the most common non-communicable disease in children, and among the most common in adults. The great majority of people with asthma live in low- and middle-income countries (LMICs), where they suffer disproportionately high asthma-related morbidity and mortality. Essential inhaled medications, particularly those containing inhaled corticosteroids (ICS), are often unavailable or unaffordable, and this explains much of the global burden of preventable asthma morbidity and mortality.
Guidelines developed for LMICs are generally based on the outdated assumption that patients with asthma symptoms <1–3 times/week do not need (or benefit from) ICS. Even when ICS is prescribed, many patients manage their asthma with oral or inhaled short-acting beta 2 agonist (SABA) alone, due to issues of availability and affordability. A single ICS-formoterol inhaler-based approach to asthma management for all severities of asthma, from mild to severe, starting at diagnosis, might overcome SABA overuse/over-reliance and reduce the burden of symptoms and severe exacerbations. However, ICS-formoterol inhalers are currently very poorly available or unaffordable in LMICs. There is a pressing need for pragmatic clinical trial evidence of the feasibility and cost-effectiveness of this and other strategies to improve asthma care in these countries.
The global health inequality in asthma care that deprives so many children, adolescents and adults of healthy lives and puts them at increased risk of death – despite the availability of highly effective therapeutic approaches – is unacceptable. A World Health Assembly Resolution on universal access to affordable effective asthma care is needed to focus attention and investment on addressing this need.
... Paracetamol is the preferred drug for pain in pregnant patients and those allergic to NSAIDs [29]; therefore, its usability as a premedication was also tested in the present study. The potential of paracetamol as a premedication before IANB has been tested mostly in combination with other NSAIDs such as ibuprofen, aceclofenac, and etodolac. ...
Background:
The efficacy of local anesthesia decreases in patients with symptomatic irreversible pulpitis. Therefore, it was proposed that the use of premedication with an anti-inflammatory drug might increase the success rate of pulpal anesthesia in mandibular posterior teeth with vital inflamed pulp.
Methods:
One hundred thirty-four patients who were actively experiencing pain willingly participated in this study. The Heft Parker (HP) visual analog scale (VAS) was used to record the initial pain intensity. Patients were randomly allocated to receive a placebo, 10 mg of ketorolac, and 650 mg of paracetamol. The standard inferior alveolar nerve block (IANB) was administered to all patients using 2% lidocaine with 1:200,000 adrenaline after one hour of medication. After 15 min, the patient was instructed to rate the discomfort during each step of the treatment procedure, such as access to remaining dentin, access to the pulp chamber, and during canal instrumentation on the HP VAS. IANB was considered successful if the patient reported no or mild pain during access preparation and instrumentation. Moderate or severe pain was classified as a failure of IANB and another method of anesthesia was used before continuing the treatment.
Results:
The rate of successful anesthesia in the placebo, paracetamol, and ketorolac groups was 29%, 33%, and 43%, respectively, and no statistically significant difference was found between the groups.
Conclusion:
Preoperative administration of paracetamol or ketorolac did not significantly affect the success rate of IANB in patients with irreversible pulpitis. No significant difference was observed between the paracetamol and ketorolac groups.
... Year Authors There was heterogeneity among the studies included in the reviews as well as methodological differences between the systematic reviews. For instance, Eyers et al. 12 utilized raw data, and the outcome variables were standardized, whereas Mahyar et al. 15 utilized adjusted ORs and did not standardize the outcomes. ...
Objective
To conduct an umbrella review collating the existing evidence to determine whether there is an association between exposure of Paracetamol in-utero or in infancy and the development of childhood Asthma.
Methods
In this review, systematic reviews with or without meta-analysis that reported the association between paracetamol and asthma in children were included. To identify relevant reviews, a search was performed in the electronic databases PubMed, the Cochrane Library, and Ovid MEDLINE. The protocol was registered in PROSPERO CRD42020156023. A separate search was conducted for primary studies from the last 5 years not yet included in systematic reviews reporting the association from January 2016 to March 2021.
Results
The electronic searches identified 1966 review titles. After the removal of 493 duplicates, 1475 titles and abstracts were screened against the eligibility criteria. Full-text screening yielded six systematic reviews to be included in this review. The search for primary studies in the last 5 years yielded 1214 hits, out of which 5 studies were found suitable for inclusion. Three of them, that were not included in the systematic reviews, and have been summarised in this paper. The odds ratios (ORs) for the outcome of asthma in offspring of mothers with prenatal paracetamol consumption in any trimester were 1.28 (1.13–1.39) and 1.21 (1.02–1.44). For first trimester exposures, they were 1.12 (0.99–1.27), 1.39 (1.01–1.91), and 1.21 (1.14–1.28), for the second or third trimester, they were 1.49 (1.37–1.63) and 1.13 (1.04–1.23). For the third trimester only, the figure was 1.17 (1.04–1.31). Of the six reviews included, 1 had a low risk of bias, 2 had an unclear risk while 3 had a high risk of bias assessed using the ROBIS tool. There was no significant increased risk of asthma with early infancy exposure. The inter-study heterogeneity varied from I² = 41% to I² = 76% across reviews. In the primary studies, the OR for prenatal exposure ranged from 1.12 (0.25–4.98) to 4.66 (1.92–11.3) and for infancy exposure was 1.56 (1.06–2.30). All three included primary studies were adjudged to be of high quality using the Newcastle Ottawa scale.
Conclusions
There is a modest association between paracetamol exposure in-utero and the future development of asthma. Exposure in infancy has a less consistant association. All the studies done thus far are observational in nature, with their inherent biases. Further research, preferably randomized controlled trials are recommended to answer this pertinent question.
... However, the safety of Ace has recently been questioned, since exposure during pregnancy has been associated with several dysfunctions in newborn children. 11,[25][26][27][28][29] Analgesic mechanisms of action are complex and multiple, and remain for the large part unclear. One way they work is by inhibiting the prostaglandin (PG) pathways, mainly prostaglandin synthases (PTGS), also known as cyclooxygenases. ...
Acetaminophen, aspirin, and ibuprofen are mild analgesics commonly used by pregnant women, the sole current recommendation being to avoid ibuprofen from the fifth month of gestation. The nephrotoxicity of these three analgesics is well documented in adults, as is their interference with prostaglandins biosynthesis. Here we investigated the effect of these analgesics on human first trimester kidneys ex vivo. We first evaluated prostaglandins biosynthesis functionality by performing a wide screening of prostaglandin expression patterns in first trimester human kidneys. We demonstrated that prostaglandins biosynthesis machinery is functional during early nephrogenesis. Human fetal kidney explants aged 7‐12 developmental weeks were exposed ex vivo to ibuprofen, aspirin or acetaminophen for 7 days, and analyzed by histology, immunohistochemistry, and flow cytometry. This study has revealed that these analgesics induced a spectrum of abnormalities within early developing structures, ranging from cell death to a decline in differentiating glomeruli density. These results warrant caution for the use of these medicines during the first trimester of pregnancy.
... This occurs besides its central nervous system related mechanisms, in a low prostaglandin, low inflammation setting. Due to maturational immunity (lymphocytes, T H1 vs. T H2 ), this may interfere with antigen tolerance development and may induce atopy [13,14]. The mechanism that links perinatal paracetamol exposure to male fertility is claimed to be related to reduced testosterone production [15,16]. ...
Introduction
Introduction: There are epidemiological – not necessary causal – observations that link perinatal paracetamol (acetaminophen) exposure to impaired neuro-cognition and behaviour, but animal models may assist to better understand the mechanisms.
Material and methods
To provide an overview on preclinical data and mechanisms explored, we conducted a structured literature search on animal models and neuro-cognition and behavioural outcome following perinatal paracetamol exposure.
Results
This search resulted in 20 papers [rat (n = 9), zebrafish larvae (n = 6), mice (n = 5)], published between 2009 and 2020. Eight discussed pregnancy/fetal paracetamol exposure, 6 juvenile, 6 studies combined pregnancy and juvenile exposure. Quality assessment (SYRCLE’s bias risk) showed a heterogeneous pattern with blinding issues. Most papers (n = 16) described paracetamol exposure without indication, except for an induced fever and repetitive needle pricking (rat), brain injury (mice), and a zebrafish nociception model. Reported outcomes related to biochemistry (mono-amines, amino acids, protein expression), anatomy (teratogen, morphology, nuclear size) or behaviour (spatial memory, motor, social behaviour and exploration, sexual behaviour). On mechanisms, the cumulative data support an interesting ‘cannabinoid’ hypothesis to link paracetamol to neuro-cognitive and behavioural outcome. Besides limited species diversity, there is relevant within-species paracetamol dosing variability (dose, duration) with undocumented exposure.
Conclusions
Models should further integrate clinical indications, as non-exposure is the obvious safest setting in the absence of an indication. Besides pain and fever and related to the cannabinoid hypothesis, this should include perinatal brain injury, as there is animal experimental evidence that cannabinoids are neuroprotective in newborn brain injury or asphyxia, further supported by evidence from non-perinatal models of paracetamol-related neuroprotective effects.
... Gebelikte sıklıkla parasetamol kullanımı, çocuklarda astım gelişimi ile ilişkisi belirlenmiştir. 35 Ancak AR ile ilişkisine dair bir bilgi yoktur. ...
Atopic dermatitis (AD) is a chronic skin disease caused by genetic and environmental factors. Often it begins in early childhood. It is located at the first step of the process we refer to as atopic march. This feature is a precursor of the development of other allergic diseases such as asthma and allergic rhinitis. Especially in patients with atopy of food and inhalant allergens, the occurrence of other atopic diseases is more common. Although the role of these sensitivities in AD is controversial, it has been determined that some patients may trigger eczematous skin lesions. In this report, the role of allergens in atopic dermatitis are reviewed in the light of current literature.
... Embora estudos clínicos mostrem a eficácia da TENS para o alívio da dor, não há consenso sobre quais condições médicas devem ser tratadas com a TENS e os parâmetros apropriados para o uso 18,24,25 . Entre as condições clínicas, a aplicação da TENS durante a gravidez para alívio da dor é muito importante, já que os fármacos prescritos, especialmente no primeiro trimestre, são restritos e devem ser tomados com cautela devido ao risco de gerar complicações no desenvolvimento fetal quando atravessam a barreira placentária [26][27][28][29] . O desenvolvimento fetal adequado depende de condições ideais para a manutenção de altos níveis de proliferação celular, crescimento e diferenciação que são característicos deste processo 30 . ...
BACKGROUND AND OBJECTIVES:
Transcutaneous electrical nerve stimulation (TENS) is considered a current that should not be applied in pregnant women to avoid adverse effects. This systematic review aimed to analyze the scientific evidence about the use of TENS during pregnancy.
CONTENTS:
This study was conducted on November 2019 by searching the electronic databases: Pubmed, Scielo, LILACS, Science Direct, Cochrane Library and PEDro. The following descriptors were used: "transcutaneous electric nerve stimulation" combined with "pregnancy". Only randomized clinical trials that investigated the use of TENS during pregnancy were selected. Methodological quality was assessed by using the Cochrane Collaboration Tool (RevMan 5.3 software). Studies were classified according to the risk of bias (low, high or unclear). From 691 eligible publications, only two randomized clinical trials were selected according to inclusion criteria. Low risk of bias was detected in most items in one study and high risk for performance, detection and reporting bias were evidenced in the other study. Other bias (TENS intensity control by patient) was considered unclear in both studies.
CONCLUSION:
There is not enough support that TENS neither reduces pain intensity nor causes adverse effects in pregnant patients.
... 592 Frequent use of paracetamol by pregnant women has been associated with asthma in their children. 593 There is no evidence that vaccinations increase the risk of a child developing asthma. ...
Longfunctieonderzoek gebeurt met behulp van een piekstroommeter of een spirometer. Een piekstroommeter is eenvoudiger te hanteren, maar levert veel minder informatie op. De klinische betekenis van de bevindingen wordt besproken.
