Introduction

Neurodevelopmental disorders typically emerge in early childhood and are characterized by impairments in personal, social, academic, and occupational functioning1. Increasing evidence suggests that maternal immune activation plays a role in the etiology of these disorders2. Maternal asthma—defined in this study as asthma existing prior to childbirth—is a known trigger of maternal immune activation, which may adversely affect fetal neurodevelopment3. Findings from animal studies, human observational research, and reviews have all suggested a potential association between maternal asthma and neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) in offspring4,5,6,7. However, no prior meta-analysis has systematically evaluated this relationship. Given the high prevalence of both asthma and ASD/ADHD and absence of relevant meta-analysis, we conducted this meta-analysis to assess the association between maternal asthma and the risk of ASD/ADHD in offspring8,9.

Methods

The objective of this study was to investigate the potential correlation between maternal asthma and the subsequent development of ASD and ADHD in the offspring. The following electronic databases, which covered studies from the inception of the database to October 2024, were retrieved in the course of this investigation: PubMed, Web of Science, Embase, and the Cochrane Library. The search formula used a combination of free terms and medical subject headings terms, mainly including: (asthma) AND (ASD OR autism spectrum disorders OR autism spectrum disorder OR ADHD OR attention deficit disorder with hyperactivity OR attention deficit-hyperactivity disorder OR attention-deficit/hyperactivity disorder OR attention deficit hyperactivity disorders). Detailed search strategies are provided in the Supplementary Search Strategy. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered with PROSPERO (CRD42024583889).

Inclusion criteria:

  1. (1)

    The maternities in the exposed group suffered from asthma.

  2. (2)

    The maternities in the control group were free of asthma.

  3. (3)

    The outcome was the prevalence of ASD/ADHD in the offspring.

  4. (4)

    The study designs belong to cohort studies or case-control studies.

Exclusion criteria:

  1. (1)

    The full text or data of the studies was not available.

  2. (2)

    The article was not written in English.

  3. (3)

    If the article had been updated, the most comprehensive or latest article was selected to be included.

  4. (4)

    Maternal asthma commenced following childbirth in the study.

Data extraction

Two assessors independently extracted data from eligible studies, with a third assessor responsible for resolving any discrepancies. The extracted data encompassed authors, publication year, country, study design, participant characteristics (gender, evaluation tool, diagnostic criteria), length of follow-up, adjusted factors, number of participants, and prevalence of ASD/ADHD in the offspring.

Based on previous studies, this study defined maternal asthma as asthma existing prior to childbirth.

Assessment of quality

Two independent assessors conducted quality assessment. In case of discrepancies, a third assessor intervened to resolve them. The Newcastle-Ottawa scale, a tool for quality assessment, was used to evaluate cohorts and case-control studies based on selection, comparability, and outcomes. Studies scoring 6 or higher were deemed high quality.

Statistical analysis

Statistical analysis was conducted using Stata 12.0. The relationship between maternal asthma and offspring ASD/ADHD was examined by calculating effect sizes with a 95% confidence interval (95% CI) for the odds ratio (OR). A positive association between maternal asthma and offspring ASD/ADHD prevalence was identified when OR > 1, while a negative association was observed when OR < 1. Heterogeneity among the studies was assessed using the chi-square test and expressed as I2, where 0% indicated no heterogeneity, 1–25% low heterogeneity, 26–50% moderate heterogeneity, and 51–100% high heterogeneity. To account for potential heterogeneity among studies due to factors such as maternal age, race, income, parity, and education, a random-effects model was utilized to enhance the reliability of the statistical findings. If more than five articles were included, publication bias and sensitivity analyses were planned. The sensitivity analysis aimed to assess result stability, while publication bias was assessed using Begg’s test. All statistical tests were two-tailed, with statistical significance denoted by P < 0.05. A GRADE analysis was conducted by the GRADEpro, and the certainty of evidence was categorized into four levels: high, moderate, low, and very low.

Result

Studies selection

The search followed an established strategy and identified 2187 terms across four electronic databases. No additional terms were sourced elsewhere. After eliminating duplicate records, 964 articles remained. Upon reviewing titles and abstracts, 932 articles were excluded. A detailed assessment of the remaining 32 articles revealed that 12 met the criteria, while 20 were exclude4,10,11,12,13,14,15,16,17,18,19,20. The 20 excluded studies were not included for the following reasons: 6 were reviews, 2 had been updated, 10 did not present significant findings, and 2 had missing data on the outcomes. Refer to Fig. 1 for a detailed overview of the process.

