Publications by authors named "Liesbeth Duijts"

162 Publications

Maternal Iron Status in Pregnancy and Child Health Outcomes after Birth: A Systematic Review and Meta-Analysis.

Nutrients 2021 Jun 28;13(7). Epub 2021 Jun 28.

Department of Pediatrics, Division of Neonatology, Erasmus MC-Sophia, University Medical Center, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands.

In pregnancy, iron deficiency and iron overload increase the risk for adverse pregnancy outcomes, but the effects of maternal iron status on long-term child health are poorly understood. The aim of the study was to systematically review and analyze the literature on maternal iron status in pregnancy and long-term outcomes in the offspring after birth. We report a systematic review on maternal iron status during pregnancy in relation to child health outcomes after birth, from database inception until 21 January 2021, with methodological quality rating (Newcastle-Ottawa tool) and random-effect meta-analysis. (PROSPERO, CRD42020162202). The search identified 8139 studies, of which 44 were included, describing 12,7849 mother-child pairs. Heterogeneity amongst the studies was strong. Methodological quality was predominantly moderate to high. Iron status was measured usually late in pregnancy. The majority of studies compared categories based on maternal ferritin, however, definitions of iron deficiency differed across studies. The follow-up period was predominantly limited to infancy. Fifteen studies reported outcomes on child iron status or hemoglobin, 20 on neurodevelopmental outcomes, and the remainder on a variety of other outcomes. In half of the studies, low maternal iron status or iron deficiency was associated with adverse outcomes in children. Meta-analyses showed an association of maternal ferritin with child soluble transferrin receptor concentrations, though child ferritin, transferrin saturation, or hemoglobin values showed no consistent association. Studies on maternal iron status above normal, or iron excess, suggest deleterious effects on infant growth, cognition, and childhood Type 1 diabetes. Maternal iron status in pregnancy was not consistently associated with child iron status after birth. The very heterogeneous set of studies suggests detrimental effects of iron deficiency, and possibly also of overload, on other outcomes including child neurodevelopment. Studies are needed to determine clinically meaningful definitions of iron deficiency and overload in pregnancy.
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http://dx.doi.org/10.3390/nu13072221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308244PMC
June 2021

The EU Child Cohort Network's core data: establishing a set of findable, accessible, interoperable and re-usable (FAIR) variables.

Eur J Epidemiol 2021 May 21;36(5):565-580. Epub 2021 Apr 21.

Department of Social Medicine, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece.

The Horizon2020 LifeCycle Project is a cross-cohort collaboration which brings together data from multiple birth cohorts from across Europe and Australia to facilitate studies on the influence of early-life exposures on later health outcomes. A major product of this collaboration has been the establishment of a FAIR (findable, accessible, interoperable and reusable) data resource known as the EU Child Cohort Network. Here we focus on the EU Child Cohort Network's core variables. These are a set of basic variables, derivable by the majority of participating cohorts and frequently used as covariates or exposures in lifecourse research. First, we describe the process by which the list of core variables was established. Second, we explain the protocol according to which these variables were harmonised in order to make them interoperable. Third, we describe the catalogue developed to ensure that the network's data are findable and reusable. Finally, we describe the core data, including the proportion of variables harmonised by each cohort and the number of children for whom harmonised core data are available. EU Child Cohort Network data will be analysed using a federated analysis platform, removing the need to physically transfer data and thus making the data more accessible to researchers. The network will add value to participating cohorts by increasing statistical power and exposure heterogeneity, as well as facilitating cross-cohort comparisons, cross-validation and replication. Our aim is to motivate other cohorts to join the network and encourage the use of the EU Child Cohort Network by the wider research community.
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http://dx.doi.org/10.1007/s10654-021-00733-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159791PMC
May 2021

A population-based study on associations of stool microbiota with atopic diseases in school-age children.

J Allergy Clin Immunol 2021 Apr 15. Epub 2021 Apr 15.

Division of Respiratory Medicine and Allergolog, Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Division of Neonatology, Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. Electronic address:

Background: Infants with less diverse gut microbiota seem to have higher risks of atopic diseases in early life, but any associations at school age are unclear.

