Infant lung function and early skin barrier impairment in the development of asthma at age 3 years.

BACKGROUND: Largely unexplored, we investigated if lower lung function, impaired skin barrier function by transepidermal water loss (TEWL), eczema, and filaggrin (FLG) mutations in infancy were associated with asthma in early childhood. METHODS: From the factorially designed randomized controlled intervention study PreventADALL, we evaluated 1337/2394 children from all randomization groups with information on asthma at age 3 years, and at age 3 months either lung function, TEWL, eczema, and/or FLG mutations. Lower lung function was defined as the time to peak tidal expiratory flow to expiratory time (tPTEF /tE ) <0.25, and skin barrier impairment as a high TEWL >9.50 g/m2 /h. Eczema was clinically observed, and DNA genotyped for FLG mutations. Asthma was defined as asthma-like symptoms (≥3 episodes of bronchial obstruction) between age 2-3 years as well as a history of doctor-diagnosed asthma and/or asthma medication use. Associations were analyzed in logistic regression models, presented with adjusted ORs (aOR) and 95% confidence intervals (CI). RESULTS: Lower lung function and skin barrier impairment were associated with asthma in general; aOR (95% CI) 5.4 (2.1, 13.7) and 1.6 (1.1, 2.5), while eczema and FLG mutations were associated with asthma in children with atopic dermatitis or allergic sensitization only. Stratifying for sex, the risk of asthma was only increased in boys with lower lung function; aOR (95% CI) 7.7 (2.5, 23.6), and in girls with FLG mutations; aOR (95% CI) 3.5 (1.5, 8.2). CONCLUSION: Lower lung function and impaired skin barrier function in infancy may increase the risk of asthma at age 3 years.

Early food intervention and skin emollients to prevent food allergy in young children (PreventADALL): a factorial, multicentre, cluster-randomised trial.

BACKGROUND: Primary prevention of food allergy by early introduction of allergenic foods seems promising. We aimed to determine whether early food introduction or the application of regular skin emollients in infants from a general population reduced the risk of food allergy. METHODS: This 2 × 2 factorial, cluster-randomised trial was done at Oslo University Hospital and Østfold Hospital Trust, Oslo, Norway, and Karolinska University Hospital, Stockholm, Sweden. Infants of women recruited antenatally at the routine 18-week ultrasound examination were cluster-randomised at birth to the following groups: (1) no intervention group; (2) the skin intervention group (skin emollients; bath additives and facial cream; from age 2 weeks to <9 months, both at least four times per week); (3) the food intervention group (early complementary feeding of peanut, cow's milk, wheat, and egg from age 3 months); or (4) combined intervention group (skin and food interventions). Participants were randomly assigned (1:1:1:1) using computer-generated randomisation based on clusters of 92 geographical areas and eight 3-month time blocks. Study personnel performing clinical assessments were masked to group allocation. The primary outcome was allergy to any interventional food at 36 months of age. The primary efficacy analysis was done by intention-to-treat analysis, which included all participants who were randomly assigned, apart from three individuals who withdrew their consent. This was a study performed within ORAACLE (the Oslo Research Group of Asthma and Allergy in Childhood; the Lung and Environment). This study is registered as ClinicalTrials.gov, NCT02449850. FINDINGS: We recruited 2697 women with 2701 pregnancies, from whom 2397 newborn infants were enrolled between April 14, 2015, and April 11, 2017. Of these infants, 597 were randomly assigned to the no intervention group, 575 to the skin intervention group, 642 to the food intervention group, and 583 to the combined intervention group. One participant in each of the no intervention, food intervention, and skin intervention groups withdrew consent and were therefore not included in any analyses. Food allergy was diagnosed in 44 children; 14 (2·3%) of 596 infants in the non-intervention group, 17 (3·0%) of 574 infants in the skin intervention group, six (0·9%) of 641 infants in the food intervention group, and seven (1·2%) of 583 infants in the combined intervention group. Peanut allergy was diagnosed in 32 children, egg allergy in 12 children, and milk allergy in four children. None had allergy to wheat. Prevalence of food allergy was reduced in the food intervention group compared with the no food intervention group (risk difference -1·6% [95% CI -2·7 to -0·5]; odds ratio [OR] 0·4 [95% CI 0·2 to 0·8]), but not compared with the skin intervention group (0·4% [95% CI -0·6 to 1· 5%]; OR 1·3 [0·7 to 2·3]), with no significant interaction effect (p=1·0). Preventing food allergy in one child required early exposure to allergenic foods in 63 children. No serious adverse events were observed. INTERPRETATION: Exposure to allergenic foods from 3 months of age reduced food allergy at 36 months in a general population. Our results support that early introduction of common allergenic foods is a safe and effective strategy to prevent food allergy. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

