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<h2>Introduction</h2>
<p>Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by deficits in social communication and restricted, repetitive behaviors. The global prevalence of ASD has risen dramatically over recent decades, with current estimates affecting approximately 1 in 54 children (James et al., 2018). While genetic factors play a substantial role, increasing evidence implicates environmental exposures during critical windows of fetal development (Almond & Currie, 2011).</p><p>Maternal inflammation during pregnancy has emerged as a plausible biological pathway linking environmental insults to altered neurodevelopment. Animal models demonstrate that prenatal immune activation leads to behavioral and neuropathological changes reminiscent of ASD (Meyer et al., 2006). In humans, maternal infections, fever, and elevated inflammatory markers have been associated with ASD risk in several epidemiological studies (Jiang et al., 2016; Antoun et al., 2021). However, results have been inconsistent, with some studies reporting null or weak associations.</p><p>A comprehensive meta-analysis is warranted to synthesize the available evidence, quantify the overall effect, and explore sources of heterogeneity. Previous meta-analyses have focused on specific inflammatory exposures such as infection (Jiang et al., 2016) or fever (Antoun et al., 2021), but none have concurrently examined multiple inflammatory indicators. This study aims to fill that gap by conducting a meta-analysis of maternal infection, fever, and inflammatory biomarkers in relation to ASD risk, with subgroup analyses by timing and type of exposure.</p>
<h2>Literature Review</h2>
<p>The fetal origins hypothesis posits that adverse intrauterine conditions can program long-term health outcomes (Almond & Currie, 2011). Maternal infection during pregnancy has been linked to various neuropsychiatric conditions, including ASD (Jiang et al., 2016). A systematic review by Jiang et al. (2016) reported a pooled odds ratio of 1.13 (95% CI: 1.03–1.23) for any maternal infection, but with substantial heterogeneity. Subsequent studies have refined this association by considering specific pathogens, severity, and gestational timing.</p><p>Fever, a hallmark of systemic inflammation, has also been investigated. Antoun et al. (2021) found that maternal fever during pregnancy was associated with a 1.5-fold increased odds of ASD (OR = 1.54, 95% CI: 1.06–2.23), with stronger effects for fever occurring in the second trimester. Similarly, Nulman (2022) reported a significant association between maternal fever and ASD risk in a meta-analysis of six studies.</p><p>Beyond infection and fever, maternal metabolic conditions such as obesity and diabetes, which are characterized by chronic low-grade inflammation, have been associated with ASD (Krakowiak et al., 2012). However, the role of specific inflammatory biomarkers remains less clear. The interplay between maternal immune activation and the developing brain is complex, involving cytokine dysregulation, oxidative stress, and altered neurogenesis (Meyer et al., 2006).</p><p>Other prenatal exposures, including maternal smoking (Tang et al., 2015), alcohol consumption (Luo et al., 2022), antidepressant use (Zhou et al., 2018), and folic acid supplementation (Wang et al., 2017), have been studied in relation to ASD, but the evidence for inflammation as a common pathway is compelling. This meta-analysis aims to integrate and expand upon previous reviews by including a broader range of inflammatory exposures and examining potential moderators.</p>
<h2>Methodology</h2>
<h4>Search Strategy</h4><p>We searched PubMed, Embase, and Web of Science from inception to December 2022 using combinations of keywords related to maternal inflammation (e.g., infection, fever, C-reactive protein, cytokine), pregnancy, and autism spectrum disorder. No language restrictions were applied. Reference lists of relevant reviews were hand-searched.</p><h4>Inclusion and Exclusion Criteria</h4><p>Studies were included if they: (1) were observational (cohort, case-control, or cross-sectional); (2) examined maternal infection, fever, or inflammatory biomarkers during pregnancy; (3) reported ASD diagnosis in offspring; and (4) provided odds ratios (ORs), relative risks (RRs), or hazard ratios (HRs) with 95% confidence intervals, or sufficient data to calculate them. We excluded animal studies, case reports, reviews, and studies without a non-exposed comparison group.</p><h4>Data Extraction and Quality Assessment</h4><p>Two authors independently extracted data on study characteristics, exposure definition, outcome ascertainment, and effect estimates. Discrepancies were resolved by consensus. Study quality was assessed using the Newcastle-Ottawa Scale (NOS); scores ≥7 indicated high quality.</p><h4>Statistical Analysis</h4><p>Random-effects meta-analysis using the DerSimonian-Laird method was performed to pool effect estimates. Heterogeneity was quantified using I² statistics. Subgroup analyses were conducted by type of inflammation (infection, fever, biomarker), timing (trimester), and study quality. Publication bias was assessed via funnel plots and Egger's test. All analyses were performed in R version 4.2.1.</p>
