Allergy and respiratory infections are global health issues (1, 2) and impact the quality of life as well as school performance of children. The rapid increase in prevalence of allergic diseases and respiratory infections is postulated to be due to environmental and lifestyle factors such as psychosocial distress, which is defined as an emotional state of discomfort resulting from exposure to stress (3). Findings from epidemiological studies strongly suggest that maternal health during preconception and over the course of pregnancy and postnatal development influence child's health. The influence of early life environment on child's health forms the basis for the Developmental Origins of Health and Disease (DOHaD) paradigm which hypothesizes that early environmental stimuli during preconception, pregnancy and early life may influence fetal and neonatal immune development and cause development of diseases including eczema, asthma, allergic rhinitis and allergic sensitization during early life (4–6).

Increasing evidence suggests that maternal distress is a risk factor for development of allergic and respiratory diseases in the offspring. In a meta-analysis of 30 studies and a cross-sectional study involving 3,758 Italian mother-child pairs, prenatal maternal distress was associated with increased risk of development of eczema, rhinitis, wheeze, and asthma in the offspring (7, 8). Prenatal maternal anxiety, depression and distress were also associated with higher risk of eczema in two Korean cohorts of children at 4 and 5 years of age (9). The Generation R study from the Netherlands reported that mothers with higher distress levels had an increased risk of having offspring who wheezed at 1–4 years of age (10). In China, schoolchildren had increased risk of rhinitis if their mothers experienced symptoms of depression during and after pregnancy (11). Furthermore, the prevalence of maternal distress has increased in recent years; prenatal depression was twice as common in a cohort of young mothers as compared to their mothers, while severe postnatal depression increased by 34% over a five-year period in a US study (12, 13).

Extensive research over the past years showed that maternal distress can influence the offspring's immune system by regulating the hypothalamic-pituitary-adrenal (HPA) axis that plays a pivotal role in regulating adaptive immunological responses to stressors (Figure 1). High maternal distress promotes cortisol production and secretion, downregulates expression of 11β-hydroxysteroid dehydrogenase 2 in the placenta and consequently exposes the fetus to excessive cortisol levels (14–16). Elevated cortisol exposure is linked to dysregulated HPA axis function in infants, which can aggravate allergic inflammation (17, 18) and favor a T-helper 2 (Th2) immune response by inhibiting interleukin-12, a Th1 cytokine (19, 20). Studies have also reported prenatal maternal distress to be linked to higher respiratory infection rates/risk in the offspring possibly due to dysregulated HPA axis and poorer maternal dietary and lifestyle habits (21, 22).

While several studies have focused on prenatal maternal distress (23), very few studies have explored the association between maternal distress during preconception and allergy as well as respiratory infections in the offspring. Among 3,008 mother-child pairs in the Southampton Women's Survey, a positive association was found between preconception maternal distress and development of eczema in infants at 12 months (24). A Swedish study of 3.2 million mother-child pairs showed that the offspring of mothers who experienced severe life events up to 6 months before and during pregnancy had increased risk of hospitalization due to asthma and other related diagnoses including bronchiolitis, eczema and respiratory infections especially in the first 2 years of life (25). Our focus on early life starting periconceptually and across critical development periods allows us to examine the earliest possible developmental influences independent of numerous confounders that emerge subsequently. This will enable the identification of earliest risk factors where interventions may be more effective.

To the best of our knowledge, there are no studies that have evaluated the impact of maternal distress during all three critical time periods, namely preconception, pregnancy and postnatal, and the development of allergic diseases and respiratory infections in the offspring. Hence, we aimed to evaluate this relationship in the Singapore PREconception Study of long Term maternal and child Outcomes (S-PRESTO) cohort.

In this study, we examined aspects of maternal distress during preconception, pregnancy and postnatal periods using a battery of validated questionnaires to assess maternal distress and their associations with eczema, rhinitis, wheeze, and allergic sensitization outcomes in the offspring in early life.

We observed associations of higher maternal distress during preconception and pregnancy with higher risks of wheeze development by ages 12 and 18 months, while social support decreased the risk. Supportive evidence is provided by the GUSTO cohort from Singapore which reported significant associations between maternal depression during pregnancy and child wheeze by age 1 year (35) and a meta-analysis which reported a 56% higher risk of wheeze in offspring whose mothers experienced prenatal psychological distress levels (36), suggesting that control of maternal distress through social support can reduce offspring wheeze risk.

Wheezing illnesses are mainly caused by respiratory viruses, and not by allergy, in young children (37). Supporting evidence of the role of viruses in the etiology of wheeze has been provided by a number of studies. The COAST study in the US identified 90% of wheezing in children up to 3 years of age to be associated with viral etiology (37). A US study of children who visited the emergency department for wheezing reported that respiratory viruses were detected in 82% of wheezing infants younger than age 2 years (38). We postulate that the associations between maternal distress and wheeze may be due to lower anti-viral responses in the offspring (Figure 1). Hyper-reactivity of the HPA axis to stress is linked to enhanced production of glucocorticoids which inhibit Th1 responses that are essential in anti-viral responses (39, 40). Maternal distress during preconception and pregnancy can also result in persisting and epigenetic changes in genes involved in stress responses (41, 42) which may be passed to the offspring. For example, murine models showed that maternal preconception distress resulted in increased expression of corticotropin releasing factor type 1, a protein key in stress responses, in mature oocytes and offspring brain (43). Higher cord blood Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1) CpG3 methylation is also linked to higher maternal depression and anxiety during third trimester of pregnancy and increased infant salivary cortisol stress responses at 3 months of age, suggesting increased HPA stress response in infants (44).