Objectives: This study sought to examine the associations of diversity, relative abundance, and functional pathways of stool microbiota with atopic diseases in school-age children.

Methods: We performed a cross-sectional study within an existing population-based prospective cohort among 1440 children 10 years of age. On stool samples, 16S ribosomal RNA gene sequencing was performed, and taxonomic and functional tables were produced. Physician-diagnosed eczema, allergy, and asthma were measured by questionnaires, allergic sensitization by skin prick tests, and lung function by spirometry.

Results: The α-diversity of stool microbiota was associated with a decreased risk of eczema (odds ratio [OR], 0.98; 95% CI, 0.97, 1.00), and β-diversity was associated with physician-diagnosed inhalant allergy (R = 0.001; P = .047). Lachnospiraceae, Ruminococcaceae_UCG-005, and Christensenellaceae_R-7_group species were associated with decreased risks of eczema, inhalant allergic sensitization, and physician-diagnosed inhalant allergy (OR range, 0.88-0.94; 95% CI range, 0.79-0.96 to 0.88-0.98), while Agathobacter species were associated with an increased risk of physician-diagnosed inhalant allergy (OR, 1.23; 95% CI, 1.08-1.42). Functional pathways related to heme and terpenoid biosynthesis were associated with decreased risks of physician-diagnosed inhalant allergy and asthma (OR range, 0.89-0.86; 95% CI range, 0.80-0.99 to 0.73-1.02). No associations of stool microbiota with lung function were observed.

Conclusions: The diversity, relative abundance and functional pathways of stool microbiota were most consistently associated with physician-diagnosed inhalant allergy in school-age children and less consistently with other atopic diseases.
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http://dx.doi.org/10.1016/j.jaci.2021.04.001DOI Listing
April 2021

First trimester fetal proportion volumetric measurements using a Virtual Reality approach.

Prenat Diagn 2021 Jun 3;41(7):868-876. Epub 2021 May 3.

The Generation R Study Group, Erasmus University Medical Center, Rotterdam, The Netherlands.

Objective: To establish feasibility and reproducibility of fetal proportion volumetric measurements, using three-dimensional (3D) ultrasound and a Virtual Reality (VR) system.

Methods: Within a population-based prospective birth cohort, 3D ultrasound datasets of 50 fetuses in the late first trimester were collected by three ultrasonographers in a single research center. V-scope software was used for volumetric measurements of total fetus, extremities, head-trunk, head, trunk, thorax, and abdomen. All measurements were performed independently by two researchers. Intraobserver and interobserver reproducibility were analyzed using Bland and Altman methods.

Results: Intraobserver and interobserver analyses of volumetric measurements of total fetus, head-trunk, head, trunk, thorax and abdomen showed intraclass correlation coefficients above 0.979, coefficients of variation below 7.51% and mean difference below 3.44%. The interobserver limits of agreement were within the ±10% range for volumetric measurements of total fetus, head-trunk, head and trunk. The interobserver limits of agreement for extremities, thorax and abdomen were -26.09% to 4.77%, -14.14% to 10.00% and -14.47% to 8.83%, respectively.

Conclusion: First trimester fetal proportion volumetric measurements using 3D ultrasound and VR are feasible and reproducible, except volumetric measurements of the fetal extremities. These novel volumetric measurements may be used in future research to enable detailed studies on first trimester fetal development and growth.
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http://dx.doi.org/10.1002/pd.5947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251560PMC
June 2021

ERS International Congress 2020: highlights from the Paediatric Assembly.

ERJ Open Res 2021 Jan 22;7(1). Epub 2021 Mar 22.

Department of Paediatrics, Division of Paediatric Respiratory Medicine and Allergology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.