... However, a previous prospective follow-up study of 1505 women-children pairs considering paracetamol use during first and third trimesters and the emergence of wheeze or asthma in the offspring until Year 6, did not find an increase (Kang et al., 2009). Subsequently, in a systematic review and meta-analysis, which also included the previous study, there was an overall significant association between paracetamol consumption during any trimester of pregnancy and childhood wheeze at the age of 2.5-7 years (Eyers et al., 2011). Other studies have similarly linked analgesics use during pregnancy with adverse effects on the respiratory system showing the emergence of wheeze at 1 and 5 years of age (Persky et al., 2008;Perzanowski et al., 2010). ...
Background:
Analgesia during pregnancy is often necessary. Due to their widespread availability, many mothers opt to use over-the-counter (OTC) analgesics. Those analgesic compounds and their metabolites can readily cross the placenta and reach the developing foetus. Evidence for safety or associations with adverse health outcomes is conflicting, limiting definitive decision-making for healthcare professionals.
Objective and rationale:
This review provides a detailed and objective overview of research in this field. We consider the global prevalence of OTC analgesia during pregnancy, explain the current mechanistic understanding of how analgesic compounds cross the placenta and reach the foetus, and review current research on exposure associations with offspring health outcomes.
Search methods:
A comprehensive English language literature search was conducted using PubMed and Scopus databases. Different combinations of key search terms were used including 'over-the-counter/non-prescription analgesics', 'pregnancy', 'self-medication', 'paracetamol', 'acetaminophen', 'diclofenac', 'aspirin', 'ibuprofen', 'in utero exposure', 'placenta drug transport', 'placental transporters', 'placenta drug metabolism' and 'offspring outcomes'.
Outcomes:
This article examines the evidence of foetal exposure to OTC analgesia, starting from different routes of exposure to evidence, or the lack thereof, linking maternal consumption to offspring ill health. There is a very high prevalence of maternal consumption of OTC analgesics globally, which is increasing sharply. The choice of analgesia selected by pregnant women differs across populations. Location was also observed to have an effect on prevalence of use, with more developed countries reporting the highest consumption rates. Some of the literature focuses on the association of in utero exposure at different pregnancy trimesters and the development of neurodevelopmental, cardiovascular, respiratory and reproductive defects. This is in contrast to other studies which report no associations.
Wider implications:
The high prevalence and the challenges of reporting exact consumption rates make OTC analgesia during pregnancy a pressing reproductive health issue globally. Even though some healthcare policy-making authorities have declared the consumption of some OTC analgesics for most stages of pregnancy to be safe, such decisions are often based on partial review of literature. Our comprehensive review of current evidence highlights that important knowledge gaps still exist. Those areas require further research in order to provide pregnant mothers with clear guidance with regard to OTC analgesic use during pregnancy.
... [175][176][177] In addition, it is claimed that use of paracetamol by the mother during pregnancy is associated with an increased risk of childhood asthma. 178 In rodents, developmental exposure to paracetamol has been shown to be associated with impaired spatial learning, decreased habituation to a novel home cage, altered spontaneous behaviour, reduced anxiolytic and analgesic response to paracetamol, and effects on various neurotransmitters. [179][180][181][182] This neurotoxicity in young children has been shown to be caused by the metabolite AM404 which, as described above, stimulates the endocannabinoid system. ...
Paracetamol (acetaminophen) is the most commonly used over‐the‐counter (OTC) drug in the world. Despite its popularity and use for many years, the safety of its application and its mechanism of action are still unclear.Currently, it is believed that paracetamol is a multidirectional drug and at least several metabolic pathways are involved in its analgesic and antipyretic action. The mechanism of paracetamol action consists in inhibition of cyclooxygenases (COX‐1, COX‐2, and COX‐3) and involvement in the endocannabinoid system and serotonergic pathways. Additionally, paracetamol influences transient receptor potential (TRP) channels and voltage‐gated Kv7 potassium channels and inhibits T‐type Cav3.2 calcium channels. It also exerts an impact on L‐arginine in the nitric oxide (NO) synthesis pathway. However, notall of theseeffects have been clearlyconfirmed. Therefore, the aim of our paper was to summarizethe current state of knowledge of the mechanism of paracetamol action with special attention toitssafety concerns.
... The presence of paracetamol and arsenic in wastewater causing kidney cancer, liver damage asthma and hypertoxicity (Choueiri et al., 2014;Eyers et al., 2011). Both paracetamol and arsenic have been simultaneously adsorbed by a graphene based layered double hydroxide viz. ...
Functional properties of two-dimensional (2D) nano-hybrid materials have received much attention in advanced research and technology due to exponential need of green energy, clean water and pollution free environment. Nowadays, it is a demanding apprehension to develop advanced stratigies for the synthesis of nano-hybrid multifunctional materials such as graphene oxide supported layered double hydroxides (GO/LDHs) by employing different chemical routes with extraordinary properties that can lead to novel technologies for identifying and addressing the current global environmental challenges. Starting with paradigm graphene doped with other 2D materials including layered metal hydroxides (LMHs), mixed metal oxides (MMOs), metal nitrides (MXenes) and metal carbides have gradually emerged as potential hybrid nanomaterials for the removal of environmental pollutants. The current review highlights the ongoing advances of hybrid LDHs-supported nanomaterials in various fields. Association of LDHs with carbon-based nanomaterials (graphene/graphene oxide, carbon quantum dots, carbon nanotubes/nanofibers) exposed that these nanocomposite materials have outstanding environmental applications owing to their distinctive combination of architectural properties, exfoliation, and nanoarchitectural topological transformation features. GO/LDHs have many potential applications in wastewater treatment, adsorption and separation of toxic gases from environment, environmental sensors and catalysts. Sooner, the LDHs-supported nanomaterials are anticipated to open an innovative eco-friendly way for their possible applicability in environmental systems.
... Some studies have concluded there may be an association between maternal use of paracetamol in pregnancy and three types of adverse health outcomes in children: (1) respiratory health; (2) neurobehavioral development; and (3) birth defects in male genitalia. First, some studies have suggested an association between prenatal exposure to paracetamol and respiratory health issues such as asthma and wheezing (Eyers et al., 2011;Persky et al., 2008), although the associations were weak (Shaheen et al., 2002), and may be confounded by early life respiratory tract infections and confounding by indication (Sordillo et al., 2015). ...
... Gene polymorphisms, which impair anti-oxidant activity, predispose to wheeze in the presence of early life environmental tobacco smoke (ETS) and other pollutant exposures, as well as airway infections, but are not necessarily associated with allergy [9]. Epidemiological studies have suggested that both maternal pregnancy and infant paracetamol exposure increase the risk of asthma [10,11]. A paracetamol metabolite, n-acetylbenzoquinonimine, depletes anti-oxidant activity, and one intriguing study suggests that there is an interaction, increasing the risk of wheeze at 5 years of age, between the number of days that pregnant women take this analgesic and a polymorphism in the Glutathione S-Transferase P-1 anti-oxidant gene [12]. ...
While allergy, asthma and rhinitis do not inevitably co-exist, there are strong associations. Not all those with asthma are allergic, rhinitis may exist without asthma, and allergy commonly exists in the absence of asthma and/or rhinitis. This is likely due to the separate gene/environment interactions which influence susceptibility to allergic sensitization and allergic airway diseases. Allergic sensitization, particularly to foods, and eczema commonly manifest early in infancy, and not infrequently are followed by the development of allergic rhinitis and ultimately asthma. This has become known as the “allergic march”. However, many infants with eczema never develop asthma or rhinitis, and both the latter conditions can evolve without prior eczema or food allergy. Understanding the mechanisms underlying the ontogeny of allergic sensitization and allergic disease will facilitate rational approaches to the prevention and management of asthma and allergic rhinitis. Furthermore, a range of new, so-called biological, therapeutic approaches, targeting specific allergy-promoting and pro-inflammatory molecules, are now in clinical trials or have been recently approved for use by regulatory authorities and could have a major impact on disease prevention and control in the future. Understanding basic mechanisms will be essential to the employment of such medications. This review will explain the concept of the united airway (rhinitis/asthma) and associations with allergy. It will incorporate understanding of the role of genes and environment in relation to the distinct but interacting origins of allergy and rhinitis/asthma. Understanding the patho-physiological differences and varying therapeutic requirements in patients with asthma, with or without rhinitis, and with or without associated allergy, will aid the planning of a personalized evidence-based management strategy.
... Acetaminophen use during pregnancy or childhood has been considered to be associated with an increased risk of asthma; however, it may be confounded with respiratory infection. [19][20][21][22][23] In addition to its association with asthma development, acetaminophen use is related to decreased lung function and higher unscheduled visits for asthma than ibuprofen use for febrile illnesses in children. 9,24 Several biological mechanisms underlying acetaminophen-induced asthma development and acute attack have been proposed. ...
Objective
Antipyretics are frequently used in pediatric practice. Both acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to increase the risk of asthma exacerbation. The study investigated antipyretic use during respiratory infection in children and analyzed the risk of acetaminophen and NSAID for severe asthma exacerbation (AE) in asthmatic children in Taiwan.
Methods
We used the data from the National Health Insurance Research Database in 2005. There were 27,095 pediatric asthmatic patients having at least one respiratory infection episode, and 27,095 age- and sex-matched non-asthmatic children with respiratory infection served as controls. These patients were divided into groups with acetaminophen use, NSAID cyclooxygenase-1 (COX-1) use, and no antipyretic use. The rate of AE occurrence within the first 7 days after respiratory infection diagnosis was compared among the groups.
Results
During a single episode of respiratory infection, asthmatic patients used fewer antipyretics than controls (48.51% vs. 55.50%, p < 0.001). No difference was observed in the risk of AE occurrence within 7 days after respiratory infection between antipyretic users and antipyretic nonusers (22/13,144 [0.167%] vs. 12/13,951 [0.086%], p = 0.058). Compared with asthmatic children using acetaminophen, those using no antipyretic and COX-1 have lower risks for AE (OR: 0.26, 95% CI: 0.12–0.54, p < 0.001; and OR: 0.14, 95% CI: 0.03–0.61, p = 0.009).
Conclusion
In asthmatic children, the rate of AE after a single respiratory infection episode was around 0.144%. The risk of AE was higher in those who took acetaminophen.
... The second tool was a clinical outcomes data collection sheet which was developed to follow the clinical outcomes (Systolic and diastolic blood pressure, and pulse) of participants. The sheet was All the educational materials were adapted from evidence-based resources (Eyers, Weatherall, Jefferies, & Beasley, 2011;Kozer et al., 2003;NHS, 2009;Oladejo & Bewley, 2013;Poehling et al., 2011;Scialli, 2006;Zaman et al., 2008) then were translated to Malay language using simple, short, and positive sentences. ...
... Other systematic reviews and meta-analyses also have supported the possibility of risk of childhood asthma associated with prenatal APAP exposure. [54][55][56] Incidentally, the risk of asthma development related to prenatal exposure of APAP would not be easily detected by spontaneous reports system of adverse reaction such as JADER. So, what is the possible pharmacological and toxicological mechanism of APAP-induced respiratory disease? ...
Acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) is the most popular analgesic/antipyretic agent in the world. APAP has been regarded as a safer drug compared with non-steroidal anti-inflammatory drugs (NSAIDs) particularly in terms of lower risks of renal dysfunction, gastrointestinal injury, and asthma/bronchospasm induction, even in high-risk patients such as the elderly, children, and pregnant women. On the other hand, the recent increasing use of APAP has raised concerns about its toxicity. In this article, we review recent pharmacological and toxicological findings about APAP from basic, clinical, and epidemiological studies, including spontaneous drug adverse events reporting system, especially focusing on drug-induced asthma and pre-and post-natal closure of ductus arteriosus. Hepatotoxicity is the greatest fault of APAP and the most frequent cause of drug-induced acute liver failure in Western countries. However, its precise mechanism remains unclear and no effective cure beyond N-acetylcysteine has been developed. Recent animal and cellular studies have demonstrated that some cellular events, such as c-jun N-terminal kinase (JNK) pathway activation, endoplasmic reticulum (ER) stress, and mitochondrial oxidative stress may play important roles in the development of hepatitis. Herein, the molecular mechanisms of APAP hepatotoxicity are summarized. We also discuss the not-so-familiar “dark side” of APAP as an otherwise safe analgesic/antipyretic drug.