Fig. 1
figure 1

Flow diagram of the selection process.

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Study characteristics

Table 1 presented the key characteristics of the twelve studies included in this meta-analysis, comprising five cohort studies and seven case-control studies. Among these, eight studies investigated ASD, while four focused on ADHD, spanning publication years from 2005 to 2024. The research was conducted in various countries: the United States (n = 5), Taiwan (n = 2), China (n = 2), Sweden (n = 1), multicenter (n = 1), Norway (n = 1), Denmark (n = 1), and Australia (n = 1). The maternal asthma group encompassed over 2507/1/2025000 individuals, whereas the control group comprised more than 5.5 million individuals. Diagnosis of ASD and ADHD, as well as medication prescriptions, were the primary outcome measures in most studies. Some studies utilized assessment tools such as the autism diagnostic observation schedule (ADOS) and autism diagnostic interview-revised (ADI-R) to standardize the evaluation of offspring with ASD, as outlined in Table 1. Pharmacological management of maternal asthma encompassed inhaled corticosteroids, leukotriene receptor antagonists, inhaled β₂-agonists, and oral corticosteroids. Adjustment for various factors, including sex, birth year, maternal age, race, education, parity, and smoking, was conducted in the majority of studies, with detailed information provided in Supplementary Tables 1-1, Supplementary Table 1-1 and Supplementary Table 1-3.

Table 1 Characteristics of included studies in the meta-analysis.
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Quality assessment

Quality assessment of case-control and cohort studies was completed by the Newcastle-Ottawa scale. All of these included studies were high quality studies, with scores ranging from 6–8. Refer to Supplementary Table 2 for the cohort study and Supplementary Table 3 for the case-control study.

ASD

The eight studies examined the correlation between maternal asthma and ASD in offspring. The pooled effect sizes revealed a heightened risk of ASD in offspring of mothers with asthma compared to the control group (OR = 1.36, 95%CI = 1.28–1.44, P < 0.001, I2 = 46.7%, Fig. 2). Subgroup analyses were performed based on gender. Among male offspring, the incidence of ASD was significantly elevated in the maternal asthma group compared to the control group (OR = 1.28, 95%CI = 1.01–1.61, P = 0.04, Fig. 3a). Conversely, in the female subgroup, there was no significant difference in ASD prevalence between the maternal asthma group and the control group (OR = 1.81, 95%CI = 0.72–4.25, P = 0.205, Fig. 3b). The GRADE analysis for the meta-analysis of the association between maternal asthma and ASD in offspring rated the certainty of evidence as low.

Fig. 2
figure 2

Forest plot of the relationship between maternal asthma and ASD in offspring (p < 0.001).

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Fig. 3: Forest plot of subgroup analysis on maternal asthma and ASD in the offspring.
figure 3

a To explore the incidence of ASD in the male offspring of mothers with asthma (p = 0.04); b to explore the incidence of ASD in the female offspring of mothers with asthma (p = 0.205).

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ADHD

In four studies examining the correlation between maternal asthma and offspring ADHD, a higher prevalence of ADHD was observed in the maternal asthma group compared to the control group (OR = 1.43, 95% CI = 1.37–1.51, P < 0.001, I2 = 74.2%, Fig. 4). Subgroup analyses for male and female offspring revealed a higher prevalence of ADHD in the maternal asthma group compared to the control group for both male (OR = 1.36, 95%CI = 1.30–1.42, P < 0.001, Fig. 5a) and female (OR = 1.45, 95%CI = 1.38–1.53, P < 0.001, Fig. 5b) offspring subgroups. The GRADE analysis for the meta-analysis of the association between maternal asthma and ADHD in offspring rated the certainty of evidence as very low.

Fig. 4
figure 4

Forest plot of the relationship between maternal asthma and ADHD (p < 0.001).

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Fig. 5: Forest plot of subgroup analysis on maternal asthma and ADHD in the offspring.
figure 5

a To explore the incidence of ADHD in the male offspring of mothers with asthma (p < 0.001); b to explore the incidence of ADHD in the female offspring of mothers with asthma (p < 0.001).

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Publication bias and sensitivity analyses

The Begg’s test of forest plots assessing maternal asthma with ASD in the offspring was found to reveal no significant publication bias (P = 0.902, SFig. 1). After the exclusion of each study individually, sensitivity analyses demonstrated that the results exhibit stability (SFig. 2).

