The impact of perinatal and at birth risk factors on the progression from preschool wheezing to adolescent asthma

Asthma is a global health concern affecting millions of children and adolescents. This review focuses on the possible factors that are associated with the transition from preschool wheezing to childhood asthma and highlights the significance of early‐life environmental exposures during pregnancy and the first 6 months of life in shaping allergies and asthma. We observed a scarcity of studies investigating this subgroup, with most focusing on wheezing trajectories. We undertook a thorough investigation of diverse perinatal exposures that have the potential to impact this transition. These factors include maternal asthma, smoking during pregnancy, diet, prepregnancy weight, infant birthweight, gestational age, and breastfeeding. Although limited, studies do suggest that maternal asthma increases the likelihood of preschool wheeze in offspring that persists through childhood with potential asthma progression. Findings concerning other perinatal exposures remain inconsistent. Further research is needed to identify asthma progression risk factors and assess perinatal exposure effects.


| INTRODUC TI ON
Pediatric asthma represents a major public health issue, currently affecting more that 12% of children worldwide, with higher prevalence rates reported in high-income countries compared with lowand middle-income countries. 1As a chronic inflammatory disease of the airways, asthma often manifests through symptoms such as wheezing, coughing, shortness of breath, and tightness in the chest, which can substantially impact health.For example, in 2019, asthma was attributed to the death of 12.9 thousand children and was responsible for 5.1 million years of healthy life lost. 2These symptoms can also impose a significant social and emotional burden, by limiting physical activities and social participation, and increasing sleep disturbances and emotional distress.Consequently, asthma is regarded as one of the leading causes of school absenteeism and is associated with poorer academic performance and reduced quality of life. 3,4If not appropriately managed, pediatric asthma can result in reduced lung function and greater respiratory events throughout adulthood, 5 which subsequently increases the risk of early-onset comorbidities and premature mortality. 6As such, the prevention and management of pediatric asthma has become a global priority, with increased interest in understanding and characterizing the natural disease progression.
Wheezing is the primary clinical manifestation of asthma and often originates in early life, with up to 50% of children wheezing during their preschool years (before age 6). 7In most cases, wheezing symptoms are transient and resolve by school age.However, in approximately 30% of cases, wheezing will persist throughout childhood and develop into pediatric asthma. 8stinguishing children with transient wheeze from those who will go on to develop asthma has important implications for prevention and management and could aid in reducing the unnecessary treatment of transient, benign wheeze.However, due to similarities in symptom presentation, differentiating transient wheezing from persistent wheezing at preschool age remains challenging.
Therefore, it is important to identify early determinants of the distinct "wheezing-to-asthma" phenotype to guide primordial interventions and to ensure timely identification of at-risk children, toward which, prevention and treatment strategies can be targeted.
The first 1000 days of life, from the gestational period (~9 months) until the age of two (24 months), marks a critical window for respiratory and immune system development, and exposures during this period can have lasting effects on lung function and immune maturity, predisposing children to respiratory illness. 91][12][13] However, these studies explore asthma as a distinct entity, rather than a heterogenous disorder with varying phenotypes.Alternatively, the identification of phenotype-specific risk factors may provide unique insights into the progression of wheezing to asthma.
During pregnancy, the health of the mother is paramount with maternal environment having important implications for the health of the offspring.Many maternal factors are potentially modifiable, and understanding the maternal characteristics during pregnancy and first 6 months after birth may provide key information to reduce respiratory burden on the offspring.In this review, we sought to summarize recent evidence on key perinatal factors that may influence susceptibility to the progression of preschool wheezing to childhood/adolescent asthma.To the best of our knowledge, there has not yet been a review conducted, and in doing so, a qualitative synthesis of the findings from these studies enables assessment of the gaps in our current understanding and recommendations for future investigations.Our literature search was conducted in PubMed and Google Scholar (search terms are available in the online supplement Data S1) and was restricted to English articles (including reviews) published in the past 15 years.Articles were selected based on subject headings and keywords.References from all articles were also considered.All relevant articles included for full-text review (Table 1) were qualitatively synthesized.