In this review, the Paediatric Assembly of the European Respiratory Society (ERS) presents a summary of the highlights and most relevant findings in the field of paediatric respiratory medicine presented at the virtual ERS International Congress 2020. Early Career Members of the ERS and Chairs of the different Groups comprising the Paediatric Assembly discuss a selection of the presented research. These cover a wide range of research areas, including respiratory physiology and sleep, asthma and allergy, cystic fibrosis, respiratory infection and immunology, neonatology and intensive care, epidemiology, bronchology and lung and airway development. Specifically, we describe the long-term effect in lung function of premature birth, mode of delivery and chronic respiratory conditions such as cystic fibrosis. In paediatric asthma, we present risk factors, phenotypes and their progression with age, and the challenges in diagnosis. We confirm the value of the lung clearance index to detect early lung changes in cystic fibrosis. For bronchiectasis treatment, we highlight the importance of identifying treatable traits. The use of biomarkers and genotypes to identify infants at risk of long-term respiratory morbidity is also discussed. We present the long-term impact on respiratory health of early life and fetal exposures to maternal obesity and intrauterine hypoxia, mechanical ventilation hyperoxia, aeroallergens, air pollution, vitamin A deficient intake and bronchitis. Moreover, we report on the use of metabolomics and genetic analysis to understand the effect of these exposures on lung growth and alveolar development. Finally, we stress the need to establish multidisciplinary teams to treat complex airway pathologies.
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http://dx.doi.org/10.1183/23120541.00893-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983204PMC
January 2021

Association between nasal and nasopharyngeal bacterial colonization in early life and eczema phenotypes.

Clin Exp Allergy 2021 May 6;51(5):716-725. Epub 2021 Apr 6.

Department of Dermatology, University Medical Center Rotterdam, Erasmus MC, Rotterdam, The Netherlands.

Background: An association has been reported between early life Staphylococcus aureus nasal carriage and higher risk of childhood eczema, but it is unclear whether this relationship is causal and associations with other bacterial species are unclear.

Objective: To examine the associations of early life nasal and nasopharyngeal bacterial carriage with eczema phenotypes, and the direction of any associations identified.

Methods: Among 996 subjects of a population-based prospective cohort study, nasal swabs for Staphylococcus  aureus, and nasopharyngeal swabs for Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae were collected and cultured from age 6 weeks to 6 years. Never, early, mid-, late transient and persistent eczema phenotypes were identified from parental-reported physician-diagnosed eczema from age 6 months until 10 years. Multinomial regression models and cross-lagged models were applied.

Results: Staphylococcus aureus nasal carriage at 6 months was associated with an increased risk of early transient and persistent eczema (OR (95% CI): 2.69 (1.34, 5.39) and 4.17 (1.12, 15.51)). The associations between Staphylococcus aureus nasal carriage and eczema were mostly cross-sectional, and not longitudinal. No associations of Staphylococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenza nasopharyngeal bacterial carriage with eczema and eczema phenotypes were observed (OR range (95% CI): 0.71 (0.35, 1.44) to 1.77 (0.84, 3.73)).

Conclusions: Early life Staphylococcus aureus nasal carriage, but not Staphylococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenza nasopharyngeal carriage, was associated with early transient and persistent eczema. Staphylococcus aureus nasal carriage and eczema were mostly cross-sectionally associated, and not longitudinally, making a causal relationship in either direction unlikely.
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http://dx.doi.org/10.1111/cea.13869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252109PMC
May 2021

Cardio-metabolic risk factors during childhood in relation to lung function and asthma.

Pediatr Allergy Immunol 2021 Jul 4;32(5):945-952. Epub 2021 May 4.

Division of Respiratory Medicine and Allergology, Department of Pediatrics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Background: Cardio-metabolic risk factors might have an adverse effect on respiratory outcomes, but associations in children are unknown. We aimed to study the longitudinal associations of cardio-metabolic risk factors with lung function and asthma at school age. We also examined whether any association was explained by child's body mass index (BMI).

Methods: In a population-based cohort study among 4988 children, cardio-metabolic risk factors were measured at 6 and 10 years and included blood pressure, cholesterol, triglycerides, insulin, and C-reactive protein (CRP) concentrations. At age 10 years, lung function was measured by spirometry and current physician-diagnosed asthma was assessed by questionnaire.

Results: After adjustment for confounders, child's BMI, and multiple testing, we observed that a higher diastolic blood pressure at the age of 6 years was associated with a higher forced vital capacity (FVC) at the age of 10 years (Z-score difference (95% CI): 0.05 (0.01, 0.08), per SDS increase in diastolic blood pressure). Also, child's CRP concentrations above the 75th percentile at both ages 6 and 10 years were related to a lower FVC as compared to CRP concentrations below the 75th percentile at both ages (Z-score difference (95% CI) -0.21 (-0.36, -0.06)). No consistent associations of other cardio-metabolic risk factors with respiratory outcomes were observed.