Discussion

In this meta-analysis of 5 cohort studies and 7 case-control studies, compared to the control group, maternal asthma increased the risk of ASD and ADHD in the offspring. The pooled effect sizes revealed a higher risk of ASD (OR = 1.36, 95%CI = 1.28–1.44) and ADHD (OR = 1.43, 95% CI = 1.37–1.51) in offspring of mothers with asthma compared to the control group. Although all 12 included studies were rated as high quality, the GRADE analysis classified the evidence certainty as low for the meta-analysis of ASD and very low for meta-analysis of ADHD because of study design and heterogeneity. The possible mechanisms were as follows:

Maternal serotonin is transported into placental cells through the 5-hydroxytryptamine (5-HT) transporter and organic cation transporter 3, crossing the placental barrier to reach the fetal circulation21. Serotonin plays a vital role in the structural and functional development of the fetal brain, particularly in neuronal proliferation and synaptogenesis22,23,24. In maternal asthma, immune activation leads to elevated interleukin-6 (IL-6), which promotes the diversion of tryptophan metabolism toward kynurenine at the expense of serotonin synthesis, resulting in decreased maternal serotonin levels25,26,27,28,29,30. During the initial stages of fetal neural development, serotonin is of maternal origin31,32. Therefore, maternal serotonin deficiency reduces fetal serotonin levels, impairing hippocampal and prefrontal cortex development and disrupting brain circuit formation, thereby contributing to neurodevelopmental disorders33. ASD model mice exhibited significantly reduced 5-HT levels compared to controls34. Certain individuals with ASD exhibited notable symptom amelioration upon administration of selective serotonin reuptake inhibitors, potentially linked to serotonin level regulation35,36. It is also postulated by some researchers that maternal IL-6 may cross the immature fetal blood-brain barrier (BBB), triggering fetal IL-6 and pro-inflammatory cytokine expression, and elevated levels could further disrupt synaptic development and functionality37,38,39.

In addition to IL-6, interleukin-17A (IL-17A) may also impact neurodevelopment. Maternal immune activation and elevated IL-6 levels are shown to elevate IL-17A levels, which can traverse the placental barrier to reach fetal circulation40,41. IL-17A triggers excessive neutrophil activation, leading to the production and release of oxidative and inflammatory mediators that have the potential to disrupt the BBB, initiating neuroinflammatory responses in the brain42. Direct injection of IL-17A into fetal ventricles had been found to activate microglia and enhance their phagocytic activity, resulting in cortical developmental abnormalities and autism-like behaviors in offspring43. Conversely, injecting IL-17A antibodies into pregnant mothers to inhibit the IL-17A signaling pathway had shown partial improvement in autism-like behaviors in offspring44.

Offspring of mothers with asthma exhibit an elevated risk of developing asthma, indicating a potential genetic component in asthma susceptibility45. Strong associations are identified between asthma and ADHD throughout the genome, with multiple shared loci, including CISD246. The presence of CISD2 is closely linked to the proper functioning of mitochondria which play a crucial role in energy metabolism and the regulation of cellular homeostasis47,48,49,50,51. The absence of CISD2 can result in mitochondrial degeneration52. Mitochondrial dysfunction may impede oxidative phosphorylation, leading to inadequate adenosine triphosphate (ATP) synthesis53. Given the high energy demands of the developing brain, this deficiency can disrupt neural development54. Moreover, insufficient ATP impairs synthesis of glutathione, the principal intracellular redox buffer, thereby undermining antioxidant defenses and exacerbating oxidative‑stress–mediated mitochondrial and neuronal injury55,56,57. Mitochondrial dysfunction is a prevalent metabolic abnormality in individuals with ASD, suggesting a potential link to neurodevelopmental disorders58,59.