Clinical Trial Considerations in Developing Treatments for Early Stages of Common, Chronic Kidney Diseases: A Scientific Workshop Cosponsored by the National Kidney Foundation and the US Food and Drug Administration.

In the past decade, advances in the validation of surrogate end points for chronic kidney disease (CKD) progression have heightened interest in evaluating therapies in early CKD. In December 2020, the National Kidney Foundation sponsored a scientific workshop in collaboration with the US Food and Drug Administration (FDA) to explore patient, provider, and payor perceptions of the value of treating early CKD. The workshop reviewed challenges for trials in early CKD, including trial designs, identification of high-risk populations, and cost-benefit and safety considerations. Over 90 people representing a range of stakeholders including experts in clinical trials, nephrology, cardiology and endocrinology, patient advocacy organizations, patients, payors, health economists, regulators and policy makers attended a virtual meeting. There was consensus among the attendees that there is value to preventing the development and treating the progression of early CKD in people who are at high risk for progression, and that surrogate end points should be used to establish efficacy. Attendees also concluded that cost analyses should be holistic and include aspects beyond direct savings for treatment of kidney failure; and that safety data should be collected outside/beyond the duration of a clinical trial. Successful drug development and implementation of effective therapies will require collaboration across sponsors, patients, patient advocacy organizations, medical community, regulators, and payors.

Fetal Thoracic Circumference and Lung Volume and Their Relation to Fetal Size and Pulmonary Artery Blood Flow.

OBJECTIVE: Research on early origins of lung disease suggests the need for studying the relationships of thoracic and lung size with fetal size and pulmonary circulation. The primary aim of this study is therefore to explore the associations between fetal thoracic circumference, lung volume, and fetal size. We also aim to assess if lung volume and thoracic circumference are associated with fetal pulmonary artery blood flow velocity measures. METHODS: Cross-sectional assessment of singleton pregnancies from the general population (n = 447) at 30 gestational weeks (GW) was performed using ultrasound measurement of fetal thoracic circumference, lung volume, head and abdominal circumference, and femur length. We obtained Doppler blood flow velocity measures from the proximal branches of the fetal pulmonary artery. Associations between variables were studied using Pearson's correlation and multiple linear regression analyses. RESULTS: Both thoracic circumference and lung volume correlated with fetal size measures, ranging from r = 0.64 between thoracic circumference and abdominal circumference, to r = 0.28 between lung volume and femur length. Adjustment for gestational age, maternal nicotine use, pre-pregnancy body mass index, and fetal sex marginally influenced the associations with abdominal circumference. The correlations of thoracic circumference and lung volume with pulmonary artery blood flow velocity measures were weak (r ≤ 0.17). CONCLUSION: We found moderate to low correlation between thoracic circumference, lung volume, and fetal size at 30 GW. The closest relationship was with the abdominal circumference. We found low correlations of thoracic circumference and lung volume with pulmonary artery blood flow velocity measures.

Skin emollient and early complementary feeding to prevent infant atopic dermatitis (PreventADALL): a factorial, multicentre, cluster-randomised trial.