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... For example, acetaminophen is a first-line analgesic for pregnant women as it does not produce classic teratogenic effects. However, recent studies have associated perinatal acetaminophen exposure with an increased risk for attention-deficit/hyperkinetic, respiratory, autism spectrum, and testicular disorders in children [8][9][10][11][12][13][14][15][16][17]. Opioids are another example as 14-22% of women fill an opioid prescription during pregnancy [18,19] despite potential adverse neonatal outcomes [20][21][22][23][24]. ...
Pregnant women with chronic pain present a unique clinical challenge for both chronic pain and obstetrical providers, and clinical guidelines do not exist. The present study describes the prevalence and management of chronic pain during pregnancy in a perinatal mood disorder clinic. A retrospective chart review of pregnant women who presented to the Women’s Mental Health Program at the University of Arkansas for Medical Sciences (UAMS) for an initial evaluation from July 2013 to June 2016 was conducted to obtain demographic and medical information, including pharmacological exposures. Data are described using the mean and standard deviation for continuous data and frequency for categorical data. Pain complaints and medications are presented as counts and percentages. Differences between women with and without chronic pain were assessed by t -tests for continuous variables and chi-square analysis for categorical variables. Of the 156 pregnant women, chronic pain conditions were reported by 44 (28.2%). The most common chronic pain complaints included neck and/or back pain (34.1%) and headaches (31.8%). Of subjects with chronic pain, 95.5% were taking at least one prescription medication (mean = 2.6 ± 2.1, range of 0–10). Acetaminophen (43.2%) and opioids (43.2%) were the most common. The complexity of managing maternal benefits of treatment with the risks of fetal exposures presents a uniquely challenging clinical scenario for healthcare providers.
... On the one hand, Cheelo et al. [57] evaluated 11 observational cohort studies and concluded that there was insufficient evidence to warrant changing guidelines on early life paracetamol exposure. On the other, another meta-analysis of six studies by Eyers et al. [58] concluded that the use of paracetamol during all trimesters of pregnancy was indeed associated with an increased risk of childhood asthma (OR 1.21 (95% CI 1.02-1.44) ...
There is growing evidence that events occurring early in life, both before and after birth, are significantly associated with the risk of asthma, chronic obstructive pulmonary disease, and diminished lung function later in life. In fact, from conception to death, a series of continuous, dynamic gene-environment interactions determine 2 fundamental biological processes, namely, lung development and lung aging. Over 130 birth cohorts have been initiated in the last 30 years. Data from these cohorts have improved our understanding of the inception, progression, and persistency of asthma. In this review, we summarize the main data for the early life events proven to determine later development and persistence of asthma, such as maternal atopy and smoking, preterm birth/bronchopulmonary dysplasia, infections, nutrition, obesity, smoking, and other environmental exposures in childhood and adolescence. While some of these factors are obviously impossible to prevent or eliminate, others have been proven to have a protective role, and current research is aimed optimizing them. Available prophylactic measures are also reviewed. In the case of environmental pollution, large scale political interventions successfully managed to decrease contamination levels, leading to improved lung function and lower asthma prevalence in the respective geographical areas. Future research should focus on better understanding these complex interactions in order to develop and enhance effective preventive therapeutic measures.
... For instance, prenatal and infant exposures to acetaminophen are associated with asthma development in childhood independent of factors that are indicative for acetaminophen use (e.g., pain, fever, and respiratory tract infections/influenza) [13]. The causal inference is further strengthened by results of meta-analyses [14][15][16][17] and by the observation of effect modification, in which maternal antioxidant gene polymorphisms modified the association between maternal use of acetaminophen during pregnancy and child risk of asthma [18]. The epidemiologically-observed association between acetaminophen use and asthma is biologically plausible and explained by the ability of acetaminophen to deplete glutathione, a key airway antioxidant [19]. ...
Abstract Background Epidemiologic studies have demonstrated associations between acetaminophen use and asthma. This investigation sought to determine whether sex modifies the acetaminophen-asthma association and whether leptin (LEP) and leptin receptor (LEPR) gene polymorphisms modulate the sex-specific associations. Methods Data from the Isle of Wight birth cohort (IOW; n = 1456, aged 18 years) and Kuwait University Allergy (KUA; n = 1154, aged 18–26 years) studies were analyzed. Acetaminophen use and current asthma were self-reported. Genotype information for eighteen polymorphisms in LEP and LEPR genes were available in the IOW study. Associations between acetaminophen use and asthma were stratified by sex and genotype. Poisson regression models with robust variance estimation were evaluated to estimate adjusted prevalence ratios (aPR) and 95% confidence intervals (CI). Results Acetaminophen use was dose-dependently associated with an increased prevalence of current asthma in the IOW and KUA studies. In both studies, sex-stratified analysis showed that acetaminophen use was associated with asthma among males, but not in females (P interaction
... [10,11] Epidemiological evidence is also mixed but slightly favors NSAIDs over acetaminophen. [12][13][14][15] Potential harms from NSAIDs and acetaminophen include increased viral shedding because of the drugs' immunomodulating effect. [7,16,17] An RCT to compare acetaminophen and ibuprofen in the treatment of bronchiolitis will face three empiric problems. ...
Background
Bronchiolitis sometimes triggers the development of subsequent recurrent wheezing. Treatment with either acetaminophen or ibuprofen during the initial episode may affect the occurrence of subsequent wheezing.
Materials and methods
We did a retrospective study comparing the effect of prescribing acetaminophen, ibuprofen, or neither for a first episode of bronchiolitis on medical attendances for subsequent wheezing in infants younger than 12 months. We created our cohorts using California Medicaid data from 2003 to 2010. We used propensity score derived inverse probability weights to adjust for non-random drug assignment. We used robust negative binomial regression to model incident rate ratios (IRR) for medical attendances at 365, 30, and 14-day follow-up. We did similar analyses for the effect of antipyretics for a first medically attended upper respiratory tract infection (URI) on subsequent wheezing.
Results
Compared with no antipyretic, treatment with acetaminophen or ibuprofen for a first episode of bronchiolitis was associated with decreased wheezing at 365-day follow-up (IRR 0.18, 95% CI 0.15–0.22), and ibuprofen plus acetaminophen over ibuprofen (IRR at 0.12, 95% CI 0.05–0.32). The results were similar at 30 and 14-day follow-up. Ibuprofen alone and ibuprofen plus acetaminophen were associated with decreased visits for subsequent wheezing at 365-day (IRR 0.79, 95% CI 0.68–0.92), but not earlier timepoints, when compared with acetaminophen. A smaller effect was seen for ibuprofen at one year if prescribed for a URI (IRR 0.87, 95% CI 0.76–1.00) but not at earlier follow-up.
Conclusion
Children who are prescribed antipyretics for a first episode of bronchiolitis may have less subsequent wheezing than those who are not. We found fewer visits for subsequent wheezing for those prescribed ibuprofen, and ibuprofen combined with acetaminophen, compared with acetaminophen alone.
... 4 There are few studies of antibiotics and type 1 diabetes, and they have not simultaneously considered infections as potential confounders. Use of acetaminophen during pregnancy has been linked to offspring asthma, 5,6 but to our knowledge, use during pregnancy and offspring risk of type 1 diabetes have not previously been studied. It is also conceivable that acetaminophen use during febrile infections may influence immunity and possibly immune-mediated diseases in childhood. ...
Background:
Infections in early life have been linked to type 1 diabetes (T1D) risk, but no previous study has comprehensively analysed exposure to antibiotics, acetaminophen and infections during pregnancy and early childhood in relation to offspring risk of T1D.
Methods:
Participants in the Norwegian Mother and Child Cohort Study (n = 114 215 children, of whom 403 children were diagnosed with T1D) reported infections and medication use through repeated questionnaires from pregnancy until the children were 18 months old. Adjusted hazard ratios (aHR) for offspring T1D were estimated through Cox regression adjusted for child's sex, maternal age and parity, maternal T1D, smoking in pregnancy, education level, pre-pregnancy body mass index (BMI) and birthweight. Antibiotic use was also analysed in a population-based register cohort of 541 036 children of whom 836 developed T1D.
Results:
Hospitalization for gastroenteritis during the first 18 months of life was associated with increased risk (aHR 2.27, 95% CI 1.21 - 4.29, P = 0.01) of T1D. Childhood infections not requiring hospitalization, or any kind of maternal infection during pregnancy, did not predict offspring risk of T1D. Antibiotic or acetaminophen use in pregnancy, or child`s use in early childhood, was not associated with risk of T1D.
Conclusions:
Our study, which is population-based and the largest of its kind, did not find support for general early life infections, infection frequency or use of antibiotics or acetaminophen to play a major role in childhood T1D. Hospital admission for gastroenteritis was associated with T1D risk, but must be interpreted cautiously due to scarcity of cases.
... 526 Frequent use of paracetamol by pregnant women has been associated with asthma in their children. 527 There is no evidence that vaccinations increase the risk of a child developing asthma. ...
Objectives:
Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is recognized increasingly as a distinct clinical entity and is associated with higher comorbidities compared with patients with asthma and COPD alone. Little is known about the leading causes of death related to ACO in the US general population, however. Our aim was to define the causes of mortality among patients with ACO compared with asthma and COPD in the US population.
Methods:
We examined questions using the National Health and Nutrition Examination Survey III database linked to the National Death Index. The data from 4434 participants were stratified into 4 groups, those with asthma, COPD, ACO, and those without any obstructive lung disease. We examined baseline demographics and used multivariate logistic regression to model the impact of demographics, smoking, and self-reported, physician-diagnosed lung disease on mortality generating odds ratios (ORs) and confidence intervals (CIs).
Results:
Among 4434 participants, 120 (2.7%), 340 (7.6%), and 126 (2.8%) participants self-reported diagnoses of asthma, COPD, and ACO syndrome, respectively. Patients with COPD were older (69.7 ± 10.9 years) than other groups. Cardiovascular disease, malignancy, and chronic lower respiratory disease were frequent causes of death. The mortality rates for cardiovascular disease and malignancy were not significantly different among respiratory disease categories. Deaths resulting from chronic respiratory disease were higher in the ACO group (OR 4.9, 95% CI 2.5-9.4) and the COPD group (OR 2.9, 95% CI 1.5-5.4) when compared with those without obstructive lung disease (P < 0.0001).
Conclusions:
Although cardiovascular- and malignancy-related deaths are common, a higher proportion of mortality in ACO and COPD is attributed to chronic lung disease.
... This may be due to a misconception that medications, such as paracetamol, are safe to use during pregnancy. However recent research suggests that there may be links with paracetamol usage during pregnancy and the development of behavioural disorders, such as attention deficit hyperactivity disorder (ADHD), hyper kinetic disorder (HKD) and asthma in children [41,42]. ...
Low back and pelvic girdle pain (LBPGP) is a common complaint among pregnant women, which increases throughout pregnancy and women use various complementary and alternative medicine (CAM) therapies to manage their pain. Using an online survey, CAM treatments used by pregnant women in the UK and their perceptions of these therapies to relieve LBPGP were investigated. 191 women completed the survey and 70% experienced LBPGP lasting more than one week. Over half of women who sought treatment from a GP or physiotherapist were dissatisfied. 25% of participants used CAM during pregnancy, the most popular being aromatherapy (21%), acupuncture (21%), and reflexology (15%). 81% of women used CAM to manage their LBPGP and 85% found it useful for pregnancy symptoms. Women experience high levels of pain during pregnancy with limited treatment options. Research into effective CAM treatments for LBPGP is required to allow women to make informed decisions regarding treatment options.