When considering maternal history of asthma, beyond the aforementioned genetic factors, long-term environmental risk factors warrant critical examination. Chronic exposure to air pollutants, particularly particulate matter less than 2.5 (PM2.5), is associated with elevated asthma prevalence60. Offspring may inherit not only genetic susceptibility but also shared environmental exposures. PM2.5 has been shown to induce endothelial dysfunction and compromise the BBB. Furthermore, PM2.5 exposure promotes systemic release of pro-inflammatory cytokines, which may traverse the disrupted BBB and impair neurodevelopment61,62. In cases of asthma during pregnancy, the intrauterine impact of pharmacological interventions cannot be overlooked. β₂-adrenergic receptor agonists, a mainstay of asthma management, were linked to increased ASD risk in offspring with prolonged in utero exposure compared to unexposed controls in a case-control study63. However, conflicting evidence exists, as other studies found no significant association between prenatal exposure to asthma medications and ASD/ADHD incidence12,64. Currently, no clear consensus exists regarding the intrauterine effects of gestational asthma medications; thus, further large-scale observational studies and controlled animal experiments are warranted to evaluate their specific impacts independent of maternal asthma pathophysiology. To delineate the etiological contributions of genetic predisposition, environmental exposures, and pharmacological impacts on offspring ASD/ADHD risk, this study should conduct subgroup analyses comparing maternal history of asthma to asthma during pregnancy. Regrettably, the lack of standardized diagnostic criteria for maternal asthma across included studies rendered the planned subgroup analyses unfeasible.

Changes in the gut microbiota has been identified as a significant potential factor in neurodevelopmental disorders in offspring. Maternal asthma may be associated with the composition of the maternal gut microbiome through the gut-lung axis65,66. Studies found that in asthma patients, not only was the microbial composition of the airways altered, but the gut microbiota was also affected, with a reduction in both Bifidobacterium and Lactobacillus levels67,68. Similarly, reduced levels of Bifidobacterium and Lactobacillus has been observed in children with ASD, with this anomaly being vertically transmitted from mother to offspring69,70,71. These alterations can compromise intestinal barrier integrity, allowing bacterial metabolites and inflammatory factors to enter systemic circulation and affect brain development. Bifidobacterium plays a role in regulating short-chain fatty acid levels, which can influence neurotransmitter synthesis71. Moreover, individuals diagnosed with ASD often experience gastrointestinal symptoms, suggesting a possible connection between neurodevelopmental disorders and the brain-gut axis72.

Subgroup analyses revealed a higher prevalence of ADHD in the maternal asthma group compared to the control asthma group for both male and female offspring. In the male subgroup, the prevalence of ASD was also higher in the offspring of mothers with asthma than in the control group, whereas no significant difference in ASD prevalence was observed between the two groups in the female subgroup. This disparity might be attributed to the limited number of studies and random variation, as the OR for this subgroup analysis was 1.81(95%CI = 0.72–4.25) based on only two studies. Additionally, diagnostic criteria for ASD are predominantly defined by male specimens, who typically exhibit more externalizing behaviors, while females tend to display internalizing symptoms that may resemble anxiety and depression, potentially leading to underdiagnosis compared to males73,74. The extreme male brain theory posits that elevated testosterone levels play a crucial role in the development of ASD75. Conversely, the female protective effect theory suggests that females may have higher genetic/mutational load76,77,78. Some researchers had posited that the Y chromosome could potentially serve as a risk factor for ASD, whereas the presence of the additional X chromosome in females might elevate the threshold for neurodevelopmental disorders79,80. These factors could elucidate the absence of a substantial correlation between maternal asthma and the risk of ASD in female progeny.

The foremost strength of this study lies in its distinction as the first meta-analysis investigating the association between maternal asthma and offspring risks of ASD/ADHD. The diagnosis of diseases is primarily based on standardized assessment tools and clinical evaluation, which enhances the credibility and accuracy of the findings. Furthermore, the studies incorporated in the analysis demonstrate high quality. This study also provides a multifaceted analysis of the underlying mechanisms, offering a comprehensive exploration from diverse perspectives. Nevertheless, limitations exist. A major limitation of this study is the failure to differentiate between maternal history of asthma and asthma during pregnancy, thereby precluding rigorous assessment of potential associations between genetic, long-term environmental risk, clinical management, and offspring ASD/ADHD risk. The meta-analysis is constrained by the limited number of studies included. Furthermore, the reliance on observational data from cohort and case-control studies may undermine the conclusion’s reliability for the lower levels of evidence inherent. The missing of some critical data remains a significant limitation of this study. Additionally, the use of diverse diagnostic tools across studies in the ASD and ADHD analyses contributed to high heterogeneity.

By demonstrating the association between maternal asthma and neurodevelopmental disorders in offspring, this study underscores the clinical imperative for early identification and screening of high-risk offspring, optimization of asthma management during pregnancy and targeted preventive strategies and surveillance for high-risk families, which may carry substantial clinical relevance.

Conclusion

This meta-analysis concludes that the maternal asthma is a risk factor for ASD/ADHD in offspring with the risk may being influenced by offspring sex.