BACKGROUND: Skin emollients applied during early infancy could prevent atopic dermatitis, and early complementary food introduction might reduce food allergy in high-risk infants. The study aimed to determine if either regular skin emollients applied from 2 weeks of age, or early complementary feeding introduced between 12 and 16 weeks of age, reduced development of atopic dermatitis by age 12 months in the general infant population. METHODS: This population-based 2×2 factorial, randomised clinical trial was done at Oslo University Hospital and Østfold Hospital Trust, Oslo, Norway; and Karolinska University Hospital, Stockholm, Sweden. Infants of women recruited antenatally at the routine ultrasound pregnancy screening at 18 weeks were cluster-randomised at birth from 2015 to 2017 to the following groups: (1) controls with no specific advice on skin care while advised to follow national guidelines on infant nutrition (no intervention group); (2) skin emollients (bath additives and facial cream; skin intervention group); (3) early complementary feeding of peanut, cow's milk, wheat, and egg (food intervention group); or (4) combined skin and food interventions (combined intervention group). Participants were randomly assigned (1:1:1:1) using computer- generated cluster randomisation based on 92 geographical living area blocks as well as eight 3-month time blocks. Carers were instructed to apply the interventions on at least 4 days per week. Atopic dermatitis by age 12 months was the primary outcome, based on clinical investigations at 3, 6 and 12 months by investigators masked to group allocation. Atopic dermatitis was assessed after completing the 12-month investigations and diagnosed if either of the UK Working Party and Hanifin and Rajka (12 months only) diagnostic criteria were fulfilled. The primary efficacy analyses was done by intention-to-treat analysis on all randomly assigned participants. Food allergy results will be reported once all investigations at age 3 years are completed in 2020. This was a study performed within ORAACLE (the Oslo Research Group of Asthma and Allergy in Childhood; the Lung and Environment). The study is registered at clinicaltrials.gov, NCT02449850. FINDINGS: 2697 women were recruited between Dec 9, 2014, and Oct 31, 2016, from whom 2397 newborn infants were enrolled from April 14, 2015, to April 11, 2017. Atopic dermatitis was observed in 48 (8%) of 596 infants in the no intervention group, 64 (11%) of 575 in the skin intervention group, 58 (9%) of 642 in the food intervention group, and 31 (5%) of 583 in the combined intervention group. Neither skin emollients nor early complementary feeding reduced development of atopic dermatitis, with a risk difference of 3·1% (95% CI -0·3 to 6·5) for skin intervention and 1·0% (-2·1 to 4·1) for food intervention, in favour of control. No safety concerns with the interventions were identified. Reported skin symptoms and signs (including itching, oedema, exanthema, dry skin, and urticaria) were no more frequent in the skin, food, and combined intervention groups than in the no intervention group. INTERPRETATION: Neither early skin emollients nor early complementary feeding reduced development of atopic dermatitis by age 12 months. Our study does not support the use of these interventions to prevent atopic dermatitis by 12 months of age in infants. FUNDING: The study was funded by several public and private funding bodies: The Regional Health Board South East, The Norwegian Research Council, Health and Rehabilitation Norway, The Foundation for Healthcare and Allergy Research in Sweden-Vårdalstiftelsen, Swedish Asthma and Allergy Association's Research Foundation, Swedish Research Council-the Initiative for Clinical Therapy Research, The Swedish Heart-Lung Foundation, SFO-V at the Karolinska Institute, Freemason Child House Foundation in Stockholm, Swedish Research Council for Health, Working Life and Welfare-FORTE, Oslo University Hospital, the University of Oslo, and Østfold Hospital Trust.

Extract and molecular-based early infant sensitization and associated factors-A PreventADALL study.

BACKGROUND: More knowledge about sensitization patterns in early infancy, including impact of molecular allergology, is needed to help predict future allergy development more accurately. OBJECTIVE: We aimed to determine the prevalence and patterns of allergic sensitization at 3 months of age, and explore possible associated factors. METHODS: From the Scandinavian antenatally recruited PreventADALL mother-child cohort, we included 1110 3-month infants with available serum. Sensitization was defined as s-IgE of ≥0.1 kUA /L by Phadiatop Infant® (ThermoFisher Scientific) including birch, cat, grass, dog, milk, egg, peanut and wheat. Further ImmunoCAP analyses to ovomucoid, casein, Ara h 1-3, omega-5-gliadin were performed in food extract s-IgE-positive children. Maternal sensitization was defined as s-IgE ≥ 0.35 kUA /L to Phadiatop® (inhalant allergen mix) and/or Fx5 (food allergen mix) at 18-week pregnancy. RESULTS: Overall 79 (7.3%) infants had specific sensitization, many with low s-IgE-levels (IQR 0.16-0.81 kUA /L), with 78 being sensitized to food extract allergens; 41 to egg, 27 to milk, 10 to peanut, and 25 to wheat. A total of 62/78 were further analysed, 18 (29%) had s-IgE to ovomucoid, casein, Ara h 1-3 and/or omega-5-gliadin. Eight infants (0.7%) were sensitized to inhalant allergens. Maternal sensitization to food allergens was associated with infant sensitization, odds ratio 3.64 (95% CI 1.53-8.68). CONCLUSION: Already at 3 months of age, 7% were sensitized to food, mostly without detectable s-IgE to food allergen molecules, and <1% to inhalant allergens. Maternal food sensitization was associated with infants' sensitization.