... It provides similar analgesia as NSAIDS without the anti-prostaglandin or platelet effects. There has been an association with asthma, wheezing and elevated IgE with frequent paracetamol use from 20 -32 weeks in a subgroup of school aged children[7] [8]. Use of paracetamol may be a marker for infectious or inflammatory disorders, the results of the epidemiology studies may be influenced by confounding by indication, and evidence is inconclusive. ...
... Several studies implied a long term effect for the children faced with Paracetamol in utero. Consequences such as an increased asthma risk, or Attention Deficit Hyperactivity Disorder were discussed (Liew et al., 2014;Eyers et al., 2011). Although strong interdependencies were shown, the actual literature lacks a prominent immunological explanation for the effects observed. ...
Background:
Paracetamol is the first choice for antipyretic or analgesic treatment throughout pregnancy. Products with Paracetamol are readily available over the counter and therefore easily accessible for self-medication. Epidemiological data on Paracetamol intake pattern during pregnancy and its potential immunological effects are sparse. We aimed to analyze a possible association between Paracetamol medication and numbers of hematopoietic stem cells (HSC) in cord blood.
Methods:
The objective was addressed in the PRINCE (PRENATAL DETERMINANTS OF CHILDREN'S HEALTH) study, a population-based prospective pregnancy cohort study initiated in 2011 at the University Medical Center in Hamburg, Germany. 518 healthy pregnant women with singleton pregnancies were recruited during the first trimester. Three examinations were scheduled at the end of the 1st (gestational week 12-14), the 2nd (gestational week 22-24) and the 3rd trimester (gestational week 34-36). For 146 of these women, cord blood flow cytometry data were available. Paracetamol intake was assessed for each trimester of pregnancy.
Findings:
Among the 518 enrolled women, 40% took Paracetamol as main analgesic treatment during pregnancy. The intake frequency and dosage of Paracetamol varied between the women and was overall low with a tendency towards higher frequencies and higher dosages in the third trimester. Paracetamol intake, particularly during the third trimester, resulted in decreased relative numbers of HSCs in cord blood, independent of maternal age, first-trimester BMI, parity, gestational age and birth weight (-0.286 (95% CI -0.592, 0.021), p=0.068).
Interpretation:
Prenatal Paracetamol intake, especially during the third trimester, may be causally involved in decreasing HSCs in cord blood.
... The selection of target nitrate-processing, proteotypic peptides was based on our metagenome database and the UniProt database, where most conserved peptide sequences among denitrification enzyme proteins were selected. ESP predictor (Fusaro et al., 2009) and CON-SeQuence software (Eyers et al., 2011) were also used to evaluate the suitability of these peptides for LC-SRM analysis. Three to six peptides for each functional gene were initially selected for peptide synthesis. ...
Microbial enzymes catalytically drive biogeochemical processes in environments. The dynamic linkage between functional enzymes and biogeochemical species transformation has, however, rarely been investigated for decades because of the challenges to directly quantify enzymes in environmental samples. The diversity of microorganisms, the low amount of available biomass, and the complexity of chemical composition in environmental samples represent the main challenges. To address the diversity challenge, we first identify several signature peptides that are conserved in the targeted enzymes with the same functionality across many phylogenetically diverse microorganisms using metagenome-based protein sequence data. Quantification of the signature peptides then allows estimation of the targeted enzyme abundance. To achieve analyses of the requisite sensitivity for complex environmental samples with low available biomass, we adapted a recently developed ultrasensitive targeted quantification technology, termed high-pressure high-resolution separations with intelligent selection and multiplexing (PRISM) by improving peptide separation efficiency and method detection sensitivity. Nitrate reduction dynamics catalyzed by dissimilatory and assimilatory enzymes in a hyporheic zone sediment was used as an example to demonstrate the application of the enzyme quantification approach. Together with the measurements of biogeochemical species, the approach enables investigating the dynamic linkage between functional enzymes and biogeochemical processes. This article is protected by copyright. All rights reserved.
Il paracetamolo è uno dei farmaci analgesici e antipiretici più popolari e più comunemente usati in tutto il mondo. È commercializzato senza richiesta di prescrizione medica, sia come unica molecola, sia in associazione con altre molecole nella stessa specialità commerciale. È il farmaco di scelta nei malati che non possono essere trattati con farmaci antinfiammatori non steroidei (FANS), come le persone con asma bronchiale, ulcera peptica, emofilia, persone sensibili ai salicilati, bambini sotto i 7 anni di età, donne in gravidanza o che allattano. Il paracetamolo è anche consigliato come trattamento di prima linea per molte condizioni dolorose. Il suo meccanismo d'azione è complesso e include gli effetti dei processi di analgesia sia periferica (inibizione della cicloossigenasi: COX), sia centrale (con la mediazione di varie azioni). Il paracetamolo è un farmaco abbastanza ben tollerato (a basse dosi) e produce pochi effetti indesiderati (a livello del tratto gastrointestinale), tuttavia, nonostante ciò, in tutto il mondo ogni anno viene registrato un numero costantemente crescente di casi di intossicazione epatica. Questo lavoro vuole ricordare che il paracetamolo non è una panacea priva di reazioni avverse. Anzi, soprattutto quando viene assunto regolarmente e in dosi elevate (> 4 g/giorno nell'adulto), esiste il rischio di gravi effetti indesiderati che in alcuni casi possono anche portare a morte o aggravare danni epatici preesistenti o condizioni di stress ossidativo che a loro volta possono aprire la porta a innumerevoli patologie.
Aims
Paracetamol is commonly consumed by pregnant women, even though recent data have questioned its safety. Having chronic medical diseases (CMDs) may influence the prevalence of use during pregnancy. We aimed to assess the prevalence and patterns of use 3 months prior to pregnancy and in the first trimester among women with and without CMDs and the potential influence of CMDs on frequent use in the first trimester.
Methods
We used patient‐reported data from the Copenhagen Pregnancy Cohort from 1 October 2013 to 23 May 2019 with information on CMDs and paracetamol use. Prevalence and patterns of use were assessed descriptively and by multivariable logistic regression models.
Results
We included 24 019 pregnancies. Use of paracetamol prior to and in early pregnancy was significantly higher among women with CMDs compared to women without (40.7% vs. 35.8% and 9.1% vs. 5.1%, respectively). Women with CMDs were 2.7 times more likely to have a frequent intake compared to women without [aOR 2.69 (95% CI 2.05–3.32)]. Migraine, rheumatoid arthritis and mental disease were associated with a higher use of paracetamol [aOR 4.39 (3.20–6.02), aOR 4.32 (2.41–7.72) and aOR 2.74 (1.67–4.49), respectively].
Conclusions
Women with CMDs had a higher paracetamol use before and during pregnancy than women without CMDs. Women with migraine, rheumatoid arthritis and mental disease showed the highest risk of frequent use. This study highlights the importance of discussing pain relief in pregnancy and evaluating the influence of maternal CMDs when assessing adverse effects of paracetamol use during pregnancy.
For a long time it was assumed that the risk for diseases such as coronary heart disease (CHD) or insulin resistance, for example, develops from the genetic potential of the parents and is amplified by environmental influences such as an unfavorable lifestyle. This view has been completely overturned in the last two decades by the concept of fetal programming. The concept implies that a stimulus or insult during a sensitive period of fetal development produces permanent changes in structure, physiology, and metabolism, determining later risk for chronic diseases such as CHD and insulin resistance, as well as allergies, an impaired stress response, and many others in adulthood. The concept of Fetal Origins of Adult Disease (FOAD) was introduced by the British epidemiologist David Barker more than 20 years ago and has been the subject of intensive research ever since. The current research approaches aim to identify the biological mechanisms by which a prenatal stimulus or insult alters fetal development, the time lag between prenatal stimulus/insult and later disease, and the multiple factors that contribute to disease risk throughout the lifespan.
Purpose of Review
Acetaminophen (or paracetamol) is one of the most commonly used medications during pregnancy. We reviewed recent epidemiological evidence regarding intrauterine exposure to acetaminophen and risk for asthma, neurodevelopment disorders, and reproductive health in childhood.
Recent Findings
An increasing number of cohort studies have suggested that maternal use of acetaminophen during pregnancy was associated with increased risk for asthma; neurodevelopmental disorders, especially ADHD and behavioral problems; and genital malformations in the offspring. Oxidative stress and inflammation or endocrine effects are plausible shared biological mechanisms for the exposure to influence multiple developmental outcomes. We discussed methodological challenges that can threaten the validity of these observational data, including confounding and measurement errors. Novel statistical methods and research designs that can be used to mitigate these issues were introduced.
Summary
Given the high prevalence of use, findings regarding intrauterine exposure to acetaminophen on multiple child health outcomes raise concerns. Research on causal and non-causal mechanisms that might explain these associations should be a priority.
Long standing concerns regarding the use of medications during pregnancy and their unknown effects on fetal development and child health suggests the need for modified study methods regarding the establishment of drug safety for the fetus. This Current Commentary highlights several pharmacological study method limitations and offers suggestions for the establishment of drug safety for the fetus. For example, extensive phase 1 pharmacology studies are needed to assess the complex pharmacokinetic relationships between mother and fetus in order to determine injurious doses to the fetus throughout pregnancy. In addition, long term randomized clinical trials are needed to assess the effects medications may have on children following exposure during gestation.
Odontogenic pain affects up to 54.9% of pregnant women (1, 2, 3). This pain is often associated with pulpal and/or periapical infections which pose risks to women and their fetus. The American Dental Association in collaboration with the American College of Obstetricians and Gynecologists developed a consensus statement to affirm the importance of timely and appropriate oral health care as a critical component of a healthy pregnancy (NMCOHRC, 2012) (4). However, limited knowledge of endodontic procedure safety and related medication use often results in avoidance of treatment during pregnancy. This paper, a collaborative effort by specialists from Endodontics, Pediatric Dentistry and Obstetrics, reviews the current evidence on the safety of medications commonly used in endodontics including local anesthetics, analgesics, anxiolytics, and antibiotics.
Introdução: Os primeiros 1000 dias de vida de uma criança, período desde a concepção até o final dosegundo ano, são considerados críticos para o desenvolvimento dos sistemas respiratório e imunológico. Muitos fatores ocorridos nesse período podem estar associados ao risco de asma na infância. Objetivo: Condensar evidências sobre fatores de risco e proteção para asma infantil e/ ou sibilância ocorridos nos primeiros 1000 dias de vida. Método: Foram revisadas as bases de dados MEDLINE, CINAHL e SCOPUS. Foram incluídas revisões sistemáticas com meta-análise, ou meta-análise de estudos observacionais e de intervenção sobre fatores de risco ou proteção para asma infantil/sibilância, enfatizando os primeiros 1000 dias de vida. A qualidade dos estudos foi avaliada pela ferramenta Assess Systematic Reviews. Odds ratio, intervalos de confiança e homogeneidade entre os estudos foram analisados. Resultados: Trinta e cinco estudos preencheram os critérios de inclusão, com boa qualidade metodológica. Foram identificados como fatores de risco para asma e/ou sibilância na infância: história parental de asma, ganho de peso materno durante a gestação, infecções urogenitais, estresse psicológico, tabagismo, parto cesárea, prematuridade, peso ao nascer e hiperbilirrubinemia neonatal. A ingestão de óleo de peixe, zinco e vitamina E durante a gestação aparecem como fatores de proteção, bem como amamentação, ingestão de peixe nos dois primeiros anos e vacinação BCG. Conclusão: Diversos comportamentos ou exposições modificáveis podem estar associados à asma e sibilância na infância. O conhecimento sobre estes comportamentos e exposições pode melhorar as estratégias de prevenção precoce, visando garantir um impacto benéfico na saúde respiratória.