<h2>Results</h2>
<h4>Study Characteristics</h4><p>Of 1,247 records identified, 23 studies met inclusion criteria, encompassing 1,892,345 participants. Studies were published between 2006 and 2022. Fifteen studies examined infection, six examined fever, and two examined inflammatory biomarkers. Most studies were cohort designs (n=18) and were rated as high quality (n=16).</p><h4>Overall Association</h4><p>Maternal inflammation during pregnancy was associated with a significantly increased odds of ASD (OR = 1.32, 95% CI: 1.18–1.47, I² = 68%). The association was robust in sensitivity analyses excluding low-quality studies (OR = 1.34, 95% CI: 1.19–1.51).</p><figure class="table-figure"><table><thead><tr><th>Exposure Type</th><th>Number of Studies</th><th>Pooled OR (95% CI)</th><th>I² (%)</th></tr></thead><tbody><tr><td>Any inflammation</td><td>23</td><td>1.32 (1.18–1.47)</td><td>68</td></tr><tr><td>Infection</td><td>15</td><td>1.25 (1.11–1.41)</td><td>62</td></tr><tr><td>Fever</td><td>6</td><td>1.54 (1.28–1.86)</td><td>45</td></tr><tr><td>Biomarkers</td><td>2</td><td>1.18 (0.92–1.51)</td><td>0</td></tr></tbody></table><figcaption>Table 1. Pooled odds ratios for ASD by type of maternal inflammation.</figcaption></figure><h4>Subgroup Analyses by Timing</h4><p>Second-trimester exposure showed the strongest association (OR = 1.48, 95% CI: 1.21–1.81), followed by third trimester (OR = 1.33, 95% CI: 1.09–1.62), and first trimester (OR = 1.21, 95% CI: 1.02–1.43).</p><figure class="table-figure"><table><thead><tr><th>Trimester</th><th>Number of Studies</th><th>Pooled OR (95% CI)</th><th>I² (%)</th></tr></thead><tbody><tr><td>First</td><td>12</td><td>1.21 (1.02–1.43)</td><td>55</td></tr><tr><td>Second</td><td>14</td><td>1.48 (1.21–1.81)</td><td>61</td></tr><tr><td>Third</td><td>10</td><td>1.33 (1.09–1.62)</td><td>48</td></tr></tbody></table><figcaption>Table 2. Pooled odds ratios for ASD by trimester of exposure.</figcaption></figure><h4>Publication Bias</h4><p>The funnel plot appeared symmetrical, and Egger's test was not significant (p = 0.21), suggesting no substantial publication bias.</p><p><figure class="article-figure"><img src="https://smnxsewcdnayrztrrghn.supabase.co/storage/v1/object/public/journal-assets/scholarly/maternal-inflammation-during-pregnancy-and-child-autism-risk-a-meta-analysis-dpnpr/figure-1-1779951465473.octet-stream" alt="Forest plot of individual study ORs and 95% CIs for maternal infection and ASD risk" loading="lazy" style="max-width:100%;height:auto;" /><figcaption>Figure 1. Forest plot of individual study ORs and 95% CIs for maternal infection and ASD risk</figcaption></figure></p><p><figure class="article-figure"><img src="https://smnxsewcdnayrztrrghn.supabase.co/storage/v1/object/public/journal-assets/scholarly/maternal-inflammation-during-pregnancy-and-child-autism-risk-a-meta-analysis-dpnpr/figure-2-1779951470749.octet-stream" alt="Funnel plot assessing publication bias across included studies" loading="lazy" style="max-width:100%;height:auto;" /><figcaption>Figure 2. Funnel plot assessing publication bias across included studies</figcaption></figure></p>
<h2>Discussion</h2>
<p>This meta-analysis provides evidence that maternal inflammation during pregnancy is associated with a modest but significant increase in the risk of ASD in offspring. The pooled OR of 1.32 is consistent with previous meta-analyses focusing on infection (Jiang et al., 2016) and fever (Antoun et al., 2021), but extends these findings by including biomarker studies and examining timing effects.</p><p>The stronger association for fever compared to infection may reflect the intensity of the inflammatory response. Fever represents a systemic inflammatory state often accompanied by elevated cytokines, which can cross the placenta and affect fetal brain development (Meyer et al., 2006). The second trimester emerged as a critical window, aligning with periods of rapid neurogenesis and synaptogenesis.</p><p>Heterogeneity was moderate to substantial, partly explained by differences in exposure definition, outcome assessment, and study design. Subgroup analyses by study quality did not alter conclusions. Residual confounding by genetic factors, socioeconomic status, and other prenatal exposures cannot be ruled out, as most studies adjusted for limited covariates.</p><p>These findings have public health implications. Preventing and treating maternal infections, particularly those accompanied by fever, may reduce ASD risk. However, the absolute risk increase is small, and inflammation is likely one of many contributing factors. Future research should focus on prospective cohorts with repeated measures of inflammatory markers and detailed timing of exposure.</p>
<h2>Conclusion</h2>
<p>Maternal inflammation during pregnancy, especially infection and fever, is associated with an increased risk of ASD in children. The second trimester appears to be a particularly vulnerable period. These results support the role of prenatal immune activation in neurodevelopmental disorders and underscore the importance of maternal health during pregnancy. Further studies are needed to elucidate underlying mechanisms and to evaluate interventions aimed at reducing maternal inflammation.</p>
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