Maternal use of nicotine products and breastfeeding 3 months postpartum.

AIM: We aimed to determine the prevalence of and factors associated with maternal use of nicotine products in relation to breastfeeding. METHODS: Nicotine use 3 months postpartum was determined in the Scandinavian PreventADALL mother-child birth cohort study recruiting 1837 women from 2014 to 2016. Electronic questionnaires at 18 weeks pregnancy and 3 months postpartum provided information on snus use, smoking or other nicotine use, infant feeding and socio-economic factors. The risk of nicotine use in relation to breastfeeding was analysed with logistic regression. RESULTS: Overall, 5.6% of women used snus (2.9%), smoked (2.7%) or both (n = 2) 3 months postpartum, while one used other nicotine products. Among the 1717 breastfeeding women, 95.1% reported no nicotine use, while 2.4% used snus, 2.5% smoked and one dual user. Compared to 3.7% nicotine use in exclusively breastfeeding women (n = 1242), the risk of nicotine use increased by partly (OR 2.26, 95% CI 1.45-3.52) and no breastfeeding (OR 4.58, 95% CI 2.57-8.21). Nicotine use before (14.5% snus, 16.4% smoking) or in pregnancy (0.2% snus, 0.4% smoking) significantly increased the risk of using nicotine during breastfeeding. CONCLUSION: Few breastfeeding women used snus or smoked 3 months postpartum, with increased risk by nicotine use before or during pregnancy.

Aortic stiffness and change in glomerular filtration rate and albuminuria in older people.

BACKGROUND: Aortic stiffness increases with age and increases pulsatile stress in the microcirculation. Abnormalities in kidney microvascular structure and function may contribute to development or progression of chronic kidney disease in older people. METHODS: We performed a longitudinal analysis of 629 community-dwelling elderly Icelandic adults from the Age, Gene/Environment Susceptibility-Reykjavik Study with two visits over a mean follow-up of 5.3 years. We evaluated the associations of carotid-femoral pulse wave velocity (CFPWV), carotid pulse pressure (CPP) and augmentation index (AI), with the change in estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) assessed as annual change and dichotomized as large changes. Models were adjusted for age, sex, height, heart rate, traditional cardiovascular disease risk factors and baseline kidney measures. RESULTS: When eGFR was analyzed as a continuous variable, higher baseline CFPWV and CPP, but not AI, were significantly associated with a larger annual decline in eGFR in models adjusted for age, sex, height, heart rate and baseline eGFR, but not after additional adjustment for the mean arterial pressure. When eGFR was analyzed as a categorical variable, higher CFPWV was significantly associated with a decrease in eGFR of ≥3 mL/min/1.73 m 2 /year [odds ratio (OR) 1.53, 95% confidence interval (CI) 1.11-2.13] and higher AI was associated with 30% eGFR decline during follow-up (OR 1.44 and 95% CI 1.03-2.00) in fully adjusted models. None of the tonometry measures was associated with change in UACR. CONCLUSIONS: Abnormalities in vascular health may play a role in large declines in eGFR beyond the traditional cardiovascular disease risks in this older Icelandic cohort.

Prevalence and complications of chronic kidney disease in a representative elderly population in Iceland.