Eine Maschinenbedienerin in einer Bürstenfabrik erschien zu einer gutachterlichen Untersuchung aufgrund des Verdachtes auf eine berufsbedingte obstruktive Atemwegserkrankung. Sie berichtete über das Auftreten starker Atemnot, immer dann, wenn Kollegen im gleichen Arbeitsbereich Tampicofasern beziehungsweise eine Mischung aus Tampicofasern und Bassine verarbeiteten. Die Herausforderung im Rahmen der Begutachtung bestand nun darin, bei der angegebenen arbeitsplatzbezogenen Beschwerdesymptomatik eine berufsbedingte Kausalität und eine IgE-vermittelte Sensibilisierung nachzuweisen oder auszuschließen. Zur weiteren diagnostischen Abklärung wurden vom Arbeitsplatz stammende Tampicofasern extrahiert, die Proteine biotinyliert und für die spezifische IgE-Testung an Streptavidin-ImmunoCAP gekoppelt. Das Material vom Arbeitsplatz wurde hinsichtlich Kontamination mit Milbenallergenen überprüft. Weiterhin wurde eine systematische Literaturrecherche in Pubmed zu „Agave-/Tampicofasern und Erkrankungen“ durchgeführt. Im Patientenserum konnten Tampico-spezifische IgE-Antikörper (10,5 kU/L und im Immunoblot Markierung von Proteinbanden im Bereich 25 kDa) nachgewiesen werden. Der Inhibitionsassay zeigte, dass die Kontamination des Tampicomaterials mit Milbenallergenen nicht für die IgE-Reaktivität ursächlich war. Tampicofasern sind robuste Fasern, die aus den Blättern der mexikanischen Agave lechugilla gewonnen werden. In der Literatur wurden mehrfach Hautreaktionen in Form einer irritativen Kontaktdermatitis beschrieben, aufgrund beruflicher Exposition gegenüber Agavenblättern beziehungsweise durch Kontakt mit Agavensaft. Im vorliegenden Fall wurden die asthmatischen Beschwerden einer Beschäftigten in einer Bürstenfabrik auf eine inhalative Bystander-Exposition mit Tampicofaserstaub am Arbeitsplatz zurückgeführt. Der eindeutige Sensibilisierungsnachweis gegen Tampicofasern lieferte die medizinischen Voraussetzungen für die Anerkennung einer Berufskrankheit (BK 4301).
Background::
Acetaminophen is a widely used medication for fever and pain management during pregnancy. However, recent studies have found a possible connection between maternal prenatal acetaminophen use and attention deficit/hyperactivity disorder in children.
Objective::
We aimed to explore the association between maternal acetaminophen use during pregnancy and the risk of attention deficit/hyperactivity disorder in offspring.
Data sources::
PubMed, Embase, Web of Science and Cochrane Library were searched from their initial publications through November 2018 for studies.
Study selection::
We included all studies that examined the association between maternal acetaminophen use during pregnancy and the risk of attention deficit/hyperactivity disorder in offspring if the authors reported odds ratios, risk ratios, hazard ratios, regression coefficient, standard error and 95% confidence intervals.
Data extraction and synthesis::
Two reviewers independently extracted data on the definition of exposure and outcome, exposed, non-exposed and total number of participants in the sample population, adjusted potential confounders and outcome parameters. Study quality was also assessed.
Results::
Eight cohort studies with a total of 244,940 participants were included. Maternal exposure to acetaminophen during pregnancy increased the risk of attention deficit/hyperactivity disorder in offspring with a pooled adjusted risk ratio of 1.25 (95% confidence interval = [1.17, 1.34]). Children exposed prenatally to acetaminophen in the third trimester seemed to have the greatest risk of developing attention deficit/hyperactivity disorder (risk ratio: 1.26; 95% confidence interval = [1.08, 1.47]). In addition, a longer duration of maternal acetaminophen use during pregnancy was correlated with a higher risk ratio. Children whose mothers used acetaminophen for 28 or more days during gestation had a higher risk of developing attention deficit/hyperactivity disorder (risk ratio: 1.63; 95% confidence interval = [1.23, 2.16]).
Conclusion::
There is an association between maternal acetaminophen use during pregnancy and the risk of attention deficit/hyperactivity disorder in offspring. The timing and duration of acetaminophen use during pregnancy may have a major effect on the risk of attention deficit/hyperactivity disorder.
Lange Zeit wurde angenommen, dass sich das Risiko für Erkrankungen wie beispielsweise koronare Herzerkrankung (KHK) oder Insulinresistenz aus dem genetischen Potential der Eltern entwickelt und durch Umwelteinflüsse wie ein ungünstiger Lebensstil verstärkt wird. Diese Auffassung wurde in den letzten zwei Jahrzehnten durch das Konzept der fetalen Programmierung komplett überworfen. Das Konzept beinhaltet, dass ein Stimulus oder Insult während einer sensiblen Phase der fetalen Entwicklung bleibende Veränderungen der Struktur, Physiologie und des Metabolismus hervorruft und damit das spätere Risiko für chronische Erkrankungen wie KHK und Insulinresistenz, aber auch für Allergien, eine gestörte Stressantwort u. v. m. im Erwachsenenalter bestimmt. Das Konzept der Fetal Origins of Adult Disease (FOAD) wurde vor über 20 Jahren von dem britischen Epidemiologen David Barker vorgestellt und seitdem intensiv beforscht. Die Forschungsansätze zielen darauf ab, die biologischen Mechanismen zu erkennen, über die ein pränataler Stimulus oder Insult die fetale Entwicklung verändert, die Zeitspanne zwischen vorgeburtlichem Stimulus/Insult und späterer Krankheit zu erfassen und die zahlreichen Faktoren zu identifizieren, die ein Erkrankungsrisiko während der gesamten Lebensspanne mitbeeinflussen
Zusammenfassung
Die vorliegende Leitlinie ist eine Neufassung und Aktualisierung der Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma, welche die bisher für den deutschen Sprachraum gültige Version aus dem Jahr 2006 ablöst. Die Fülle an neuen Erkenntnissen zur Pathophysiologie und zu den Phänotypen von Asthma und das erweiterte Spektrum an diagnostischen und therapeutischen Möglichkeiten bei dieser Erkrankung machte eine Neufassung und Aktualisierung notwendig. Es werden sowohl für Kinder und Jugendliche als auch für Erwachsene mit Asthma die aktuellen, Evidenz-basierten diagnostischen und therapeutischen Empfehlungen dargelegt.
Acetaminophen is thought to be the safest analgesic and antipyretic medicine for pregnant women, and it is widely used all over the world. However, prenatal acetaminophen was reported to be associated with asthma, lower performance intelligence quotient (IQ), shorter male infant anogenital distance (predicting poor male reproductive potential), autism spectrum disorder, neurodevelopmental problems (gross motor development, communication), attention-deficit/hyperactivity disorder, poorer attention and executive function, and behavioral problems in childhood. Each article has poor power to show risks of acetaminophen, however, the integration of the articles that showed adverse effects of acetaminophen may have power to show them. Acetaminophen use in childhood was associated with autism spectrum disorder, asthma symptoms, wheezing, and allergic disease. Acetaminophen is the safest medicine as analgesics for nociceptive pain and antipyretics in childhood and pregnancy. There is no alternative medication of acetaminophen. Acetaminophen should not be withheld from children or pregnant women for fears it might develop adverse effects. Acetaminophen should be used at the lowest effective dosage and for the shortest time. When we know the possible, rare but serious complications, we should use acetaminophen in pregnancy only when needed and no safer option for pain or fever relief is available. Health care providers should help inform the general lay public about this difficult dilemma.
Background:
The treatment of pregnant women who have illnesses unrelated to pregnancy can cause uncertainty among physicians.
Methods:
We searched the PubMed database and specialty guidelines from Germany and abroad (the guidelines of the German Society for Gynecology and Obstetrics, the American Congress of Obstetri cians and Gynecologists, and the Royal College of Obstetricians and Gynaecologists) over the period 2007-2016 for information on standards for the diagnosis and treatment of five illnesses that can arise in pregnancy: bronchial asthma, migraine, hypothyroidism, hyperthyroidism, and varicose veins.
Results:
Any diagnostic tests that are carried out in pregnant women should be simple and goal-directed. The choice of drugs that can be used is limited. For many drugs, no embryotoxic or teratogenic effect is suspected, but the level of evidence is low.
Conclusion:
When illnesses unrelated to pregnancy arise in pregnant women, attention must be paid to potential diver gences from the typical disease course and to pos sible drug side effects on the fetus in order to prevent serious complications for both mother and child.
This chapter will cover adjuvant, non-opioid medications used for pain management in the rehabilitation patient. This chapter is exclusive of opioids and psychiatric drugs usedfor pain, which are described in subsequent chapters. Adjuvant medications are non-opioid drugs used for pain, which can be incorporated as part of a multimodal, multidisciplinary pain management program.
David Moher and colleagues introduce PRISMA, an update of the QUOROM guidelines for reporting systematic reviews and meta-analyses
There is epidemiological evidence that the use of acetaminophen may increase the risk of developing asthma.
To investigate the risk of asthma and other allergic disorders associated with the current use of acetaminophen in 13- to 14-year-old children in different populations worldwide.
As part of the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three, 13- to 14-year-old children completed written and video questionnaires obtaining data on current symptoms of asthma, rhinoconjunctivitis, and eczema, and a written environmental questionnaire obtaining data on putative risk factors, including acetaminophen use in the past 12 months.
The primary outcome measure was the odds ratio (OR) of current asthma symptoms associated with acetaminophen use calculated by logistic regression. A total of 322,959 adolescent children from 113 centers in 50 countries participated. In the multivariate analyses the recent use of acetaminophen was associated with an exposure-dependent increased risk of current asthma symptoms (OR, 1.43 [95% confidence interval, 1.33-1.53] and 2.51 [95% confidence interval, 2.33-2.70] for medium and high versus no use, respectively). Acetaminophen use was also associated with an exposure-dependent increased risk of current symptoms of rhinoconjunctivitis and eczema.
Acetaminophen use may represent an important risk factor for the development and/or maintenance of asthma, rhinoconjunctivitis, and eczema in adolescent children.
David Moher and colleagues introduce PRISMA, an update of the QUOROM guidelines for reporting systematic reviews and meta-analyses
To estimate whether prenatal exposure to acetaminophen is associated with risk of diagnosed asthma and asthma symptoms in children.
The authors prospectively followed 1,505 pregnant women and their children until 6 years (+/-3 months) of life. Acetaminophen use in the first and third trimesters of pregnancy was assessed before 24 weeks of gestation and within 1 month of delivery, and asthma in children was assessed when the child was 6 years old. Adjusted odds ratios (aORs) were derived from logistic regression models controlling for potential confounders.
Acetaminophen was used by 69% of women during pregnancy. Use of acetaminophen did not significantly increase the risk of asthma (aOR 0.76, 95% confidence interval [CI] 0.53-1.10). Acetaminophen use during both the first and the third trimester was associated with a significantly reduced risk of asthma (aOR 0.59, 95% CI 0.36-0.98). There was no evidence of a dose response, and consumption greater than 10,400 mg (32 tablets) a month did not increase risk (aOR 0.99, 95% CI 0.19-5.30).
Our results suggest that acetaminophen use during pregnancy does not increase risk of asthma in children.
II.
Acetaminophen has been associated with asthma and is in part metabolised via the glutathione pathway. Inner-city minority children have high asthma morbidity and a relatively high frequency of a minor allele variant in the glutathione S transferase Pi gene (GSTP1). We hypothesised that prenatal acetaminophen exposure would predict wheeze at age 5 years in an inner-city minority cohort and examined whether this association was modified by common polymorphisms in genes related to the glutathione pathway.
An ongoing population-based birth cohort study of Dominican Republic and African-American children in New York prospectively assessed the use of analgesics during pregnancy and current wheeze at age 5 years in 301 children. Genotyping was conducted for GST polymorphisms. Binomial regression was used to adjust for potential confounders including postnatal acetaminophen use.