Conclusion: Blood pressure and CRP, but not lipids and insulin, were associated with lower lung function but not with asthma. The underlying mechanisms and long-term effects of these associations require further investigation.
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http://dx.doi.org/10.1111/pai.13509DOI Listing
July 2021

Increased Th22 cell numbers in a general pediatric population with filaggrin haploinsufficiency: The Generation R Study.

Pediatr Allergy Immunol 2021 Mar 14. Epub 2021 Mar 14.

Department of Dermatology, Erasmus MC, University Medical Center Rotterdam-Sophia Children's Hospital-Center of Pediatric Dermatology, Rotterdam, The Netherlands.

Background: Mutations in the filaggrin gene (FLG) affect epidermal barrier function and increase the risk of atopic dermatitis (AD). We hypothesized that FLG mutations affect immune cell composition in a general pediatric population. Therefore, we investigated whether school-aged children with and without FLG mutations have differences in T- and B-cell subsets.

Methods: This study was embedded in a population-based prospective cohort study, the Generation R Study, and included 523 children of European genetic ancestry aged 10 years. The most common FLG mutations in the European population (R501X, S1085CfsX36, R2447X, and S3247X) were genotyped. Additionally, 11-color flow cytometry was performed on peripheral blood samples to determine helper T (Th), regulatory T (Treg), and CD27 and CD27 memory B cells. Subset analysis was performed in 358 non-AD and 102 AD cases, assessed by parental questionnaires.

Results: FLG mutations were observed in 8.4% of the total population and in 15.7% of the AD cases. Children with any FLG mutation had higher Th22 cell numbers compared to FLG wild-type children in the general and non-AD population. Children with and without FLG mutations had no difference in Th1, Th2, Th17, Treg, or memory B-cell numbers. Furthermore, in children with AD, FLG mutation carriership was not associated with differences in T- and B-cell subsets.

Conclusions: School-aged children of a general population with FLG mutations have higher Th22 cell numbers, which reflects the immunological response to the skin barrier dysfunction. FLG mutations did not otherwise affect the composition of the adaptive immunity in this general pediatric population.
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http://dx.doi.org/10.1111/pai.13502DOI Listing
March 2021

Changes in Family Poverty Status and Child Health.

Pediatrics 2021 04 8;147(4). Epub 2021 Mar 8.

Public Health, and

Objectives: In this study, we aim to assess the associations over time between poverty and child weight status, asthma, and health-related quality of life (HRQoL).

Methods: We analyzed data for 3968 children from the Generation R Study, a population-based cohort study in the Netherlands. Net household income and the number of adults and children living from this income were measured at 4 time-points (during pregnancy and at ages 2, 3, and 6). Poverty was defined on the basis of the equivalized household income being <60% of the median national income. Child health outcomes were measured at age 6 years. The association was explored by using logistic and linear regression models.

Results: In this cohort, 9.8% of children were born into poverty and 6.0% had experienced 3 to 4 episodes of poverty. Independent of current poverty status, children born into poverty had an odds ratio (OR) of 1.68 for having overweight/obesity and a lower physical HRQoL (OR = -1.32) than those not born into poverty. Children having experienced 3 to 4 episodes of poverty had an OR of 1.94 for having asthma and a lower physical HRQoL (OR = -3.32) compared with children from never-poor families. Transition out of poverty before age 2 was associated with lower risk of asthma and a higher physical HRQoL compared with children who remained in poverty.

Conclusions: Being born into poverty or experiencing multiple episodes of poverty is associated with negative child health outcomes, such as having overweight, asthma, or a lower HRQoL. Support for children and families with a low household income is warranted.
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http://dx.doi.org/10.1542/peds.2020-016717DOI Listing
April 2021

Maternal iron status during early pregnancy and school-age, lung function, asthma, and allergy: The Generation R Study.

Pediatr Pulmonol 2021 Jun 3;56(6):1771-1778. Epub 2021 Mar 3.

