Nasopharyngeal microbiota in children is associated with severe asthma exacerbations.

BACKGROUND: The respiratory microbiome has been associated with the etiology and disease course of asthma. OBJECTIVE: We sought to assess the nasopharyngeal microbiota in children with a severe asthma exacerbation and their associations with medication, air quality, and viral infection. METHODS: A cross-sectional study was performed among children aged 2 to 18 years admitted to the medium care unit (MCU; n = 84) or intensive care unit (ICU; n = 78) with an asthma exacerbation. For case-control analyses, we matched all cases aged 2 to 6 years (n = 87) to controls in a 1:2 ratio. Controls were participants of either a prospective case-control study or a longitudinal birth cohort (n = 182). The nasopharyngeal microbiota was characterized by 16S-rRNA-gene sequencing. RESULTS: Cases showed higher Shannon diversity index (ICU and MCU combined; P = .002) and a distinct microbial community composition when compared with controls (permutational multivariate ANOVA R2 = 1.9%; P < .001). We observed significantly higher abundance of Staphylococcus and "oral" taxa, including Neisseria, Veillonella, and Streptococcus spp. and a lower abundance of Dolosigranulum pigrum, Corynebacterium, and Moraxella spp. (MaAsLin2; q < 0.25) in cases versus controls. Furthermore, Neisseria abundance was associated with more severe disease (ICU vs MCU MaAslin2, P = .03; q = 0.30). Neisseria spp. abundance was also related with fine particulate matter exposure, whereas Haemophilus and Streptococcus abundances were related with recent inhaled corticosteroid use. We observed no correlations with viral infection. CONCLUSIONS: Our results demonstrate that children admitted with asthma exacerbations harbor a microbiome characterized by overgrowth of Staphylococcus and "oral" microbes and an underrepresentation of beneficial niche-appropriate commensals. Several of these associations may be explained by (environmental or medical) exposures, although cause-consequence relationships remain unclear and require further investigations.

The ADEM2 project: early pathogenic mechanisms of preschool wheeze and a randomised controlled trial assessing the gain in health and cost-effectiveness by application of the breath test for the diagnosis of asthma in wheezing preschool children.

BACKGROUND: The prevalence of asthma-like symptoms in preschool children is high. Despite numerous efforts, there still is no clinically available diagnostic tool to discriminate asthmatic children from children with transient wheeze at preschool age. This leads to potential overtreatment of children outgrowing their symptoms, and to potential undertreatment of children who turn out to have asthma. Our research group developed a breath test (using GC-tof-MS for VOC-analysis in exhaled breath) that is able to predict a diagnosis of asthma at preschool age. The ADEM2 study assesses the improvement in health gain and costs of care with the application of this breath test in wheezing preschool children. METHODS: This study is a combination of a multi-centre, parallel group, two arm, randomised controlled trial and a multi-centre longitudinal observational cohort study. The preschool children randomised into the treatment arm of the RCT receive a probability diagnosis (and corresponding treatment recommendations) of either asthma or transient wheeze based on the exhaled breath test. Children in the usual care arm do not receive a probability diagnosis. Participants are longitudinally followed up until the age of 6 years. The primary outcome is disease control after 1 and 2 years of follow-up. Participants of the RCT, together with a group of healthy preschool children, also contribute to the parallel observational cohort study developed to assess the validity of alternative VOC-sensing techniques and to explore numerous other potential discriminating biological parameters (such as allergic sensitisation, immunological markers, epigenetics, transcriptomics, microbiomics) and the subsequent identification of underlying disease pathways and relation to the discriminative VOCs in exhaled breath. DISCUSSION: The potential societal and clinical impact of the diagnostic tool for wheezing preschool children is substantial. By means of the breath test, it will become possible to deliver customized and high qualitative care to the large group of vulnerable preschool children with asthma-like symptoms. By applying a multi-omics approach to an extensive set of biological parameters we aim to explore (new) pathogenic mechanisms in the early development of asthma, creating potentially interesting targets for the development of new therapies. TRIAL REGISTRATION: Netherlands Trial Register, NL7336, Date registered 11-10-2018.

Recognising symptoms of congenital myasthenic syndromes in children: A guide for paediatricians.