BACKGROUND: Chronic kidney disease (CKD) is common in the elderly, but data are limited on the distribution of glomerular filtration rate (GFR) and albuminuria and the prevalence of CKD and related complications in this population. METHODS: A cross-sectional study of 3173 older Icelandic adults [42% men; mean (standard deviation, SD) age of 80 (5) years] was performed to examine the distribution of estimated glomerular filtration rate (eGFR) from creatinine and cystatin C, the albumin-to-creatinine ratio (ACR), and CKD-related metabolic complications (hyperparathyroidism, anemia, hypoalbuminemia, increased anion gap, acidosis, hyperphosphatemia and hyperkalemia). RESULTS: There was substantial variability in eGFR [mean (SD) 64 (18) mL/min/1.73 m(2)] and ACR [median (interquartile range) 8 (5, 17) mg/g]. The prevalence (95% confidence interval) of reduced eGFR (<60 mL/min/1.73 m(2)), albuminuria (ACR >30 mg/g) and CKD (either reduced eGFR or albuminuria) was 40% (38-41), 14% (12-15) and 45% (43-47), respectively. The prevalence of complications was higher among those with versus without CKD: hyperparathyroidism (38 versus 15%), anemia (26 versus 14%), hypoalbuminemia (19 versus 13%), increased anion gap (9 versus 5%), acidosis (5 versus 1%); (P ≤ 0.02 for all), except hyperphosphatemia (1 versus 1%) and hyperkalemia (0% overall). CONCLUSIONS: The burden of CKD and CKD-related complications is high among community dwelling elderly Icelandic adults. The wide range of eGFR and ACR suggests heterogeneity in processes leading to CKD and that factors beyond aging contribute to the development of CKD in the elderly.

Comparing GFR Estimating Equations Using Cystatin C and Creatinine in Elderly Individuals.

Current guidelines recommend reporting eGFR using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations unless other equations are more accurate, and recommend the combination of creatinine and cystatin C (eGFRcr-cys) as more accurate than either eGFRcr or eGFRcys alone. However, preferred equations and filtration markers in elderly individuals are debated. In 805 adults enrolled in the community-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, we measured GFR (mGFR) using plasma clearance of iohexol, standardized creatinine and cystatin C, and eGFR using the CKD-EPI, Japanese, Berlin Initiative Study (BIS), and Caucasian and Asian pediatric and adult subjects (CAPA) equations. We evaluated equation performance using bias, precision, and two measures of accuracy. We first compared the Japanese, BIS, and CAPA equations with the CKD-EPI equations to determine the preferred equations, and then compared eGFRcr and eGFRcys with eGFRcr-cys using the preferred equations. Mean (SD) age was 80.3 (4.0) years. Median (25th, 75th) mGFR was 64 (52, 73) ml/min per 1.73 m(2), and the prevalence of decreased GFR was 39% (95% confidence interval, 35.8 to 42.5). Among 24 comparisons with the other equations, CKD-EPI equations performed better in 9, similar in 13, and worse in 2. Using the CKD-EPI equations, eGFRcr-cys performed better than eGFRcr in four metrics, better than eGFRcys in two metrics, and similar to eGFRcys in two metrics. In conclusion, neither the Japanese, BIS, nor CAPA equations were superior to the CKD-EPI equations in this cohort of community-dwelling elderly individuals. Using the CKD-EPI equations, eGFRcr-cys performed better than eGFRcr or eGFRcys.

Midlife Blood Pressure and Late-Life GFR and Albuminuria: An Elderly General Population Cohort.

BACKGROUND: Chronic kidney disease (CKD) is common in the elderly, but the cause is often not identifiable. Some posit that age-related reductions in glomerular filtration rate (GFR) and increases in albuminuria are normal, whereas others suggest that they are a consequence of vascular disease. STUDY DESIGN: Cross-sectional analysis of a substudy of a prospective cohort. SETTING & PARTICIPANTS: AGES (Age, Gene/Environment Susceptibility)-Reykjavik Study. PREDICTOR: Exposure to higher blood pressure in midlife. OUTCOMES & MEASUREMENTS: Measured GFR using plasma clearance of iohexol and urine albumin-creatinine ratio. RESULTS: GFR was measured in 805 participants with mean age in midlife and late life of 51.0±5.8 and 80.8±4.0 (SD) years, respectively. Mean measured GFR was 62.4±16.5 mL/min/1.73 m(2) and median albuminuria was 8.0 (IQR, 5.4-16.5) mg/g. Higher midlife systolic and diastolic blood pressures were associated with lower later-life GFRs. Associations persisted after adjustment. Higher midlife systolic and diastolic blood pressures were also associated with higher albumin-creatinine ratios, and associations remained significant even after adjustment. LIMITATIONS: This is a study of survivors, and people who agreed to participate in this study were healthier than those who refused. Blood pressure may encompass effects of the other risk factors. Results may not be generalizable to populations of other races. We were not able to adjust for measured GFR or albuminuria at the midlife visit. CONCLUSIONS: Factors other than advanced age may account for the high prevalence of CKD in the elderly. Midlife factors are potential contributing factors to late-life kidney disease. Further studies are needed to identify and treat midlife modifiable factors to prevent the development of CKD.