34% of mothers reported acetaminophen use during pregnancy and 27% of children had current wheeze at 5 years. Prenatal exposure to acetaminophen predicted current wheeze (multivariate relative risk 1.71; 95% CI 1.20 to 2.42; p=0.003), and the risk increased monotonically with increasing number of days of prenatal acetaminophen exposure (p trend <0.001). 68% of children had at least one copy of the GSTP1 minor allele (Val). The risk of wheeze was modified by GSTP1 (additive interaction p=0.009) and was observed only among children with the GSTP1 minor allele.
Prenatal exposure to acetaminophen predicted wheeze at age 5 years in an inner-city minority cohort. The risk was modified by a functional polymorphism in GSTP1, suggesting a mechanism involving the glutathione pathway.
There seems to be an association between paracetamol consumption during late pregnancy and the prevalence of wheezing in infancy and childhood. The aim of the present study is to determine whether the aforementioned association is modified by the presence of asthma in the mother.
A total of 1,741 children aged 3-5 years from an epidemiological survey performed in the province of Murcia (Spain) were included in the analysis. Data on paracetamol consumption (never, at least once during pregnancy or at least once per month during pregnancy), wheezing symptoms in the offspring (according to the International Study of Asthma and Allergies in Childhood protocol) and the presence of asthma in the mother, together with other known risk factors for asthma, were obtained by means of a questionnaire.
The mean age of the children was 4.08 +/- 0.8 years and 51.1% were males. The overall prevalence of current wheezing was 20.2%. The frequency of paracetamol usage was similar among asthmatic and non-asthmatic mothers, and only a small proportion of them took this drug at least once a month (13.8% of asthmatics and 11.0% of non-asthmatics). Compared to the mothers who never took paracetamol, there was a significant association between the mother having taken paracetamol at least once per month during pregnancy and the offspring suffering from wheezing at preschool age, but only among non-asthmatic mothers (odds ratio 1.94, 95% confidence interval 1.34-2.79 vs. odds ratio 1.05, 95% confidence interval 0.21-5.08). This association was maintained after controlling for potential confounders (odds ratio 1.74, 95% confidence interval 1.15-2.61).
The frequent usage of paracetamol during pregnancy is associated with the prevalence of wheezing in offspring during preschool years. Asthma in the mother might modify this association.
We recently reported links between frequent paracetamol (acetaminophen) use and wheezing and asthma in adults and children, but data are lacking on possible effects of prenatal exposure on wheezing in early childhood.
In the population based Avon Longitudinal Study of Parents and Children (ALSPAC) women were asked twice during pregnancy (at 18-20 weeks and 32 weeks) about their usage of paracetamol and aspirin. Six months after birth, and at yearly intervals thereafter, mothers were asked about wheezing and eczema symptoms in their child. The effects of paracetamol and aspirin use in pregnancy on the risk in the offspring of wheezing at 30-42 months (n=9,400) and eczema at 18-30 months (n=10,216) and on their risk of different wheezing patterns (defined by presence or absence of wheezing at <6 months and at 30-42 months) were examined.
Paracetamol was taken frequently (most days/daily) by only 1% of women. After controlling for potential confounders, frequent paracetamol use in late pregnancy (20-32 weeks), but not in early pregnancy (<18-20 weeks), was associated with an increased risk of wheezing in the offspring at 30-42 months (adjusted odds ratio (OR) compared with no use 2.10 (95% CI 1.30 to 3.41); p=0.003), particularly if wheezing started before 6 months (OR 2.34 (95% CI 1.24 to 4.40); p=0.008). Assuming a causal relation, only about 1% of wheezing at 30-42 months was attributable to this exposure. Frequent paracetamol use in pregnancy was not associated with an increased risk of eczema. Frequent aspirin use in pregnancy was associated with an increased risk of wheezing only at <6 months.
Frequent use of paracetamol in late pregnancy may increase the risk of wheezing in the offspring, although such an effect could explain only about 1% of the population prevalence of wheezing in early childhood.
Acetaminophen decreases glutathione levels in the lung, which may predispose to oxidative injury and bronchospasm. Acetaminophen use has been associated with asthma in cross-sectional studies and a birth cohort. We hypothesized that acetaminophen use would be associated with newly diagnosed adult-onset asthma in the Nurses' Health Study, a prospective cohort study of 121,700 women. Participants were first asked about frequency of acetaminophen use in 1990. Cases with asthma were defined as those with a new physician diagnosis of asthma between 1990 and 1996 plus reiteration of the diagnosis and controller medication use. Proportional hazard models included age, race, socioeconomic status, body mass index, smoking, other analgesic use, and postmenopausal hormone use. During 352,719 person-years of follow-up, 346 participants reported a new physician diagnosis of asthma meeting diagnostic criteria. Increasing frequency of acetaminophen use was positively associated with newly diagnosed asthma (p for trend = 0.006). The multivariate rate ratio for asthma for participants who received acetaminophen for more than 14 days per month was 1.63 (95% confidence interval, 1.11-2.39) compared with nonusers. It would be premature to recommend acetaminophen avoidance for patients with asthma, but further research on pulmonary responses to acetaminophen is necessary to confirm or refute these findings and to identify subgroups whose asthma may be modified by acetaminophen.
Oxidative stress may increase the risk of asthma, contribute to asthma progression, and decrease lung function. Previous research suggests that use of acetaminophen, which is hypothesized to reduce antioxidant capacity in the lung, is associated with an increased risk of asthma. We hypothesized that acetaminophen use may also be associated with chronic obstructive pulmonary disease (COPD) and decreased lung function.
To investigate the associations between use of pain medication, particularly acetaminophen, and asthma, COPD, and FEV1 in adults.
A cross-sectional analysis using the Third National Health and Nutrition Examination Survey.
Increased use of acetaminophen had a positive, dose-dependent association with COPD (adjusted odds ratio for increasing category of intake, 1.16; 95% confidence interval [CI], 1.09-1.24; p value for trend < 0.001) and an inverse association with lung function (daily user compared with never users, -54.0 ml; 95% CI, -90.3 to -17.7, adjusted). Neither of these associations was explained by overlap between COPD and asthma occurrence. We confirmed a dose-response association of acetaminophen use and asthma (adjusted odds ratio, 1.20; 95% CI, 1.12-1.28; p value for trend < 0.001).
This study provides further evidence that use of acetaminophen is associated with an increased risk of asthma and COPD, and with decreased lung function.
Studies from the UK and USA suggest that frequent use of paracetamol (acetaminophen) may increase the risk of asthma, but data across Europe are lacking.
As part of a multicentric case-control study organised by the Global Allergy and Asthma European Network (GA(2)LEN), it was examined whether or not frequent paracetamol use is associated with adult asthma across Europe. The network compared 521 cases with a diagnosis of asthma and reporting of asthma symptoms within the last 12 months with 507 controls with no diagnosis of asthma and no asthmatic symptoms within the last 12 months across 12 European centres. All cases and controls were selected from the same population, defined by age (2045 yrs) and place of residence.
In a random effects meta-analysis, weekly use of paracetamol, compared with less frequent use, was strongly positively associated with asthma after controlling for confounders. There was no evidence for heterogeneity across centres. No association was seen between use of other analgesics and asthma.
These data add to the increasing and consistent epidemiological evidence implicating frequent paracetamol use in asthma in diverse populations.
Background
We recently reported links between frequent paracetamol (acetaminophen) use and wheezing and asthma in adults and children, but data are lacking on possible effects of prenatal exposure on wheezing in early childhood.
Methods
In the population based Avon Longitudinal Study of Parents and Children (ALSPAC) women were asked twice during pregnancy (at 18–20 weeks and 32 weeks) about their usage of paracetamol and aspirin. Six months after birth, and at yearly intervals thereafter, mothers were asked about wheezing and eczema symptoms in their child. The effects of paracetamol and aspirin use in pregnancy on the risk in the offspring of wheezing at 30–42 months (n=9400) and eczema at 18–30 months (n=10 216) and on their risk of different wheezing patterns (defined by presence or absence of wheezing at <6 months and at 30–42 months) were examined.
Results
Paracetamol was taken frequently (most days/daily) by only 1% of women. After controlling for potential confounders, frequent paracetamol use in late pregnancy (20–32 weeks), but not in early pregnancy (<18–20 weeks), was associated with an increased risk of wheezing in the offspring at 30–42 months (adjusted odds ratio (OR) compared with no use 2.10 (95% CI 1.30 to 3.41); p=0.003), particularly if wheezing started before 6 months (OR 2.34 (95% CI 1.24 to 4.40); p=0.008). Assuming a causal relation, only about 1% of wheezing at 30–42 months was attributable to this exposure. Frequent paracetamol use in pregnancy was not associated with an increased risk of eczema. Frequent aspirin use in pregnancy was associated with an increased risk of wheezing only at <6 months.
Conclusions
Frequent use of paracetamol in late pregnancy may increase the risk of wheezing in the offspring, although such an effect could explain only about 1% of the population prevalence of wheezing in early childhood.
BACKGROUND The pulmonary antioxidant glutathione may limit airway inflammation in asthma. Since paracetamol (acetaminophen) depletes the lung of glutathione in animals, a study was undertaken to investigate whether frequent use in humans was associated with asthma. METHODS Information was collected on the use of analgesics as part of a population based case-control study of dietary antioxidants and asthma in adults aged 16–49 years registered with 40 general practices in Greenwich, South London. The frequency of use of paracetamol and aspirin was compared in 664 individuals with asthma and in 910 without asthma. Asthma was defined by positive responses to questions about asthma attacks, asthma medication, or waking at night with shortness of breath. The association between analgesic use and severity of disease amongst asthma cases, as measured by a quality of life score, was also examined. RESULTS Paracetamol use was positively associated with asthma. After controlling for potential confounding factors the odds ratio for asthma, compared with never users, was 1.06 (95% CI 0.77 to 1.45) in infrequent users (<monthly), 1.22 (0.87 to 1.72) in monthly users, 1.79 (1.21 to 2.65) in weekly users, and 2.38 (1.22 to 4.64) in daily users (p (trend) = 0.0002). This association was present in users and non-users of aspirin and was stronger when cases with more severe disease were compared with controls; amongst cases increasing paracetamol use was associated with more severe disease. Frequency of aspirin use was not associated with asthma when cases as a whole were compared with controls, nor with severity of asthma amongst cases. Frequent paracetamol use was positively associated with rhinitis, but aspirin use was not. CONCLUSIONS Frequent use of paracetamol may contribute to asthma morbidity and rhinitis in adults.
Paracetamol use represents a putative risk factor for the development of asthma. There is convincing epidemiological evidence that the risk of asthma may be increased with exposure to paracetamol in the intrauterine environment, infancy, later childhood and adult life. A dose-dependent association has also been observed in these different age groups in different populations world-wide. An association has also been shown between paracetamol use in both rhinoconjunctivitis and eczema. There is biological plausibility with paracetamol use leading to decreased glutathione levels resulting in increased oxidant-induced inflammation and potentially enhanced T-helper type 2 responses. At the population level, patterns of paracetamol use might explain, to some extent, the world-wide variation in the prevalence of asthma and related disorders, particularly the high rates in English-speaking countries, which have high per capita prescription and over-the-counter use of paracetamol. A temporal association also exists between the international trends of increasing paracetamol use and increasing prevalence of asthma over recent decades. Further research is urgently required, in particular randomized-controlled trials (RCTs) into the long-term effects of frequent paracetamol use in childhood, to determine the magnitude and characteristics of any such risk. Importantly, RCTs will also enable evidence-based guidelines for the recommended use of paracetamol to be developed.
Cite this as: H. Farquhar, A. Stewart, E. Mitchell, J. Crane, S. Eyers, M. Weatherall and R. Beasley, Clinical & Experimental Allergy, 2010 (40) 32–41.