AIM: Congenital myasthenic syndromes (CMS) are a rare and diverse group of treatable neuromuscular transmission disorders. Diagnosis is often substantially delayed. This study aimed to identify common symptoms of CMS in children and their manifestation to aid diagnosis and early intervention. METHODS: We performed a retrospective cohort study, including 18 children (median age 13 years, range 9 years 5 months-18 years 0 month) with CMS. Data on CMS symptoms and their manifestation were extracted from patients' charts and supplemented with parental telephone interviews. Descriptive analyses were used to identify common symptoms. RESULTS: A median diagnostic delay of 4 years and 7 months (interquartile range: 51 months) was observed. Proximal muscle weakness (100%), ptosis (89%), clumsy gait (82%), difficulty eating solid foods (78%) and recurrent respiratory tract infections (72%) were most common in these patients. Symptoms mostly co-occurred and frequently had a fluctuating character, aggravated by infections or fatigue. CONCLUSION: Early referral to diagnose CMS is crucial to enable timely initiation of treatment. Heightened attention to a combination of symptoms related to muscle weakness, rather than individual symptoms, should support paediatricians in flagging these neuromuscular disorders. Medical history taking should be tailored to parents' perceptions, asking questions about recognisable symptoms of muscle weakness.

Exploring professionals' views regarding prenatal counselling in congenital diaphragmatic hernia.

OBJECTIVES: Congenital diaphragmatic hernia (CDH) is a congenital malformation in which the diaphragm and lungs are underdeveloped, leading to cardiorespiratory and other problems. This study aimed to explore professionals' views regarding prenatal counselling in CDH. METHODS: A qualitative study was performed among healthcare professionals involved in the care of CDH patients in Radboud university medical center Amalia Children's Hospital. Semi-structured interviews were conducted until saturation was achieved. Transcripts were qualitatively analysed to gain insight into professionals' views regarding counselling. RESULTS: Eighteen professionals with various backgrounds were included. The professionals agreed that the first counselling session should be soon after diagnosis and additional sessions should be offered. Concerning counselling content, participants considered explanation of the diagnosis, prognosis, short- and long-term consequences, treatment options and practical aspects important. As for decision-making about possible termination of pregnancy, all professionals emphasised the importance of the parental role, but the preferred parental involvement varied. Regarding practical aspects, preferred counsellors were a neonatologist, obstetrician, paediatric surgeon and/or medical social worker. Participants emphasised that the counselling should be adjusted to parents' needs. CONCLUSIONS: This study gained insight into professionals' views regarding the timeline, content, decision-making process, and practical aspects of prenatal counselling in CDH.

It Is Not Just the FEV1 That Matters, but the Personal Goals We Reach Along the Way: Qualitative, Multicenter, Prospective, Observational Study.

BACKGROUND: The COVID-19 pandemic has boosted the use of forced expiratory volume in 1 second (FEV1) telemonitoring in pediatric asthma, but a consensus on its most efficient and effective implementation is still lacking. To find answers, it is important to study how such an intervention is perceived, experienced, and used by both patients and health care professionals (HCPs). OBJECTIVE: The aim of this study was to provide perspectives on how FEV1 home monitoring should be used in pediatric asthma. METHODS: This is a qualitative, multicenter, prospective, observational study which included patients with asthma aged 6-16 and HCPs. Primary outcomes were results of 2 surveys that were sent to all participants at study start and after 3-4 months. Secondary outcomes consisted of FEV1 device usage during 4 months after receiving the FEV1 device. RESULTS: A total of 39 participants (26 patients and 13 HCPs) were included in this study. Survey response rates were 97% (38/39) at the start and 87% (34/39) at the end of the study. Both patients and HCPs were receptive toward online FEV1 home monitoring and found it contributive to asthma control, self-management, and disease perception. The main concerns were about reliability of the FEV1 device and validity of home-performed lung function maneuvers. FEV1 devices were used with a median frequency of 7.5 (IQR 3.3-25.5) during the 4-month study period. CONCLUSIONS: Patients and HCPs are receptive toward online FEV1 home monitoring. Frequency of measurements varied largely among individuals, yet perceived benefits remained similar. This emphasizes that online FEV1 home monitoring strategies should be used as a means to reach individual goals, rather than being a goal on their own.

The PRIDE Study: Evaluation of online methods of data collection.