A new non-invasive method of infant spirometry demonstrates a level of repeatability that is comparable to traditional methods.

AIM: The FloRight system provides novel non-invasive infant spirometry based on electromagnetic inductance plethysmography. We investigated the consistency of repeated measurements carried out in a Norwegian neonatal intensive care unit (NICU) using the system and how well these were tolerated. METHODS: Tidal flow-volume loops were obtained from 10 preterm infants at discharge, 10 stable growing preterm infants weighing about 1500 g and 10 term-born infants. A nurse experienced with the system measured all patients before and after meals, and these measurements were repeated by nurses new to the system. RESULTS: The measurements were well tolerated by the infants. The repeatability for the two parameters 'tidal volume' (Vt) and 'time to peak tidal expiratory flow to total expiratory time' (Tptef/Te) were relatively poor, similar to previous methods. However, the repeatability was good for the new 'flow-volume gravity mid-point' (FVg) parameter. Repeatability was better for term than preterm infants, when measurements were obtained by the experienced nurse and for measurements carried out before meals. CONCLUSION: The FloRight system proved feasible in a NICU setting. The repeatability of the lung function measurements was similar to those reported for traditional infant spirometry. The nurse's experience and the relationship to meals appeared to be important.

Maternal use of snus as smokeless tobacco in pregnancy and infant lung function.

Background: Smoking in pregnancy has detrimental effects on infant respiratory health, while the effects of other nicotine-containing products on infant lung function are unclear. We aimed to explore if smokeless tobacco such as snus used in pregnancy increased the risk of lower lung function in infancy and if the associations differed by sex. Methods: From the Scandinavian population-based Preventing Atopic Dermatitis and ALLergies in Children birth cohort, we included 1163 infants with available tidal flow-volume measurements at 3 months of age and maternal self-reported use of nicotine-containing products in pregnancy. The risk of a ratio of time to peak tidal expiratory flow to total expiratory time <25th percentile by any nicotine exposure, snus exclusively and cigarette smoking with or without other nicotine-containing products was explored by regression analyses adjusting for maternal age, education and asthma. Results: Overall 120 out of 1163 (10.3%) infants were exposed to any nicotine in utero, 71 out of 120 by snus exclusively and 49 out of 120 by smoking, with six also exposed to snus. By pregnancy week 6, 85.8% of mothers reported stopping nicotine use. The risk of lower lung function was higher in children exposed in utero to nicotine-containing products with an odds ratio (OR) of 1.63 (95% confidence interval (CI) 1.02-2.59) with a similar tendency for snus exclusively (OR 1.55, 95% CI 0.88-2.71) and smoking (OR 1.79, 0.84-3.84). Effect estimates were similar after adjusting for covariates. No differences of the effect by sex were observed. Conclusion: Our study suggests that in utero exposure to not only cigarettes, but also snus, may negatively affect infant lung function.

The gene encoding phosphodiesterase 4D confers risk of ischemic stroke.

We previously mapped susceptibility to stroke to chromosome 5q12. Here we finely mapped this locus and tested it for association with stroke. We found the strongest association in the gene encoding phosphodiesterase 4D (PDE4D), especially for carotid and cardiogenic stroke, the forms of stroke related to atherosclerosis. Notably, we found that haplotypes can be classified into three distinct groups: wild-type, at-risk and protective. We also observed a substantial disregulation of multiple PDE4D isoforms in affected individuals. We propose that PDE4D is involved in the pathogenesis of stroke, possibly through atherosclerosis, which is the primary pathological process underlying ischemic stroke.

Fetal thoracic circumference in mid-pregnancy and infant lung function.

