Global Modelling Links Maternal Hypertensive Disorders to Early Childhood Allergic Disease Burden

Abstract

As common pregnancy-related pathologies, maternal hypertensive disorders (MHD) are widespread globally, exhibiting a spectrum of severity and varying prevalence from pregnancy-induced hypertension to preeclampsia and eclampsia. MHD have been implicated in maternal and foetal immune alterations and are linked to increased allergic diseases in offsprings in several studies, albeit with overall inconclusive results [1, 2]. Here, we harnessed comprehensive global data and systematically assessed the links between MHD and common allergic diseases, atopic dermatitis (AD) and asthma, in offsprings.

Disease data was obtained from Global Burden of Disease 2019 (GBD2019) database, covering close to 200 countries globally (Figure 1A). Per GBD definition, MHD includes gestational hypertension (onset after 20-week gestation), pre-eclampsia, severe preeclampsia, and eclampsia, but excludes chronic hypertension (onset prior to pregnancy or prior to 20-week gestation) unless superimposed preeclampsia or eclampsia develop. AD refers to relapsing inflammation of the dermal layer of the skin with disruption of the epidermal barrier (dermatitis) associated with elevated serum IgE and some degree of immune dysregulation, which can be localised or widespread. Asthma is defined as a chronic lung disease characterised by reversible airway obstruction due to spasms and secretions in the bronchi usually resulting from an allergic reaction or hypersensitivity and causing difficulty in breathing.

We focused on the early age group of 1–4-year-old, the peak incidence ages for AD and the first early manifestation of asthma [3]. Ratios of 1–4-year-old AD or asthma cases versus number of pregnancies 2-year prior for each country were calculated. These ratios were used as proxies of percentages of pregnancies with offsprings developing AD (AD%) or asthma (asthma%) at the 2-year-old timepoint. These results were then compared with percentages of MHD-affected pregnancies (MHD%) at 2-year prior timepoint (Figure 1B). They were modelled as close proxies of the links between MHD and offspring allergic diseases. Additionally, socioeconomic status, reflected by GDP, was accounted as a potential confounder [3, 4].

Figure 1C illustrates the predicted response curves of AD% as a function of MHD%. The most recent available timepoint with complete data coverage, 2018, is shown as representative. Generally, across GDP quantiles (red, 25%; green, 50%; blue, 75%), MHD% were associated with elevated AD%. Likewise, MHD% were associated with increased asthma% (Figure 1D). Interestingly, aforementioned associations seemed to dissipate with age. For example, AD% for 10–14-year-old and 15–19-year-old exhibited less striking correlations with MHD% 12- and 17-year prior, respectively.

Collectively, we for the first time demonstrated positive associations between MHD% and offspring AD% and asthma% for 1–4-year-old on a global scale. This holds true for the updated GBD2021 data as well.

Previous research on smaller observational cohorts primarily concentrated on preeclampsia, a severe form of MHD. Our global analyses offer a more comprehensive overview, covering the whole MHD spectrum, while accounting for potential external confounders.

For ecological studies like ours, there are always issues regarding confounders. We have attempted to account for these by adjusting socioeconomic data like GDP. Notably, when corrected for socio-demographic index instead of GDP, our findings remained unchanged, highlighting their robustness.

The correlations between MHD and offspring allergy seemed to dissipate with age, suggesting that other confounders such as nutrition and pollution might mask the MHD effects later in life. More comprehensive studies interrogating other factors are thus warranted.

A main limitation of our study is the changing reporting and diagnosis criteria for MHD and allergic diseases across countries and different time periods. For example, asthma in 1–4-year-old age group inevitably overlaps with some preschool wheezing cases [5], which requires more precise classification for future thorough investigations. Additionally, other confounders particularly the environmental factors might vary as well [6]. These aspects have been partially accounted in our modelling via including effects from time and countries and adjusting for socioeconomics. Furthermore, global data for detailed breakdowns of MHD entities and other allergic diseases beyond AD and asthma like food allergy are lacking. More comprehensive data might be available in the future and will allow more detailed and stratified analyses.

Mechanisms underlying our findings remain unclear. Potential mediators include MHD-related pregnancy complications like preterm birth and low birth weight, which are particularly linked to the more severe spectrum of preeclampsia, but only weakly associated with general MHD [7, 8]. On the other hand, we previously reported that preeclampsia impaired foetal Treg development [9], crucial for atopy prevention, potentially explaining our observations. Investigating whether these mechanisms extend to other forms of MHD, and other immunopathology is necessary.

Overall, aligning with previous reported associations between preeclampsia and early childhood allergies in some smaller-scale studies [2], our findings consolidating their findings and provides a global perspective with a novel approach. Our work also supports the Developmental Origin of Health and Disease (DOHAD) concept and showcases a novel methodology for DOHAD-related research, unravelling the maternal impacts on offspring non-communicable diseases.

Both authors contributed to concept and design, acquisition, analysis and interpretation of data, drafting of the manuscript and critical revision of the manuscript for important intellectual content. Both authors have read and approved the manuscript.

The authors have nothing to report.

The authors declare no conflicts of interest.