BACKGROUND: Large birth cohort studies are extremely valuable in assessing associations between early life exposures and long-term outcomes. Establishing new birth cohorts is challenging due to declining participation rates. Online methods of data collection may increase feasibility, but have not been evaluated thoroughly. OBJECTIVE: The primary objective of the ongoing PRegnancy and Infant DEvelopment (PRIDE) Study is to identify exposures during pregnancy and in early life that may affect short-term or long-term health of mother and/or child. In this manuscript, we aimed to evaluate methods of recruitment and online data collection applied. POPULATION: Dutch women aged ≥18 years in early pregnancy. DESIGN: Prospective cohort study. METHODS: Initially, only prenatal care providers recruited participants, but alternative recruitment methods were added as a result of disappointing participation rates, including collaboration with "Moeders voor Moeders" (organisation that visits women in early pregnancy) and Facebook advertisements. Data on demographic characteristics, obstetric history, maternal health, life style factors, occupational exposures, nutrition, pregnancy complications, and infant outcomes are primarily collected through Web-based questionnaires at multiple time points during and after pregnancy. Additional data collection components include paternal questionnaires, blood and saliva sampling, and linkage to medical records. PRELIMINARY RESULTS: By September 2019, 9573 women were included in the PRIDE Study, of which 1.3% completed paper-based questionnaires. Mean age of the women analysed was 30.6 years, 71.1% had a high level of education, 57.2% were primiparae, and mean gestational age at enrolment was 9.9 (range 3, 37) weeks, with slight differences between recruitment methods. Pregnancy outcome was known for 89.8%. Retention rate at 6 months after the estimated date of delivery was estimated at 70%. Multiple validation studies conducted within the PRIDE Study indicated high data quality. CONCLUSION(S): Although challenging and time-consuming, online methods for recruitment and data collection may enable the establishment of new birth cohort studies.

Depression and anxiety during pregnancy: The influence of maternal characteristics.

BACKGROUND: Depression and anxiety during pregnancy are associated with adverse health outcomes for both mother and child. This study aims to investigate the occurrence of symptoms of depression and anxiety in early and late pregnancy, the longitudinal changes from early to late pregnancy, and factors associated with symptoms of depression and anxiety in pregnant women in the Netherlands. METHODS: We studied 2897 women participating in the PRegnancy and Infant DEvelopment (PRIDE) Study. To assess symptoms of depression and anxiety, web-based questionnaires including the Hospital Anxiety and Depression Scale (HADS) and multiple questions on maternal characteristics were completed in early and late pregnancy. Cross-sectional and longitudinal multivariable linear regression analyses were conducted. RESULTS: The depressive symptoms in our population increased, with a prevalence of probable depression from 5.4% in early pregnancy to 10.0% in late pregnancy (P < .001), whereas the anxiety symptoms decreased, with a prevalence of probable anxiety from 17.9% to 14.2% (P < .001). Characteristics associated with depressive or anxiety symptoms included low level of education, multiparity, a history of depression, severe nausea, extreme fatigue, lack of physical exercise, and negative life events. Being non-Dutch, not living with a partner, and having an unplanned pregnancy or a long time to pregnancy were associated with the depressive and/or anxiety symptoms in early pregnancy only. DISCUSSION: Symptoms of depression and anxiety are common in both early and late pregnancy. Screening for risk factors in early pregnancy is important, since prenatal depression and anxiety may be related to adverse maternal and child health outcomes.

A virtual asthma clinic for children: fewer routine outpatient visits, same asthma control.

eHealth is an appealing medium to improve healthcare and its value (in addition to standard care) has been assessed in previous studies. We aimed to assess whether an eHealth intervention could improve asthma control while reducing 50% of routine outpatient visits.In a multicentre, randomised controlled trial with a 16-month follow-up, asthmatic children (6-16 years) treated in eight Dutch hospitals were randomised to usual care (4-monthly outpatient visits) and online care using a virtual asthma clinic (VAC) (8-monthly outpatient visits with monthly web-based monitoring). Outcome measures were the number of symptom-free days in the last 4 weeks of the study, asthma control, forced expiratory volume in 1 s, exhaled nitric oxide fraction, asthma exacerbations, unscheduled outpatient visits, hospital admissions, daily dose of inhaled corticosteroids and courses of systemic corticosteroids.We included 210 children. After follow-up, symptom-free days differed statistically between the usual care and VAC groups (difference of 1.23 days, 95% CI 0.42-2.04; p=0.003) in favour of the VAC. In terms of asthma control, the Childhood Asthma Control Test improved more in the VAC group (difference of 1.17 points, 95% CI 0.09-2.25; p=0.03). No differences were found for other outcome measures.Routine outpatient visits can partly be replaced by monitoring asthmatic children via eHealth.