| Maternal asthma
Maternal asthma has been shown to increase offspring susceptibility to respiratory disease, with a meta-analysis of 33 studies revealing a threefold greater odds of wheeze and asthma in children of asthmatic mothers compared with children of nonasthmatic mothers. 23This meta-analysis also found maternal asthma to be a stronger risk factor than paternal asthma, indicating nongenetic factors during the perinatal period appear to play a notable role in influencing offspring asthma susceptibility.
In contrast, limited evidence exists regarding the influence of maternal asthma on the progression of preschool wheeze to childhood asthma in the offspring.We identified only one study 14 that explored maternal asthma as a risk factor for childhood asthma in offspring with preschool wheezing.Using data from the UK Clinical Practice Research Datalink (CPRD-GOLD), Bloom et al. 14 found that maternal asthma was positively associated with asthma progression.Specifically, mothers requiring asthma relievers during pregnancy (aHR 1.17, 95% CI 1.09, 1.26), mothers requiring asthma preventers during pregnancy (aHR 1.32, 95% CI 1.18, 1.48), and mothers whose asthma worsened during pregnancy (aHR 1.53, 95% CI 1.36, 1.71) were at greater risk than nonasthmatic mothers of having offspring with preschool wheezing, which progressed to asthma (5-8 years).Studies that focus on persistent wheeze confirmed maternal asthma as a key determinant of risk for wheeze from infancy through childhood, which could also include an asthma subgroup (but not investigated in this study).For example, a meta-analysis 24 of studies analyzing wheeze trajectories from infancy through childhood and adolescence included seven studies estimating the effect of maternal asthma on the persistent wheeze phenotype.Notably, five studies reported early persistent wheezing as their outcome, characterized by wheeze onset in preschool that persisted through childhood.While two studies reported persistent controlled wheezing as their outcome, which defined children with early persistent wheeze who were also receiving asthma treatment.Consistent across studies, maternal asthma was positively associated with both the early persistent wheezing and early controlled wheezing trajectories, yielding a pooled odds ratio of

Key message
Wheezing is the primary clinical manifestation of asthma and presents transiently in most children during their preschool years.However, in a subset of children, preschool wheezing will persist and progress into pediatric asthma.
Perinatal exposures may influence this transition; however, there currently exists a paucity of research, and much of the available evidence is limited to the analysis of wheeze trajectories rather than the distinct wheeze-to-asthma phenotype.Whilst our synthesis suggests maternal asthma increases the risk of persistent wheeze in offspring with potential asthma progression, our findings were less consistent for other perinatal exposures.More studies exploring early determinants of preschool wheeze-to-asthma are needed to further our understanding and to guided targeted interventions for at-risk children.

TA B L E 1
Characteristics and results of studies evaluating risk factors associated with the progression of preschool wheezing to childhood asthma.Prenatal dietary inflammatory index (DII) scores provide a measure of the inflammatory potential the overall diet based on the pro-inflammatory and anti-inflammatory properties of the foods, food components and nutrients consumed.Multitrigger wheeze refers to wheezing that shows discrete exacerbations, but also symptoms between episodes.Abbreviations: aHR, adjusted hazard ratio; aOR, adjusted odds ratio; aRR, adjusted risk ratio; BMI, Body Mass Index; CI, confidence interval; OR, odds ratio; Q, quartile.

TA B L E 1 (Continued)
2.95 (95% CI 2.46, 3.52; reference group: never wheeze phenotype) and 2.65 (95% CI 2.01, 3.50; reference group: never wheeze phenotype), respectively.Although the reviewed studies did not confirm a diagnosis of asthma in children belonging to the early persistent wheeze trajectory phenotype, three of the studies [25][26][27] did identify the persistent wheeze trajectory as a strong predictor of childhood asthma, thereby indicating a common pathway of risk with maternal asthma.

| Maternal smoking during pregnancy
Maternal smoking during pregnancy has profound and lasting impacts on the developing lungs of neonates, leading to permanent structural changes, which can heighten susceptibility to respiratory disease. 28In a meta-analysis 29 19 However, the sample of persistent wheezers was comparatively small in these studies (PIAMA: 3.5%, n = 99; NLSCY: 9.8%, n = 267 and PASTURE: 3.3%, n = 32), and the prevalence of smoking during pregnancy was relatively low in the PIAMA (15%) and NLSCY (18%) studies (unreported in PASTURE study).

| Maternal diet
Maternal diet and nutrition during pregnancy plays an important role in the development of foetal airways and can directly influence the immune response of infants to allergens. 34Increasing research 34,35 has explored the role of prenatal diet on the risk of preschool wheezing or childhood asthma in offspring; however, findings have been inconsistent, and exposures have varied from individual nutrients or foods to whole dietary patterns.
Furthermore, studies have typically assessed preschool wheezing and childhood asthma as distinct outcomes, 36 with no studies reporting on the effects of perinatal diet on the progression from preschool wheezing to childhood asthma.Two studies were identified that considered the effects of prenatal diet on longitudinal phenotypes of wheezing from infancy through childhood, although their findings are not comparable due to differences in dietary exposures.In the Project Viva cohort, Hanson et al. 15 explored the inflammatory potential of the prenatal diet during the first and second trimesters in association with offspring wheeze trajectories from 1 to 9 years.The potential inflammatory effects of the prenatal diet were assessed using the validated Dietary Inflammatory Index (DII), which scores the overall diet based on the pro-inflammatory and anti-inflammatory properties of the foods, food components, and nutrients consumed.
The average prenatal DII score, calculated based on DII scores from the first and second trimester, was transformed into quartiles (Q1-Q4), with the highest quartile representing the highest dietary inflammatory potential.While there was no evidence supporting an association between pro-inflammatory prenatal diets and persistent wheezing in offspring, mothers with a DII score in the second quartile (Q2) had lower odds of having offspring with persistent wheezing (aOR: 0.56, 95% CI 0.32, 0.97) than mothers with a DII in the lowest tertile (Q1).However, these results were not interpreted.Furthermore, while asthma was not confirmed in children belonging to the persistent wheeze trajectory, a separate analysis also found no association between DII scores and current asthma in mid-childhood (median age 7.7 years).In the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort, Willers et al. 22 explored the frequency of fruit, vegetables, fish, egg, milk, milk products, nuts, and nut products during the last month of pregnancy on wheeze trajectories from 1 to 8 years.
Daily nut consumption was found to be a significant predictor of the persistent wheeze phenotype (aOR 2.14, 95% CI 1.29, 3.56) and was positively associated with asthma at all ages (aOR 1.58, 95% CI 1.16, 2.15).However, as with the previous study, asthma was not confirmed in the persistent wheeze group.