Division of Neonatology, Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: Iron deficiency during early life could affect the developing lung and immune system, and influence child's respiratory or allergy outcomes in later life.

Objective: To examine the associations of maternal iron status during early pregnancy with child's lung function, asthma, inhalant allergic sensitization, and physician-diagnosed inhalant allergy at school-age.

Methods: In a population-based cohort study, among 3825 mother-child pairs, ferritin, transferrin concentrations, and transferrin saturation were measured from maternal venous blood samples during early pregnancy. In children at the age of 10 years, spirometry was used to determine child's lung function, current asthma and physician-diagnosed inhalant allergy were assessed by questionnaires, and inhalant allergic sensitization was measured by skin prick tests. We used multivariable regression models to examine the associations.

Results: After adjustment for gestational age at maternal iron status measurement and sociodemographic or lifestyle-related confounders, a higher maternal transferrin concentration was associated with a higher risk of physician-diagnosed inhalant allergy (odds ratio [95% confidence interval]: 1.13 [1.01 to1.26]), but not with lung function, asthma, or inhalant allergic sensitization. This association did not attenuate after further adjustment for maternal hemoglobin levels or early growth factors. We observed no consistent association of maternal ferritin concentrations or transferrin saturation with child's respiratory or allergy outcomes.

Conclusion: Higher maternal transferrin concentrations during pregnancy, reflecting lower serum iron levels, were associated with an increased risk of child's physician-diagnosed inhalant allergy but not lung outcomes. Underlying mechanisms and clinical implications need to be explored.
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http://dx.doi.org/10.1002/ppul.25324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251584PMC
June 2021

Maternal dietary quality, inflammatory potential and childhood adiposity: an individual participant data pooled analysis of seven European cohorts in the ALPHABET consortium.

BMC Med 2021 02 22;19(1):33. Epub 2021 Feb 22.

HRB Centre for Health and Diet Research, School of Public Health, Physiotherapy, and Sports Science, University College Dublin, Dublin, Republic of Ireland.

Background: Mounting evidence suggests that maternal diet influences pregnancy and birth outcomes, but its contribution to the global epidemic of childhood obesity has not as yet been definitively characterized. We investigated whether maternal whole diet quality and inflammatory potential influence childhood adiposity.

Methods: We harmonized and pooled individual participant data from 16,295 mother-child pairs in seven European birth cohorts. Maternal pre-, early-, late-, and whole-pregnancy (any time during pregnancy) dietary quality and inflammatory potential assessed with the Dietary Approaches to Stop Hypertension (DASH) score and the energy-adjusted Dietary Inflammatory Index (E-DII™) score, respectively. Primary outcome was childhood overweight and obesity (OWOB) (age-and-sex-specific BMI z-score > 85th percentile). Secondary outcomes were sum of skinfold thickness (SST), fat mass index (FMI) and fat-free mass index (FFMI). We used multivariable regression analyses (adjusting for maternal lifestyle and sociodemographic factors) to assess the associations of maternal DASH and E-DII scores with offspring adiposity outcomes in cohort-specific analyses, with subsequent random-effect meta-analyses.

Results: The study mothers had a mean (SD) age of 30.2 (4.6) years and a mean BMI of 23.4 (4.2) kg/m. Higher early-pregnancy E-DII scores (more pro-inflammatory diet) tended to be associated with a higher odds of late-childhood [10.6 (1.2) years] OWOB [OR (95% CI) 1.09 (1.00, 1.19) per 1-SD E-DII score increase], whereas an inverse association was observed for late-pregnancy E-DII score and early-childhood [2.8 (0.3) years] OWOB [0.91 (0.83, 1.00)]. Higher maternal whole pregnancy DASH score (higher dietary quality) was associated with a lower odds of late-childhood OWOB [OR (95% CI) 0.92 (0.87, 0.98) per 1-SD DASH score increase]; associations were of similar magnitude for early and late-pregnancy [0.86 (0.72, 1.04) and 0.91 (0.85, 0.98), respectively]. These associations were robust in several sensitivity analyses and further adjustment for birth weight and childhood diet did not meaningfully alter the associations and conclusions. In two cohorts with available data, a higher whole pregnancy E-DII and lower DASH scores were associated with a lower late-childhood FFMI in males and a higher mid-childhood FMI in females (P interactions < 0.10).