Ataxia-telangiectasia: recommendations for multidisciplinary treatment.

Ataxia-telangiectasia is a rare, neurodegenerative, and multisystem disease, characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, progressive respiratory failure, and an increased risk of malignancies. It demands specialized care tailored to the individual patient's needs. Besides the classic ataxia-telangiectasia phenotype, a variant phenotype exists with partly overlapping but some distinctive disease characteristics. This guideline summarizes frequently encountered medical problems in the disease course of patients with classic and variant ataxia-telangiectasia, in the domains of neurology, immunology and infectious diseases, pulmonology, anaesthetic and perioperative risk, oncology, endocrinology, and nutrition. Furthermore, it provides a practical guide with evidence- and expert-based recommendations for the follow-up and treatment of all these different clinical topics.

Cost-effectiveness of FENO-based and web-based monitoring in paediatric asthma management: a randomised controlled trial.

BACKGROUND: In children with asthma, web-based monitoring and inflammation-driven therapy may lead to improved asthma control and reduction in medications. However, the cost-effectiveness of these monitoring strategies is yet unknown. OBJECTIVE: We assessed the cost-effectiveness of web-based monthly monitoring and of 4-monthly monitoring of FENO as compared with standard care. METHODS: An economic evaluation was performed alongside a randomised controlled multicentre trial with a 1-year follow-up. Two hundred and seventy-two children with asthma, aged 4-18 years, were randomised to one of three strategies. In standard care, treatment was adapted according to Asthma Control Test (ACT) at 4-monthly visits, in the web-based strategy also according to web-ACT at 1 month intervals, and in the FENO-based strategy according to ACT and FENO at 4-monthly visits. Outcome measures were patient utilities, healthcare costs, societal costs and incremental cost per quality-adjusted life year (QALY) gained. RESULTS: No statistically significant differences were found in QALYs and costs between the three strategies. The web-based strategy had 77% chance of being most cost-effective from a healthcare perspective at a willingness to pay a generally accepted €40 000/QALY. The FENO-based strategy had 83% chance of being most cost-effective at €40 000/QALY from a societal perspective. CONCLUSIONS: Economically, web-based monitoring was preferred from a healthcare perspective, while the FENO-based strategy was preferred from a societal perspective, although in QALYs and costs no statistically significant changes were found as compared with standard care. As clinical outcomes also favoured the web-based and FENO-based strategies, these strategies may be useful additions to standard care. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NTR1995).

Prenatal maternal psychological stress and childhood asthma and wheezing: a meta-analysis.

The aim of this study was to systematically review and meta-analyse observational studies on prenatal maternal psychological stress and the subsequent development of asthma and wheezing in early childhood.All available published literature from 1960 until November 2013 was systematically searched through electronic databases (PubMed, Embase, PsycInfo and Web of Science). All observational studies assessing associations between any form of prenatal maternal psychological stress and respiratory morbidity in the child were included. Data extraction, quality assessment and meta-analyses were performed.The overall meta-analysis included 10 studies and showed that the prevalence of wheezing, asthma and other respiratory symptoms is higher in children of mothers who were exposed to or experienced some form of psychological stress during pregnancy than in mothers who did not (pooled OR 1.56 (95% CI 1.36-1.80)). Comparable results were observed in subgroup analyses of stress exposure, perceived stress, asthma and wheezing.This study demonstrates that prenatal maternal psychological stress is associated with respiratory morbidity, including asthma and wheezing in the child. Future studies examining the early origins of asthma and wheezing need to account for the impact of prenatal maternal stress.

Monitoring strategies in children with asthma: a randomised controlled trial.