| Maternal prepregnancy weight
Maternal obesity increases the likelihood of numerous pregnancy complications and can influence foetal growth and the long-term health of offspring. 37Current evidence regarding prepregnancy BMI or obesity on offspring wheezing and asthma has been somewhat inconsistent, and only one study has reported on the progression from preschool wheezing to childhood asthma.In the Southampton Women's Survey (SWS) birth cohort, 20  Other studies have explored associations between maternal prepregnancy weight and trajectories of wheeze from infancy through childhood but did not ascertain the progression to asthma.
In the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) cohort, Caudri et al. 32 stated that they found a borderline significant association between prepregnancy maternal BMI (kg/ m 2 ) and persistent wheezing from 0 to 9 years (although the exact p-value was not reported).A positive association was reported in the ALSPAC cohort, with Granell et al. 31 finding that the risk of persistent wheeze from birth to 7 years increased with every 1

| Infant birthweight and gestational age
Infant birthweight and gestational age serve as important indicators of fetal development and the subsequent susceptibility of the neonate to various diseases. 38In the context of preschool wheezing and childhood asthma, infants born preterm (before 37 weeks of gestation) or with low birthweight (<2500 g) often exhibit restricted growth, underdeveloped lungs, and immature immune systems, making them vulnerable to respiratory illnesses. 39Accordingly, these parameters of neonatal development have frequently been explored as early determinants of wheezing and asthma, and despite some inconsistencies, most evidence has typically shown that low birthweight and preterm infants are at greater risk of preschool wheezing and childhood asthma.However, evidence regarding the impact of neonatal development on the progression of preschool wheezing to childhood asthma is currently limited.
Several studies have considered the impact of infant birthweight on longitudinal wheeze phenotypes.Specifically, wheeze trajectories from birth to mid-childhood were modeled in the Project Viva, 40 the PIAMA, 32 the ALSPAC, 31 the GUSTO, 41 and the NLSCY cohorts. 33nsistent across studies, birthweight did not predict persistent wheezing.Notably, none of these of these studies ascertained an asthma diagnosis in mid-childhood, and most of these results are based on birthweight modeled as a continuous variable.In contrast, a small Italian study (n = 74) 16 followed preschool children (median age 3.8 years) with and without wheeze at baseline over a 5-year period to track the development of asthma.Both persistent wheezing (aOR 6.5, 95% CI 3.4, 28.6, p = .02)and low birthweight (<3000 g; aOR 10.3, 95% CI 1.5, 27.5, p = .01)were strong predictors of asthma at follow-up.However, the phenotype of persistent wheezing to asthma was not assessed as an outcome.Although 77% of children who developed asthma reported wheezing at baseline and so these associations could be indicative of a pathway from wheezing to asthma.
Only one study explored gestational age as a determinant of the progression of preschool wheezing to asthma in the UK. 14 In their analysis of the CPRD-GOLD database, Bloom et al. 14 found children born premature (<37 weeks) were more likely to develop schoolage asthma from preschool wheeze (aHR 1.59, 95% CI 1.44, 1.77).
Another three studies considered how gestational age effects the likelihood of persistent wheezing (which could include asthmatic children also).In the UK millennium birth cohort, 17   1.94).In this study, very preterm was also a risk factor for asthma at 7 and 11 years; however, the wheezing to asthma phenotype was not considered as an outcome.In contrast, preterm birth (defined as birth <37 weeks of gestation) did not predict persistent wheezing in the NLSCY cohort 33 or the ALSPAC cohort. 31However, Granell et al. 31 did find that as duration of pregnancy increased (per 1 week), the risk of persistent wheezing decreased by 7% (aRR 0.93, 95% CI 0.88, 0.98), indicating a protective effect of increased gestation.

| Breastfeeding
Breastfeeding supports infant health and may protect against the development of wheezing and asthma by enhancing the immune