Conclusions: A pro-inflammatory, low-quality maternal antenatal diet may adversely influence offspring body composition and OWOB risk, especially during late-childhood. Promoting an overall healthy and anti-inflammatory maternal dietary pattern may contribute to the prevention of childhood obesity, a complex health issue requiring multifaceted strategy.
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http://dx.doi.org/10.1186/s12916-021-01908-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898733PMC
February 2021

Identifying distinct trajectories of acute otitis media in children: A prospective cohort study.

Clin Otolaryngol 2021 Jul 21;46(4):788-795. Epub 2021 Feb 21.

Department of Otolaryngology-Head and Neck Surgery, Erasmus MC, Rotterdam, The Netherlands.

Objectives: To identify possibly distinct acute otitis media (AOM) trajectories in childhood and identify determinants associated with specific AOM trajectories. To explore which child will become prone to recurrent AOM episodes and which will not.

Design: Population-based prospective cohort study among 7863 children from birth until 10 years and their mothers.

Methods: This study was embedded in the Generation R Study: a population-based prospective cohort study. Data on AOM and determinants were collected by repeated parental questionnaires. Distinct AOM trajectories within the population were identified with latent-class analyses. Next, using multivariate analysis we checked whether specific determinants were associated with specific trajectories.

Results: Three distinct trajectories were identified; that is, non-otitis prone, early AOM-that is children who suffered AOM episodes until 3 years of age but not beyond, and persistent AOM-that is children who remained otitis-prone. Male gender (OR: 1.26, CI: 1.11-1.43) and day-care attendance (OR: 1.31, CI: 1.06-1.60) were associated with increased odds of early AOM. Breastfeeding was beneficial for children in both the early-AOM and persistent-AOM trajectories (OR: 0.78 and 0.77, respectively). Birth in the summer or autumn as compared with birth in the spring decreased odds of AOM only in the persistent-AOM trajectory. Half of all AOM-prone children recovered after the age of 3 years.

Conclusion: Specific determinants are associated with different AOM trajectories. Future research is needed to better predict which child will remain otitis-prone and which recovers after the age of 3 years to better tailor treatment towards the needs of the individual child.
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http://dx.doi.org/10.1111/coa.13736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248120PMC
July 2021

Associations of maternal dietary inflammatory potential and quality with offspring birth outcomes: An individual participant data pooled analysis of 7 European cohorts in the ALPHABET consortium.

PLoS Med 2021 01 21;18(1):e1003491. Epub 2021 Jan 21.

HRB Centre for Health and Diet Research, School of Public Health, Physiotherapy, and Sports Science, University College Dublin, Dublin, Republic of Ireland.

Background: Adverse birth outcomes are major causes of morbidity and mortality during childhood and associate with a higher risk of noncommunicable diseases in adult life. Maternal periconception and antenatal nutrition, mostly focusing on single nutrients or foods, has been shown to influence infant birth outcomes. However, evidence on whole diet that considers complex nutrient and food interaction is rare and conflicting. We aim to elucidate the influence of whole-diet maternal dietary inflammatory potential and quality during periconceptional and antenatal periods on birth outcomes.