BACKGROUND: Asthma guidelines recommend monitoring of asthma control. However, in a substantial proportion of children, asthma is poorly controlled and the best monitoring strategy is not known. OBJECTIVES: We studied two monitoring strategies for their ability to improve asthma outcomes in comparison with standard care (SC): web-based monthly monitoring with the (Childhood) Asthma Control Test (ACT or C-ACT) and 4-monthly monitoring of FENO. METHODS: In this randomised controlled, partly blinded, parallel group multicentre trial with a 1-year follow-up, children aged 4-18 with a doctor's diagnosis of asthma treated in seven hospitals were randomised to one of the three groups. In the web group, treatment was adapted according to ACT obtained via a website at 1-month intervals; in the FENO group according to ACT and FENO, and in the SC group according to the ACT at 4-monthly visits. The primary endpoint was the change from baseline in the proportion of symptom-free days (SFD). RESULTS: Two-hundred and eighty children (mean age 10.4 years, 66% boys) were included; 268 completed the study. Mean changes from baseline in SFD were similar between the groups: -2.1% (web group, n=90), +8.9% (FENO group, n=91) versus 0.15% (SC, n=87), p=0.15 and p=0.78. Daily dose of inhaled corticosteroids (ICS) decreased more in the web-based group compared with both other groups (-200 µg/day, p<0.01), while ACT and SFD remained similar. CONCLUSIONS: The change from baseline in SFD did not differ between monitoring strategies. With web-based ACT monitoring, ICS could be reduced substantially while control was maintained. TRIAL REGISTRATION NUMBER: NTR 1995.

Respiratory disease and respiratory physiology: putting lung function into perspective: paediatric asthma.

Dealing with paediatric asthma in daily practice, we are mostly interested in the airway function: the hallmark of asthma is the variability of airway patency. Various pulmonary function tests (PFT) can be used to quantify airway caliber in asthmatic children. The choice of the test is based on the developmental age of the child, knowledge of the diagnosis/underlying pathophysiology, clinical questions and reasoning, and treatment. PFT is performed to monitor the severity of asthma and the response to therapy, but can also be used as a diagnostic tool, and to study growth and development of the lungs and airways. This review aims to provide clinicians an overview of the differences in assessing PFT in infants and preschool children compared with older cooperative children, which tests are feasible in infants and young children, the limitations of and usefulness of these tests, and of their interpretation in these age groups.

Using Web-Based Questionnaires and Obstetric Records to Assess General Health Characteristics Among Pregnant Women: A Validation Study.

BACKGROUND: Self-reported medical history information is included in many studies. However, data on the validity of Web-based questionnaires assessing medical history are scarce. If proven to be valid, Web-based questionnaires may provide researchers with an efficient means to collect data on this parameter in large populations. OBJECTIVE: The aim of this study was to assess the validity of a Web-based questionnaire on chronic medical conditions, allergies, and blood pressure readings against obstetric records and data from general practitioners. METHODS: Self-reported questionnaire data were compared with obstetric records for 519 pregnant women participating in the Dutch PRegnancy and Infant DEvelopment (PRIDE) Study from July 2011 through November 2012. These women completed Web-based questionnaires around their first prenatal care visit and in gestational weeks 17 and 34. We calculated kappa statistics (κ) and the observed proportions of positive and negative agreement between the baseline questionnaire and obstetric records for chronic conditions and allergies. In case of inconsistencies between these 2 data sources, medical records from the woman's general practitioner were consulted as the reference standard. For systolic and diastolic blood pressure, intraclass correlation coefficients (ICCs) were calculated for multiple data points. RESULTS: Agreement between the baseline questionnaire and the obstetric record was substantial (κ=.61) for any chronic condition and moderate for any allergy (κ=.51). For specific conditions, we found high observed proportions of negative agreement (range 0.88-1.00) and on average moderate observed proportions of positive agreement with a wide range (range 0.19-0.90). Using the reference standard, the sensitivity of the Web-based questionnaire for chronic conditions and allergies was comparable to or even better than the sensitivity of the obstetric records, in particular for migraine (0.90 vs 0.40, P=.02), asthma (0.86 vs 0.61, P=.04), inhalation allergies (0.92 vs 0.74, P=.003), hay fever (0.90 vs 0.64, P=.001), and allergies to animals (0.89 vs 0.53, P=.01). However, some overreporting of allergies was observed in the questionnaire and for some nonsomatic conditions sensitivity of both measurement instruments was low. The ICCs for blood pressure readings ranged between 0.72 and 0.92 with very small mean differences between the 2 methods of data collection. CONCLUSIONS: Web-based questionnaires can be used to validly collect data on many chronic disorders, allergies, and blood pressure readings among pregnant women.

Monitoring childhood asthma: web-based diaries and the asthma control test.