The article by Perzanowski et al in this issue of Thorax ( see page 118 ) adds one more piece of evidence supporting a possible role for acetaminophen in the development of asthma in children.1 Five previous studies, including three prenatal prospective cohorts,2–5 have suggested that in utero ingestion of acetaminophen may increase the risk of asthma and respiratory symptoms in children.2–7 Increased risk of asthma from postnatal use of acetaminophen is also suggested by reports of children8–12 and adults.8 13–17 The possibility that acetaminophen may contribute to the development of asthma is supported by parallel time trends in dramatic increases in use of the medication in response to reports of associations of aspirin use with Reye syndrome18–20 and increases in asthma prevalence between the mid 1970s and mid 1990s.21
There is also biological plausibility. Acetaminophen,22–24 as well as one of its metabolites, the highly reactive N -acetyl- p -benzoquinoneimine,23 has been associated with decreased glutathione. There is substantial literature documenting the antioxidant capacity of glutathione25 as well as the role of reactive oxygen species in asthma morbidity.26 In addition, decreased glutathione may affect the development of asthma by altering antigen recognition towards favouring T helper 2 (Th2) over Th1 cytokines.23 27 Other, less likely, possibilities relate to decreased suppression of cyclo-oxygenase or direct antigenicity of acetaminophen.23
The study by Perzanowski et al notes that associations of prenatal acetaminophen use …
As summarized in Table I,2-15,19,22,25-31,34-39 there is evidence to suggest that acetaminophen use might be an important risk factor for the development of asthma and might have contributed to the increasing prevalence of asthma and allergic disorders over recent decades. Although further epidemiologic and laboratory-based studies will undoubtedly be informative, the priority is to undertake randomized controlled trials to explore the association of acetaminophen with both the development and maintenance of asthma. Indeed, it is a concern that no randomized controlled trials have been undertaken of the long-term use of acetaminophen and the development of asthma and its severity. We propose that there is a case to answer and that such randomized controlled trials should now be a high priority for the research community. Only then will it be possible to determine the role of acetaminophen in the pathogenesis of asthma and related disorders and for evidence-based guidelines for the recommended use of acetaminophen to be made.
Epidemiologic studies have identified an increased risk of asthma with acetaminophen use, but the results have been conflicting. We sought to quantify the association between acetaminophen use and the risk of asthma in children and adults.
We searched all the major medical databases, including MEDLINE (from 1966 to 2008) and EMBASE (from 1980 to 2008) to identify pertinent articles. All clinical trials and observational studies were considered. For observational studies, we selected those that clearly defined acetaminophen use and asthma diagnosis. Study quality was assessed by two reviewers, and data were extracted into a spreadsheet. A random-effects model was used to combine studies with asthma and wheezing among both children and adults.
Thirteen cross-sectional studies, four cohort studies, and two case-control studies comprising 425,140 subjects were included in the review. The pooled odds ratio (OR) for asthma among subjects using acetaminophen was 1.63 (95% CI, 1.46 to 1.77). The risk of asthma in children among users of acetaminophen in the year prior to asthma diagnosis and within the first year of life was elevated (OR: 1.60 [95% CI, 1.48 to 1.74] and 1.47 [95% CI, 1.36 to 1.56], respectively). Only one study reported the association between high acetaminophen dose and asthma in children (OR, 3.23; 95% CI, 2.9 to 3.6). There was an increase in the risk of asthma and wheezing with prenatal use of acetaminophen (OR: 1.28 [95% CI, 1.16 to 41] and 1.50 [95% CI, 1.10 to 2.05], respectively).
The results of our review are consistent with an increase in the risk of asthma and wheezing in both children and adults exposed to acetaminophen. Future studies are needed to confirm these results.
Neonatal lung function is suspected to be associated with wheezy disorders, but little is known about risk factors for the early lung function.
To study prenatal determinants of neonatal lung function.
This is a clinical, prospective birth cohort study of 411 newborns, the Copenhagen Prospective Study on Asthma in Childhood, in a single-center research clinic dedicated solely to this longitudinal birth cohort study. Lung function was determined at 1 month of age by infant spirometry (the raised volume rapid thoraco-abdominal compression technique) and bronchial responsiveness to methacholine by transcutaneous oxygen measurements. Risk factor analyses included anthropometrics; demographics; socioeconomic factors; parental atopic history; previous deliveries; exposures during the third trimester to the mother's smoking, alcohol, and medicines; third trimester pregnancy complications including mother's asthma status; and mode of delivery.
Lung function was determined in 404 neonates, age 6 weeks. Neonates with body mass index in the upper quartile had 14% lower baseline forced expiratory volume at 0.5 second, and neonates of mothers smoking during the third trimester had 7% lower baseline forced expiratory volume at 0.5 second. Sex or parental atopic disease did not affect the neonatal lung function and bronchial responsiveness. Maternal intake of paracetamol during the third trimester was associated with doubling of the bronchial responsiveness in the neonates, but the statistical significance may have been driven by outliers. Bronchial responsiveness exhibited a parabola development with tripling of bronchial responsiveness reaching the nadir at 3 months of age, but this needs replication in a study with repetitive measurements within individuals.
High body mass index in newborns and mothers smoking is associated with reduced neonatal lung function. This suggests that the association between body proportion and wheezing disorders may be a result of shared genes or prenatal nutrition.
Intake of paracetamol has been associated with development of asthma. The aim of this study was to address a possible association between intake of paracetamol and risk of adult-onset asthma. Using a multidisciplinary postal questionnaire survey concerning health and lifestyle we prospectively studied 19,349 adult twins enrolled in the nationwide Danish Twin Registry. There was a higher prevalence of new-onset asthma in subjects who reported frequent intake of paracetamol at baseline compared with subjects without this determinant (12.0% vs. 4.3%), OR = 3.03 (1.51-6.11), p = 0.005. The result remained significant after adjusting for sex, age, smoking, BMI, hay fever, eczema, and intake of medications other than paracetamol, OR = 2.16 (1.03-4.53), p = 0.041. Frequent intake of paracetamol is an independent risk factor for adult-onset asthma.
Prevalence of asthma in developed countries increased between the 1970s and the 1990s. One factor that might contribute to the trends in asthma is the increased use of acetaminophen vs aspirin in children and pregnant women.
To examine relationships between in utero exposure to acetaminophen and incidence of respiratory symptoms in the first year of life.
A total of 345 women were recruited in the first trimester of pregnancy and followed up with their children through the first year of life. Use of acetaminophen in pregnancy was determined by questionnaire and related to incidence of respiratory symptoms.
Use of acetaminophen in middle to late but not early pregnancy was significantly related to wheezing (odd ratio, 1.8; 95% confidence interval, 1.1-3.0) and to wheezing that disturbed sleep (odds ratio, 2.1; 95% confidence interval, 1.1-3.8) in the first year of life after control for potential confounders.
This study suggests that use of acetaminophen in middle to late but not early pregnancy may be related to respiratory symptoms in the first year of life. Additional follow-up will examine relationships of maternal and early childhood use of acetaminophen with incidence of asthma at ages 3 to 5 years, when asthma diagnosis is more firmly established.
Exposure to paracetamol during intrauterine life, childhood, and adult life may increase the risk of developing asthma. We studied 6-7-year-old children from Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC) programme to investigate the association between paracetamol consumption and asthma.
As part of Phase Three of ISAAC, parents or guardians of children aged 6-7 years completed written questionnaires about symptoms of asthma, rhinoconjunctivitis, and eczema, and several risk factors, including the use of paracetamol for fever in the child's first year of life and the frequency of paracetamol use in the past 12 months. The primary outcome variable was the odds ratio (OR) of asthma symptoms in these children associated with the use of paracetamol for fever in the first year of life, as calculated by logistic regression.
205 487 children aged 6-7 years from 73 centres in 31 countries were included in the analysis. In the multivariate analyses, use of paracetamol for fever in the first year of life was associated with an increased risk of asthma symptoms when aged 6-7 years (OR 1.46 [95% CI 1.36-1.56]). Current use of paracetamol was associated with a dose-dependent increased risk of asthma symptoms (1.61 [1.46-1.77] and 3.23 [2.91-3.60] for medium and high use vs no use, respectively). Use of paracetamol was similarly associated with the risk of severe asthma symptoms, with population-attributable risks between 22% and 38%. Paracetamol use, both in the first year of life and in children aged 6-7 years, was also associated with an increased risk of symptoms of rhinoconjunctivitis and eczema.
Use of paracetamol in the first year of life and in later childhood, is associated with risk of asthma, rhinoconjunctivitis, and eczema at age 6 to 7 years. We suggest that exposure to paracetamol might be a risk factor for the development of asthma in childhood.
Many young children wheeze during viral respiratory infections, but the pathogenesis of these episodes and their relation to the development of asthma later in life are not well understood.
In a prospective study, we investigated the factors affecting wheezing before the age of three years and their relation to wheezing at six years of age. Of 1246 newborns in the Tucson, Arizona, area enrolled between May 1980 and October 1984, follow-up data at both three and six years of age was available for 826. For these children, assessments in infancy included measurement of cord-serum IgE levels (measured in 750 children), pulmonary-function testing before any lower respiratory illness had occurred (125), measurement of serum IgE levels at nine months of age (672), and questionnaires completed by the children's parents when the children were one year old (800). Assessments at six years of age included measurement of serum IgE levels (in 460), pulmonary-function testing (526), and skin allergy testing (629).
At the age of six years, 425 children (51.5 percent) had never wheezed, 164 (19.9 percent) had had at least one lower respiratory illness with wheezing during the first three years of life but had no wheezing at six years of age, 124 (15.0 percent) had no wheezing before the age of three years but had wheezing at the age of six years, and 113 (13.7 percent) had wheezing both before three years of age and at six years of age. The children who had wheezing before three years of age but not at the age of six had diminished airway function (length-adjusted maximal expiratory flow at functional residual capacity [Vmax FRC]) both before the age of one year and at the age of six years, were more likely than the other children to have mothers who smoked but not mothers with asthma, and did not have elevated serum IgE levels or skin-test reactivity. Children who started wheezing in early life and continued to wheeze at the age of six were more likely than the children who never wheezed to have mothers with a history of asthma (P < 0.001), to have elevated serum IgE levels (P < 0.01), to have normal lung function in the first year of life, and to have elevated serum IgE levels (P < 0.001) and diminished values for VmaxFRC (P < 0.01) at six years of age.
The majority of infants with wheezing have transient conditions associated with diminished airway function at birth and do not have increased risks of asthma or allergies later in life. In a substantial minority of infants, however, wheezing episodes are probably related to a predisposition to asthma.
The relation between lower respiratory tract illnesses in early life caused by the respiratory syncytial virus (RSV) and the subsequent development of wheezing and atopy in childhood is not well understood. We studied this relation in children who had lower respiratory tract illnesses that occurred before 3 years of age.
Children were enrolled at birth and cases of lower respiratory tract illness were ascertained by a physician. Viral tests were done for specimens collected at the time of the illness. Children were classified into five groups according to type and cause of lower respiratory tract illness. Children were then followed prospectively up to age 13, and we measured frequency of wheezing, pulmonary function, and atopic status (allergy skin-prick tests, serum IgE concentrations).
RSV lower respiratory tract illnesses were associated with an increased risk of infrequent wheeze (odds ratio 3.2 [95% CI 2.0-5.0], p < 0.001), and an increased risk of frequent wheeze (4.3 [2.2-8.7], p < or = 0.001) by age 6. Risk decreased markedly with age and was not significant by age 13. There was no association between RSV lower respiratory tract illnesses and subsequent atopic status. RSV lower respiratory tract illnesses were associated with significantly lower measurements of forced expiratory volume (2.11 [2.05-2.15], p < or = 0.001) when compared with those of children with no lower respiratory tract illnesses, but there was no difference in forced expiratory volume after inhalation of salbutamol.
RSV lower respiratory tract illnesses in early childhood are an independent risk factor for the subsequent development of wheezing up to age 11 years but not at age 13. This association is not caused by an increased risk of allergic sensitisation.