Methods And Findings: We harmonized and pooled individual participant data (IPD) from up to 24,861 mother-child pairs in 7 European mother-offspring cohorts [cohort name, country (recruitment dates): ALSPAC, UK (1 April 1991 to 31 December 1992); EDEN, France (27 January 2003 to 6 March 2006); Generation R, the Netherlands (1 April 2002 to 31 January 2006); Lifeways, Ireland (2 October 2001 to 4 April 2003); REPRO_PL, Poland (18 September 2007 to 16 December 2011); ROLO, Ireland (1 January 2007 to 1 January 2011); SWS, United Kingdom (6 April 1998 to 17 December 2002)]. Maternal diets were assessed preconceptionally (n = 2 cohorts) and antenatally (n = 7 cohorts). Maternal dietary inflammatory potential and quality were ranked using the energy-adjusted Dietary Inflammatory Index (E-DII) and Dietary Approaches to Stop Hypertension (DASH) index, respectively. Primary outcomes were birth weight and gestational age at birth. Adverse birth outcomes, i.e., low birth weight (LBW), macrosomia, small-for-gestational-age (SGA), large-for-gestational-age (LGA), preterm and postterm births were defined according to standard clinical cutoffs. Associations of maternal E-DII and DASH scores with infant birth outcomes were assessed using cohort-specific multivariable regression analyses (adjusted for confounders including maternal education, ethnicity, prepregnancy body mass index (BMI), maternal height, parity, cigarettes smoking, and alcohol consumption), with subsequent random-effects meta-analyses. Overall, the study mothers had a mean ± SD age of 29.5 ± 4.9 y at delivery and a mean BMI of 23.3 ± 4.2 kg/m2. Higher pregnancy DASH score (higher dietary quality) was associated with higher birth weight [β(95% CI) = 18.5(5.7, 31.3) g per 1-SD higher DASH score; P value = 0.005] and head circumference [0.03(0.01, 0.06) cm; P value = 0.004], longer birth length [0.05(0.01, 0.10) cm; P value = 0.010], and lower risk of delivering LBW [odds ratio (OR) (95% CI) = 0.89(0.82, 0.95); P value = 0.001] and SGA [0.87(0.82, 0.94); P value < 0.001] infants. Higher maternal prepregnancy E-DII score (more pro-inflammatory diet) was associated with lower birth weight [β(95% CI) = -18.7(-34.8, -2.6) g per 1-SD higher E-DII score; P value = 0.023] and shorter birth length [-0.07(-0.14, -0.01) cm; P value = 0.031], whereas higher pregnancy E-DII score was associated with a shorter birth length [-0.06(-0.10, -0.01) cm; P value = 0.026] and higher risk of SGA [OR(95% CI) = 1.18(1.11, 1.26); P value < 0.001]. In male, but not female, infants higher maternal prepregnancy E-DII was associated with lower birth weight and head circumference, shorter birth length, and higher risk of SGA (P-for-sex-interaction = 0.029, 0.059, 0.104, and 0.075, respectively). No consistent associations were observed for maternal E-DII and DASH scores with gestational age, preterm and postterm birth, or macrosomia and LGA. Limitations of this study were that self-reported dietary data might have increased nondifferential measurement error and that causality cannot be claimed definitely with observational design.

Conclusions: In this cohort study, we observed that maternal diet that is of low quality and high inflammatory potential is associated with lower offspring birth size and higher risk of offspring being born SGA in this multicenter meta-analysis using harmonized IPD. Improving overall maternal dietary pattern based on predefined criteria may optimize fetal growth and avert substantial healthcare burden associated with adverse birth outcomes.
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http://dx.doi.org/10.1371/journal.pmed.1003491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819611PMC
January 2021

Large-scale association analyses identify host factors influencing human gut microbiome composition.

Nat Genet 2021 02 18;53(2):156-165. Epub 2021 Jan 18.

Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10 < P < 5 × 10) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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http://dx.doi.org/10.1038/s41588-020-00763-1DOI Listing
February 2021

Dietary Quality and Dietary Inflammatory Potential During Pregnancy and Offspring Emotional and Behavioral Symptoms in Childhood: An Individual Participant Data Meta-analysis of Four European Cohorts.

Biol Psychiatry 2021 03 24;89(6):550-559. Epub 2020 Oct 24.

HRB Centre for Health and Diet Research, School of Public Health, Physiotherapy and Sports Science, University College Dublin, Belfield, Dublin, Ireland. Electronic address:

Background: The impact of maternal diet during pregnancy on child neurodevelopment is of public health and clinical relevance. We evaluated the associations of dietary quality based on the Dietary Approaches to Stop Hypertension (DASH) score and dietary inflammatory potential based on the energy-adjusted Dietary Inflammatory Index (E-DII) score during pregnancy with emotional and behavioral symptoms of offspring at 7 to 10 years of age.

Methods: Individual participant data for 11,870 mother-child pairs from four European cohorts participating in the ALPHABET project were analyzed. Maternal antenatal DASH and E-DII scores were generated from self-completed food frequency questionnaires. Symptoms of depression and anxiety, aggressive behavior, and attention-deficit/hyperactivity disorder in children were assessed using mother-reported tests and classified within the normal or borderline/clinical ranges using validated cutoffs. Adjusted odds ratios were determined by multivariable logistic regression models and aggregated by the two-level individual participant data meta-analysis method.