Supporting evidence of the link between maternal distress and lower immunity in the offspring is also provided by a number of studies; Rusconi et al. reported that higher maternal GHQ scores i.e. poorer mental health during and after pregnancy increased the risk of wheezing as well as respiratory and gastroenteric infections in the offspring at 1–2 years (45). In another cohort of more than 1.6 million Danish children, maternal stressful events up to 11 months before pregnancy were linked to higher risk of infectious disease hospitalization in the offspring (46).

In this study, we did not observe any associations between maternal distress experienced preconception, or during the pregnancy or postnatal periods and eczema, rhinitis and allergic sensitization in the offspring. Existing studies have yielded conflicting results on the association between maternal distress and these allergic outcomes (47). In support of our findings, the Ulm SPATZ Health Study reported that mothers belonging to the highest quartile in relation to prenatal distress, anxiety and depression did not observe more parental report of child eczema diagnosis by 2 years (48). The GUSTO cohort reported non-significant associations between maternal depression and anxiety during pregnancy as assessed by EPDS and STAI, respectively, with child eczema by age 1 year (35). The LISA Study did not observe significant associations between maternal distress during pregnancy and child eczema in the first 6 years of life (49). Similarly, the ALSPAC study reported no associations between maternal anxiety at 18 and 32 weeks of pregnancy and child allergic sensitization at 7.5 years (34). The Western Australian Pregnancy Cohort also did not observe significant associations between maternal distress during pregnancy and child rhinitis at ages 6 and 14 years (50). Contrary to our observations, the UK Southampton Women's Survey observed that preconception distress as assessed by the Short Form (36) Health Survey was linked to higher risk of eczema development in the offspring at 12 months (24). The China National Birth Cohort Study also reported an association between maternal distress during pregnancy and infant eczema development at 6 months (51). Another study of 24200 mother-child pairs in Taiwan reported that postpartum depression at 6 months was associated with an increased risk of child eczema at 3 years (52). The Viadana study reported that maternal stressful life events during pregnancy increased the risk of allergic rhinitis in children aged ~8.5 years (8). Possible explanations for these discrepancies include the use of different types of distress assessments methods. For example, the Ulm SPATZ study used Trier Inventory of Chronic Stress, Pregnancy Related Anxiety Questionnaire and Hospital Anxiety and Depression Scale while the UK Southampton Women's Survey used the Short Form (36) Health Survey. Moreover, although rhinitis can also be viral-induced (53), our study did not differentiate between allergic and infectious rhinitis which might have reduced the strength of associations between maternal distress and rhinitis. Taken together, our observations suggest that maternal distress may result in specific lower anti-viral immune responses to respiratory viruses in the offspring rather than allergic disease development.

The strengths of this study include the comprehensive assessment of maternal distress at multiple time points via a battery of validated questionnaires from preconception to pregnancy and after birth. The specific design of this preconceptional study can offer new insights into the earliest precursors and risk factors of child's health in an Asian population. A limitation of our study is the modest sample size. However, we have increased the reliability of our results using robust statistical methods. Although we used questionnaires to gather information on allergic disease diagnosis and maternal mental health, these questionnaires had also been used by numerous studies in the field (54–71). This limitation is also mitigated by regular follow-ups to reduce recall bias. We also did not assess physiological responses to maternal distress in both mothers and offspring and this should be evaluated in future research.

In conclusion, maternal distress during critical early life periods was associated with an increased risk of wheeze development in children in the first 18 months of life. This study highlights the importance of supporting maternal mental health, even before pregnancy, to improve offspring's health.

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

The studies involving human participants were reviewed and approved by SingHealth Centralised Institutional Review Board (reference 2014/692/D). Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

HL and QY analyzed the data and wrote the manuscript. MK provided intellectual input and wrote the manuscript. YHC provided statistical advice and intellectual input. ET, AG, OT, JE, KG, PG, YSC, JC, HV, BL, LS and MM contributed to the study design and provided intellectual input. EL conceptualized the study design, contributed to the analysis and wrote the manuscript. All authors critically reviewed the manuscript.

This work is supported by the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Programme, administered by the Singapore Ministry of Health's National Medical Research Council (NMRC), Singapore-NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014. Additional funding is provided by the Singapore Institute for Clinical Sciences, Agency for Science and Technology. KG is supported by the UK Medical Research Council (MC_UU_12011/4), the National Institute for Health Research [NIHR Senior Investigator (NF-SI-0515-10042) and NIHR Southampton Biomedical Research Centre (IS-BRC-1215-20004)], the European Union (Erasmus+ Programme ImpENSA 598488-EPP-1-2018-1-DE-EPPKA2-CBHE-JP) and the British Heart Foundation (RG/15/17/3174).

KG has received reimbursement for speaking at conferences sponsored by Nestle. KG and YC are part of an academic consortium that has received research funding from Abbot Nutrition, Nestle and Danone. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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