BACKGROUND AND AIM: Impaired lung function in early infancy is associated with later wheeze and asthma, while fetal thoracic circumference (TC) predicts severity of neonatal lung hypoplasia. Exploring fetal origins of lung function in infancy, we aimed to determine if fetal TC in mid-pregnancy was associated with infant lung function. METHODS: From the prospective Scandinavian general population-based PreventADALL mother-child birth cohort, all 851 3-month-old infants with tidal flow-volume measurements in the awake state and ultrasound fetal size measures at 18 (min-max 16-22) weeks gestational age were included. Associations between fetal TC and time to peak tidal expiratory flow to expiratory time (tPTEF /tE ) were analyzed in linear regression models. To account for gestational age variation, we adjusted TC for simultaneously measured general fetal size, by head circumference (TC/HC), abdominal circumference (TC/AC), and femur length (TC/FL). Multivariable models were adjusted for maternal age, maternal asthma, pre-pregnancy body mass index, parity, nicotine exposure in utero, and infant sex. RESULTS: The infants (47.8% girls) were born at mean (SD) gestational age of 40.2 (1.30) weeks. The mean (SD) tPTEF /tE  was 0.39 (0.08). The mean (SD) TC/HC was 0.75 (0.04), TC/AC 0.87 (0.04), and TC/FL 4.17 (0.26), respectively. Neither TC/HC nor TC/AC were associated with infant tPTEF /tE while a week inverse association was observed between TC/FL and tPTEF /tE  ( ß ^ $\hat{\beta }$ = -0.03, 95% confidence interval [-0.05, -0.007], p = 0.01). CONCLUSION: Mid-pregnancy fetal TC adjusted for fetal head or abdominal size was not associated with tPTEF /tE in healthy, awake 3-month-old infants, while a weak association was observed adjusting for fetal femur length.

Third trimester fetal lung volume, thoracic circumference, and early infant lung function.

BACKGROUND: We aimed to investigate the relationship between fetal third trimester lung volume (LV), thoracic circumference (TC), fetal weight, as well as fetal thoracic and weight growth, and early infant lung function. METHODS: Fetal LV, TC and estimated weight were measured with ultrasound at 30 gestational weeks in 257 fetuses from the general population-based prospective cohort study Preventing Atopic Dermatitis and ALLergies in Children (PreventADALL). Fetal thoracic growth rate and weight increase were calculated using TC and estimated fetal weight measured by ultrasound during pregnancy, and TC and birthweight of the newborn. Lung function was assessed by tidal flow-volume measurement in awake infants at 3 months of age. The associations between fetal size (LV, TC, and estimated weight) and growth (thoracic growth rate and fetal weight increase) measures and the time to peak tidal expiratory flow to expiratory time ratio (tPTEF /tE ) as well as tidal volume standardized for body weight (VT /kg) were analyzed using linear and logistic regression models. RESULTS: We observed no associations between fetal LV, TC or estimated fetal weight and tPTEF /tE as a continuous variable, tPTEF /tE < 25th percentile, or VT /kg. Similarly, fetal thoracic growth and weight increase were not associated with infant lung function. Analyses stratified for sex showed a significant inverse association between fetal weight increase and VT /kg (p = 0.02) in girls. CONCLUSION: Overall, fetal third trimester LV, TC, estimated fetal weight, thoracic growth rate and weight increase were not associated with infant lung function at 3 months of age.

Birth mode is associated with development of atopic dermatitis in infancy and early childhood.

Background: Birth by caesarean section (CS) is associated with development of allergic diseases, but its role in the development of atopic dermatitis (AD) is less convincing. Objective: Our primary aim was to determine if birth mode was associated with AD in 3-year-olds and secondarily to determine if birth mode was associated with early onset and/or persistent AD in the first 3 years of life. Methods: We included 2129 mother-child pairs from the Scandinavian population-based prospective PreventADALL cohort with information on birth mode including vaginal birth, either traditional (81.3%) or in water (4.0%), and CS before (6.3%) and after (8.5%) onset of labor. We defined early onset AD as eczema at 3 months and AD diagnosis by 3 years of age. Persistent AD was defined as eczema both in the first year and at 3 years of age, together with an AD diagnosis by 3 years of age. Results: AD was diagnosed at 3, 6, 12, 24, and/or 36 months in 531 children (25%). Compared to vaginal delivery, CS was overall associated with increased odds of AD by 3 years of age, with adjusted odds ratio (95% confidence interval) of 1.33 (1.02-1.74), and higher odds of early onset AD (1.63, 1.06-2.48). The highest odds for early onset AD were observed in infants born by CS after onset of labor (1.83, 1.09-3.07). Birth mode was not associated with persistent AD. Conclusion: CS was associated with increased odds of AD by 3 years of age, particularly in infants presenting with eczema at 3 months of age.

