Intrauterine Exposure To Acetaminophen (paracetamol) And Childhood Asthma: Systematic Review And Meta-Analysis

Background: Past studies have reported conflicting results regarding the association between acetaminophen use during pregnancy and the risk of developing childhood asthma. Objectives: To perform an updated review on past studies investigating the association between prenatal acetaminophen use and the risk of developing asthma within the first ten years of life. Methods: A systematic review and meta-analysis was conducted using PubMed search (1950-December 1, 2011) to identify studies that investigated the association between intrauterine exposure to acetaminophen and childhood asthma. Inclusion criteria consisted of a study design restricted to prospective cohort studies, primary exposure of acetaminophen intake during pregnancy, and primary outcome of physician-diagnosed asthma or a combination of two of the following indicators of asthma (use of asthma medication, hospitalization due to asthmatic symptoms, wheezing, and ER visits due to wheezing). Study quality was assessed and data was extracted by one reviewer. An inverse variance fixed-effects model was used, and adjusted odds ratio was calculated to compare effect sizes of studies. Results: The review comprised of six studies: two studies assessed physician-diagnosed asthma among children under the age of 2 years and four studies ascertained asthma outcome between the ages 2 and 10 years. The overall pooled estimate calculated from all six studies was 1.12 (95%CI: 1.03, 1.22). Children whose asthma status was recorded before the age of 2 had an overall pooled aOR of 1.18 [95%CI:1.13,1.23] while children between the ages of 2 and 10 years had a pooled aOR of 1.13[95%CI:1.01, 1.26]. For studies that did a follow-up among children under the age of 2 years, subgroup analyses of acetaminophen exposure during different stages of pregnancy displayed consistent statistically significant associations between prenatal acetaminophen use and childhood asthma. The subgroup analysis of different stages of pregnancy for studies that reported asthma outcome among children older than 2 years of age showed that risk of childhood asthma was only associated with intrauterine exposure to acetaminophen during the later stages of pregnancy (aOR[95%CI]: 1.23[1.08, 1.42]). There was not enough information to verify a dose-response relationship. Conclusions: The findings support a modest association of exposure to prenatal acetaminophen use with childhood asthma development. By reviewing only prospective studies, we established temporality, thus further strengthening our hypothesis that acetaminophen use during pregnancy causes an increased risk of childhood asthma. Further studies need to be conducted to confirm this association, and specify the dose, frequency and trimester use of acetaminophen. (Word count 398

Ventilation Defect Formation in Healthy and Asthma Subjects Is Determined by Lung Inflation

Background: Imaging studies have demonstrated that ventilation during bronchoconstriction in subjects with asthma is patchy with large ventilation defective areas (Vdefs). Based on a theoretical model, we postulated that during bronchoconstriction, as smooth muscle force activation increases, a patchy distribution of ventilation should emerge, even in the presence of minimal heterogeneity the lung. We therefore theorized that in normal lungs, Vdefs should also emerge in regions of the lung with reduced expansion. Objective: We studied 12 healthy subjects to evaluate whether Vdefs formed during bronchoconstriction, and compared their Vdefs with those observed in 9 subjects with mild asthma. Methods: Spirometry, low frequency (0.15 Hz) lung elastance and resistance, and regional ventilation by intravenous $^{13}$NN-saline positron emission tomography were measured before and after a challenge with nebulized methacholine. Vdefs were defined as regions with elevated residual 13NN after a period of washout. The average location, ventilation, volume, and fractional gas content of the Vdefs, relative to those of the rest of the lung, were calculated for both groups. Results: Consistent with the predictions of the theoretical model, both healthy subjects and those with asthma developed Vdefs. These Vdefs tended to form in regions that, at baseline, had a lower degree of lung inflation and, in healthy subjects, tended to occur in more dependent locations than in subjects with asthma. Conclusion: The formation of Vdefs is determined by the state of inflation prior to bronchoconstriction

Plot of change in fractional gas content (<i>Fgas</i>) in healthy subjects and subjects after bronchoconstriction versus baseline <i>Fgas</i>.

<p>Mean Lung Fgas increased after bronchoconstriction for both healthy subjects and subjects with asthma. Subjects that initially had a lower baseline mean lung <i>Fgas</i> had a larger increase in mean lung <i>Fgas</i> during bronchoconstriction when compared to those that started off with a higher baseline mean lung <i>Fgas</i>.</p

Analysis of geometric center of the lungs (<i>GCLung</i>) and ventilation defects (<i>GCVdef</i>).

<p>The left column shows projections of <i>Vdefs</i> (in red) for healthy subjects and the right column for subject with mild asthma. The white cross represents the <i>GCLung</i> and the orange cross is the <i>GCVdef</i>. There are three views of the lung in each image (clockwise from top left): transverse viewed caudo-cranially, sagittal, and coronal. In these images, Vdefs that deviate toward the bottom of the page result in negative distances between <i>GCLung</i> and <i>GCVdef</i> in the transverse, sagittal and coronal planes.</p

Vertical location of <i>Vdefs</i> versus FEV₁.

<p>Note that although some asthma subjects had dependent locations of <i>Vdefs</i> similar to healthy controls, the healthy controls always had dependent <i>Vdefs</i> regardless of the strength of constriction. This suggests that the significant difference in vertical location of <i>Vdefs</i> between subjects with asthma and healthy controls is likely not due to any difference in the dose of methacholine.</p

Results.

<p>Values are means ± SD. <i>Rlow</i>, low-frequency resistance; <i>Elow</i>, low-frequency elastance; <i>Fgas</i>, fractional gas content; <i>Vdef</i>, ventilation defect; , specific ventilation inside <i>Vdefs</i> vs. outside; , coefficient of variation of specific ventilation; F_Vdef, fraction of total imaged volume occupied by <i>Vdefs</i>. % change refers to the change during bronchoconstriction compared to baseline. *P<0.05 compared to Healthy.</p>†<p>P<0.05 compared to ratio of 1.</p

Plots of Geometric Centers in subjects with asthma vs. healthy subjects.

<p>A. The ventral deviation of calculated geometric center of ventilation defects (<i>GCVdef</i>) from the geometric center of the lungs (<i>GCLung</i>). Both healthy subjects and subjects with asthma demonstrated a vertical dependence in <i>Vdefs</i>. However healthy subjects have a significantly (P = .028) lower ventral deviation compared to that of subjects with asthma. B. The horizontal (x-axis) deviation of calculated geometric center of ventilation defects (<i>GCVdef</i>) from the geometric center of the lungs (<i>GCLung</i>). (p>0.05).</p