BACKGROUND: Data from asthma diaries are frequently used as an end point in asthma studies; however, data on the validity of Web-based diaries are scarce. OBJECTIVES: First, we examined the validity of a Web-based diary in assessing asthma control. Second, we determined the cutoff points for well-controlled asthma of the Childhood Asthma Control Test (C-ACT) and the Asthma Control Test (ACT), and calculated the minimal important difference for both tests. METHODS: Children with asthma, ages 4-18 years (n = 228) completed a 4-week Web-based diary, C-ACT, ACT, and an asthma-related quality-of-life questionnaire at baseline and after 1-year follow-up. RESULTS: The completion rate of the Web-based diaries was 89%. The diary scores correlated strongly with C-ACT and ACT scores (r = -0.73, P < .01; r = -0.64, P < .01, respectively) and the changes in diary scores correlated well with changes in C-ACT and ACT scores. The best cutoff points for well-controlled asthma were C-ACT ≥ 22 and ACT ≥ 23. The minimal important differences were 1.9 (95% CI, 1.3-2.5) for ACT and 1.6 (95% CI, 1.1-2.1) for C-ACT, and -0.7 points/d (95% CI, -1.1 to -0.4) for the Web-based diary. CONCLUSIONS: Our Web-based diary was valid for recording asthma symptoms. Cutoff points of ≥22 (C-ACT) and ≥23 (ACT) define well-controlled asthma. We recommend a 2 C-ACT and ACT points difference as minimally important.

Classification and pharmacological treatment of preschool wheezing: changes since 2008.

Since the publication of the European Respiratory Society Task Force report in 2008, significant new evidence has become available on the classification and management of preschool wheezing disorders. In this report, an international consensus group reviews this new evidence and proposes some modifications to the recommendations made in 2008. Specifically, the consensus group acknowledges that wheeze patterns in young children vary over time and with treatment, rendering the distinction between episodic viral wheeze and multiple-trigger wheeze unclear in many patients. Inhaled corticosteroids remain first-line treatment for multiple-trigger wheeze, but may also be considered in patients with episodic viral wheeze with frequent or severe episodes, or when the clinician suspects that interval symptoms are being under reported. Any controller therapy should be viewed as a treatment trial, with scheduled close follow-up to monitor treatment effect. The group recommends discontinuing treatment if there is no benefit and taking favourable natural history into account when making decisions about long-term therapy. Oral corticosteroids are not indicated in mild-to-moderate acute wheeze episodes and should be reserved for severe exacerbations in hospitalised patients. Future research should focus on better clinical and genetic markers, as well as biomarkers, of disease severity.

Maternal depressive symptoms during pregnancy and infant wheezing up to 2 years of age.

PURPOSE: To determine whether maternal depressive symptoms at multiple time points during pregnancy are associated with infant wheezing in the first 2 years of life to assess etiologically relevant time windows. METHODS: We included Dutch women participating in the PRIDE Study with delivery in 2013-2019. Maternal depressive symptoms were assessed with the Hospital Anxiety and Depression Scale and Edinburgh Depression Scale at enrollment and in gestational weeks 17 and 34. The International Study of Asthma and Allergies in Childhood questionnaire was used to assess infant wheezing biannually postpartum. Adjusted risk ratios (RRs) and 95% confidence intervals (CIs) were estimated with modified Poisson regression. RESULTS: Among 5294 pregnancies included, maternal depressive symptoms in gestational weeks 15-22 was associated with any wheezing in the first 2 years of life (RR 1.36, 95% CI 1.04-1.78) and with current wheezing at 12 (RR 1.29, 95% CI 1.03-1.61) and 18 months (RR 1.33, 1.04-1.69). Depressive symptoms in gestational weeks 32-35 seemed to be associated with any wheezing reported at two years (RR 1.27, 95% CI 0.96-1.69) and current wheezing at 12 months (RR 1.28, 95% CI 1.02-1.60). Four trajectories of depressive symptoms were identified. Only the trajectory with increasing symptoms throughout pregnancy seemed to be associated with infant wheezing (RR 1.36, 95% CI 0.97-1.89). CONCLUSIONS: Maternal depressive symptoms in mid- and late pregnancy may be associated with development of infant wheezing, particularly those with onset in the second half of pregnancy. Research is needed to identify biological pathways and associations with more objective, long-term respiratory morbidity.