Fetal pulmonary artery Doppler blood flow velocity measures and early infant lung function. A prospective cohort study.

BACKGROUND: Reduced lung function at birth has evident antenatal origins and is associated with an increased risk of wheezing and asthma later in life. Little is known about whether blood flow in the fetal pulmonary artery, may impact postnatal lung function. OBJECTIVE: Our primary aim was to investigate the potential associations between fetal Doppler blood flow velocity measures in the fetal branch pulmonary artery, and infant lung function by tidal flow-volume (TFV) loops at three months of age in a low-risk population. Our secondary aim was to explore the association between Doppler blood flow velocity measures in the umbilical and middle cerebral arteries, and the same lung function measures. METHODS: In 256 non-selected pregnancies from the birth cohort study Preventing Atopic Dermatitis and ALLergies in Children (PreventADALL) we performed fetal ultrasound examination with Doppler blood flow velocity measurements at 30 gestational weeks (GW). We recorded the pulsatility index, peak systolic velocity, time-averaged maximum velocity, acceleration time/ejection time ratio, and time velocity integral primarily in the proximal pulmonary artery close to the pulmonary bifurcation. The pulsatility index was measured in the umbilical and middle cerebral arteries and the peak systolic velocity in the middle cerebral artery. The cerebro-placental ratio (ratio between pulsatility index in the middle cerebral and umbilical arteries) was calculated. Infant lung function was assessed using TFV loops in awake, calmly breathing three months old infants. The outcome was the time to peak tidal expiratory flow to expiratory time ratio (tPTEF/tE), tPTEF/tE <25th percentile, and tidal volume per kg body weight (VT/kg). Potential associations between fetal Doppler blood flow velocity measures and infant lung function were assessed using linear and logistic regressions. RESULTS: The infants were born at median (min - max) 40.3 (35.6 - 42.4) GW, with a mean (SD) birth weight of 3.52 (0.46) kg, and 49.4% were females. The mean (SD) tPTEF/tE was 0.39 (0.1) and the 25th percentile was 0.33. Neither univariable nor multivariable regression models revealed any associations between fetal pulmonary blood flow velocity measures and tPTEF/tE, tPTEF/tE <25th percentile, or VT/kg at three months of age. Similarly, we did not observe associations between Doppler blood flow velocity measures in the umbilical and middle cerebral arteries and infant lung function measures. CONCLUSION: In a cohort of 256 infants from the general population, fetal third-trimester Doppler blood flow velocity measures in the branch pulmonary, umbilical, and middle cerebral arteries were not associated with infant lung function measures at three months of age.

Skin Barrier Function and Infant Tidal Flow-Volume Loops-A Population-Based Observational Study.

Background: The relationship between the skin barrier- and lung function in infancy is largely unexplored. We aimed to explore if reduced skin barrier function by high transepidermal water loss (TEWL), or manifestations of eczema or Filaggrin (FLG) mutations, were associated with lower lung function in three-month-old infants. Methods: From the population-based PreventADALL cohort, 899 infants with lung function measurements and information on either TEWL, eczema at three months of age and/or FLG mutations were included. Lower lung function by tidal flow-volume loops was defined as a ratio of time to peak tidal expiratory flow to expiratory time (tPTEF/tE) <0.25 and a tPTEF <0.17 s (<25th percentile). A high TEWL >8.83 g/m2/h (>75th percentile) denoted reduced skin barrier function, and DNA was genotyped for FLG mutations (R501X, 2282del4 and R2447X). Results: Neither a high TEWL, nor eczema or FLG mutations, were associated with a lower tPTEF/tE. While a high TEWL was associated with a lower tPTEF; adjusted OR (95% CI) 1.61 (1.08, 2.42), the presence of eczema or FLG mutations were not. Conclusions: Overall, a high TEWL, eczema or FLG mutations were not associated with lower lung function in healthy three-month-old infants. However, an inverse association between high TEWL and tPTEF was observed, indicating a possible link between the skin barrier- and lung function in early infancy.