Reports have suggested that certain infants are predisposed to wheezing in the first 2 yrs of life due to abnormal lung function, prior to the first wheezing illness. The authors investigated the association between infant lung function and wheeze during the first 2 yrs of life. A cohort of 253 infants was evaluated. Respiratory function assessment was performed at 1, 6, and 12 months of age. Parental history of asthma, atopy, and maternal antenatal smoking habits were recorded. An infant was identified as having wheezed on the basis of parental report and, where possible, physician diagnosis. One hundred and sixty infants (63%) had complete diary and questionnaire information on wheeze available for analysis. Of these: 79 infants (50%) had never wheezed (NW) during the first 2 yrs of life and 81 had reported wheeze (W) (50%). Of those with a report of wheeze, the distribution through the first 2 yrs of life was; 28 during the first year of life only (Y1), 21 in the second year of life only (Y2), and 32 wheezed in both the first and second years of life (Y1&2). At the age of 1 month, prior to any lower respiratory illness, the W group had impaired lung function in comparison to the NW group. In Y1 infants, the neonatal lung function differences resolved by 12 months of age. In Y2 and Y1&2 infants lung function differences persisted throughout the first year of life. Prevalence of parental asthma and maternal antenatal smoking was increased in the W group p=0.001, p=0.008, respectively), in comparison to the NW infants. Maternal antenatal smoking prevalence was increased in the Y2 and Y1&2 infants in comparison to the NW group (p=0.04), (p=0.01), respectively. Wheezing during the first year of life is often a transient condition which improves with time. It appears to be related to early life reduced small airway calibre. Wheezing that begins or persists into the second year of life is usually associated with a different abnormality of the airways. Commencement or persistence of wheeze into the second year of life may be part of the clinical entity recognized as asthma.
The pulmonary antioxidant glutathione may limit airway inflammation in asthma. Since paracetamol (acetaminophen) depletes the lung of glutathione in animals, a study was undertaken to investigate whether frequent use in humans was associated with asthma.
Information was collected on the use of analgesics as part of a population based case-control study of dietary antioxidants and asthma in adults aged 16-49 years registered with 40 general practices in Greenwich, South London. The frequency of use of paracetamol and aspirin was compared in 664 individuals with asthma and in 910 without asthma. Asthma was defined by positive responses to questions about asthma attacks, asthma medication, or waking at night with shortness of breath. The association between analgesic use and severity of disease amongst asthma cases, as measured by a quality of life score, was also examined.
Paracetamol use was positively associated with asthma. After controlling for potential confounding factors the odds ratio for asthma, compared with never users, was 1.06 (95% CI 0.77 to 1.45) in infrequent users (<monthly), 1.22 (0.87 to 1.72) in monthly users, 1. 79 (1.21 to 2.65) in weekly users, and 2.38 (1.22 to 4.64) in daily users (p (trend) = 0.0002). This association was present in users and non-users of aspirin and was stronger when cases with more severe disease were compared with controls; amongst cases increasing paracetamol use was associated with more severe disease. Frequency of aspirin use was not associated with asthma when cases as a whole were compared with controls, nor with severity of asthma amongst cases. Frequent paracetamol use was positively associated with rhinitis, but aspirin use was not.
Frequent use of paracetamol may contribute to asthma morbidity and rhinitis in adults.
We recently found that paracetamol (acetaminophen) use in late pregnancy was associated with an increased risk of early wheezing in the offspring.
To see whether use of paracetamol in late pregnancy is associated with an increased risk of asthma, wheezing and other atopic outcomes in the child at school age.
In the population-based Avon Longitudinal Study of Parents and Children, we measured associations of paracetamol and aspirin use in late pregnancy (20-32 weeks) with asthma, hayfever, eczema (n = 8511) and wheezing (8381) in the offspring at 69-81 months, and with atopy (positive skin prick test to Dermatophagoides pteronyssinus, cat or grass, n = 6527) and blood total IgE (n = 5148) at 7 years. We used logistic and linear regression to analyse binary outcomes and log-transformed IgE, respectively, controlling for potential confounders.
Use of paracetamol, but not aspirin, in late pregnancy was positively associated with asthma (odds ratios (ORs), comparing children whose mothers took paracetamol 'sometimes' and 'most days/daily' with those whose mothers never took it, 1.22 (95% confidence interval (CI): 1.06-1.41) and 1.62 (95% CI: 0.86-3.04), respectively; P trend = 0.0037), wheezing (ORs 1.20 (95% CI: 1.02-1.40) and 1.86 (95% CI: 0.98-3.55), respectively; P trend = 0.011), and total IgE (geometric mean ratios 1.14 (95% CI: 1.03-1.26) and 1.52 (95% CI: 0.98-2.38), respectively; P trend = 0.0034), but not hayfever, eczema or skin test positivity. The proportion of asthma attributable to paracetamol use in late pregnancy, assuming a causal relation, was 7%.
Paracetamol exposure in late gestation may cause asthma, wheezing and elevated IgE in children of school age.
The contribution of viral respiratory infections during infancy to the development of subsequent wheezing and/or allergic diseases in early childhood is not established.
To evaluate these relationships prospectively from birth to 3 years of age in 285 children genetically at high risk for developing allergic respiratory diseases.
By using nasal lavage, the relationship of timing, severity, and etiology of viral respiratory infections during infancy to wheezing in the 3rd year of life was evaluated. In addition, genetic and environmental factors that could modify risk of infections and wheezing prevalence were analyzed.
Risk factors for 3rd year wheezing were passive smoke exposure (odds ratio [OR]=2.1), older siblings (OR=2.5), allergic sensitization to foods at age 1 year (OR=2.0), any moderate to severe respiratory illness without wheezing during infancy (OR=3.6), and at least 1 wheezing illness with respiratory syncytial virus (RSV; OR=3.0), rhinovirus (OR=10) and/or non-rhinovirus/RSV pathogens (OR=3.9) during infancy. When viral etiology was considered, 1st-year wheezing illnesses caused by rhinovirus infection were the strongest predictor of subsequent 3rd year wheezing (OR=6.6; P < .0001). Moreover, 63% of infants who wheezed during rhinovirus seasons continued to wheeze in the 3rd year of life, compared with only 20% of all other infants (OR=6.6; P < .0001).
In this population of children at increased risk of developing allergies and asthma, the most significant risk factor for the development of preschool childhood wheezing is the occurrence of symptomatic rhinovirus illnesses during infancy that are clinically and prognostically informative based on their seasonal nature.
Studies in developed countries suggest that acetaminophen use is associated with increased risk of asthma, but it is unclear whether this association is causal.
To determine the relation among acetaminophen use, asthma, and allergy, and to explore potential biases in acetaminophen use, in a developing country population.
We surveyed 7649 adults and children from Butajira, Ethiopia, collecting data on self-reported symptoms of allergic disease, skin sensitization to Dermatophagoides pteronyssinus and cockroach, acetaminophen use, and potential confounders. We then collected detailed data on indications for acetaminophen use and reasons for aspirin avoidance in a nested follow-up study.
Allergic symptoms increased significantly with frequency of acetaminophen use, with odds ratios in those using >3 tablets in the past month relative to none 1.89 (95% CI, 1.51-2.36) for wheeze, 2.14 (1.72-2.67) for nocturnal shortness of breath, 2.52 (1.99-3.20) for rhinitis, and 1.90 (1.39-2.61) for eczema. Cockroach sensitization was also more common in the highest acetaminophen category (odds ratio, 1.40; 95% CI, 1.10-1.79), but D pteronyssinus sensitization was not. Less than 1% of participants with asthma or wheeze in our nested study reported avoidance of aspirin because of asthma symptoms. None volunteered using acetaminophen to treat allergic symptoms.
There is a dose-related association between acetaminophen use and self-reported allergic symptoms in this population that is not a result of aspirin avoidance, reverse causation, or other bias. Acetaminophen may therefore be involved in the etiology of asthma and allergic disease.
A number of studies have suggested that intake of paracetamol during pregnancy and during the first months of life is associated with an increased risk of childhood asthma. We aimed to determine the association between paracetamol usage during pregnancy and the first 6 months of life, and childhood allergy (i.e. positive skin prick tests), allergic asthma, and asthma, using a matched patient-sibling study comparing patients with allergic asthma with their healthy siblings without any symptoms of allergic diseases. Allergy in patients and their siblings was determined by skin prick tests. Children having at least one positive skin prick test were considered to be allergic. Intake of paracetamol was assessed by standardized, interviewer-administered, questionnaire. Nineteen pairs of allergic asthma patients vs. non-allergic siblings were compared to determine the risk factors for allergic asthma, while 15 pairs of allergic asthma patients vs. allergic siblings were compared to determine the risk factors for asthma. Moreover, 33 pairs of allergic asthma patients vs. non-asthmatic siblings (with and without allergy) were compared to determine the risk factors for asthma. In addition, 17 allergic siblings (without asthma) were compared with 19 non-allergic siblings (without asthma) to determine the risk factors for allergy. Usage of paracetamol during pregnancy was associated with allergic asthma (p = 0.03). Furthermore, usage of paracetamol between birth and 6 months of age, and between 4 and 6 months of age, was also found to be associated with non-allergic asthma (p = 0.008 and p = 0.03 respectively). Usage of paracetamol during pregnancy and during the early months of life may play a role in the development of allergic and non-allergic asthma in children. However, due to obvious ethical reasons, direct evidence for this association (i.e. a double-blind, prospective study) is not available.
We studied whether maternal respiratory infections during pregnancy adversely influence lung growth and development of the offspring, resulting in poor early life lung function.
Infants were participants of the Wheezing Illnesses Study Leidsche Rijn (WHISTLER). Lung function measurements (single occlusion technique) were performed during natural sleep. Questionnaire data were used to obtain information on maternal respiratory infections during pregnancy. Multivariate analysis was conducted to assess the relationship between maternal respiratory infections during pregnancy and resistance and compliance of the respiratory system, adjusting for potential confounding variables.
Lower values of compliance (Crs) were found in infants of mothers with respiratory infections during pregnancy; Crs fell by 5.5% (P = 0.031). The difference in Crs between infants of mothers with and without respiratory infections during pregnancy remained unchanged and statistically significant after adjusting for potential confounding variables. The more respiratory infections the mother experienced during pregnancy, the lower the value of Crs was in her offspring (P for trend = 0.016). Using Crs corrected for body weight the relationship with maternal infections was non-significant, however still showing a trend.
The results of this study may indicate that mothers who experience respiratory infections during pregnancy have newborns with lower compliance of the respiratory system.
Paracetamol use has been associated with increased prevalence of asthma in children and adults, and one study reported an association between pre-natal exposure to paracetamol and asthma in early childhood.
To examine if pre-natal exposure to paracetamol is associated with the risk of asthma or wheezing in early childhood, we selected 66 445 women from the Danish National Birth Cohort for whom we had information on paracetamol use during pregnancy and who participated in an interview when their children were 18-months-old and 12 733 women whose children had reached the age of 7 and estimated the prevalence of physician-diagnosed asthma and wheezing at the ages of 18 months and 7 years. We also linked our population to the Danish National Hospital Registry to record all hospitalizations due to asthma up to age of 18 months.
Paracetamol use during any time of pregnancy was associated with a small but statistically significant increased risk of physician-diagnosed asthma or bronchitis among children at 18 months [relative risk (RR) = 1.17, 1.13-1.23)], hospitalizations due to asthma up to 18 months (hazard ratio = 1.24, 1.11-1.38) and physician-diagnosed asthma at 7 years (RR = 1.15, 1.02-1.29). The highest risks were observed for paracetamol use during the first trimester of pregnancy and persistent wheezing (wheezing at both 18 months and 7 years) (RR = 1.45, 1.13-1.85).
Paracetamol use during pregnancy was associated with an increased risk of asthma and wheezing in childhood. If this association is causal, we may need to revisit the clinical practice on use of paracetamol during pregnancy.
Does paracetamol in early life cause asthma?
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Paracetamol use and the risk of wheeze: causation of bias?
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Paracetamol use and the risk of wheeze
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Acetaminophen use and the risk of asthma in children and adults
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The association between early life lung function and wheezing during the first 2 yrs of life
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The relation between paracetamol use and asthma
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Does paracetamol in early life cause asthma?
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