Results: Higher maternal DASH scores (indicating better dietary quality) were associated with lower risk of depressive and anxiety symptoms, aggressive behavior symptoms, and attention-deficit/hyperactivity disorder symptoms within the borderline/clinical ranges: odds ratio [OR] 0.97, 95% confidence interval [CI], 0.95-0.99; OR 0.97, 95% CI, 0.94-0.99; OR 0.97, 95% CI, 0.95-0.98, per one-unit DASH score increase, respectively. For depression and anxiety, aggressive behavior, and attention-deficit/hyperactivity disorder symptoms, a one-unit increase in E-DII scores (a more proinflammatory diet) was associated with a 7% increased risk of all three analyzed emotional and behavioral symptoms: OR 1.07, 95% CI, 1.03-1.11; OR 1.07, 95% CI, 1.02-1.13; OR 1.07, 95% CI, 1.01-1.13, respectively.

Conclusions: Our findings suggest that a maternal low-quality and proinflammatory diet may increase the risk of emotional and behavioral symptoms in children.
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http://dx.doi.org/10.1016/j.biopsych.2020.10.008DOI Listing
March 2021

Associations of DASH Diet in Pregnancy With Blood Pressure Patterns, Placental Hemodynamics, and Gestational Hypertensive Disorders.

J Am Heart Assoc 2021 01 25;10(1):e017503. Epub 2020 Dec 25.

The Generation R Study Group Erasmus MC, University Medical Center Rotterdam the Netherlands.

Background The Dietary Approaches to Stop Hypertension (DASH) diet improves blood pressure in nonpregnant populations. We hypothesized that adherence to the DASH diet during pregnancy improves hemodynamic adaptations, leading to a lower risk of gestational hypertensive disorders. Methods and Results We examined whether the DASH diet score was associated with blood pressure, placental hemodynamics, and gestational hypertensive disorders in a population-based cohort study among 3414 Dutch women. We assessed DASH score using food-frequency questionnaires. We measured blood pressure in early-, mid-, and late pregnancy (medians, 95% range: 12.9 [9.8-17.9], 20.4 [16.6-23.2], 30.2 [28.6-32.6] weeks gestation, respectively), and placental hemodynamics in mid- and late pregnancy (medians, 95% range: 20.5 [18.7-23.1], 30.4 [28.5-32.8] weeks gestation, respectively). Information on gestational hypertensive disorders was obtained from medical records. Lower DASH score quartiles were associated with a higher mid pregnancy diastolic blood pressure, compared with the highest quartile (<0.05). No associations were present for early- and late pregnancy diastolic blood pressure and systolic blood pressure throughout pregnancy. Compared with the highest DASH score quartile, the lower DASH score quartiles were associated with a higher mid- and late pregnancy umbilical artery pulsatility index (≤0.05) but not with uterine artery resistance index. No associations with gestational hypertensive disorders were present. Conclusions A higher DASH diet score is associated with lower mid pregnancy diastolic blood pressure and mid- and late pregnancy fetoplacental vascular function but not with uteroplacental vascular function or gestational hypertensive disorders within a low-risk population. Further studies need to assess whether the effects of the DASH diet on gestational hemodynamic adaptations are more pronounced among higher-risk populations.
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http://dx.doi.org/10.1161/JAHA.120.017503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955484PMC
January 2021

COVID-19 in children with underlying chronic respiratory diseases: survey results from 174 centres.

ERJ Open Res 2020 Oct 26;6(4). Epub 2020 Oct 26.

Dept of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: Early reports suggest that most children infected with severe acute respiratory syndrome coronavirus 2 ("SARS-CoV-2") have mild symptoms. What is not known is whether children with chronic respiratory illnesses have exacerbations associated with SARS-CoV-2 virus.

Methods: An expert panel created a survey, which was circulated twice (in April and May 2020) to members of the Paediatric Assembly of the European Respiratory Society (ERS) and the social media of the ERS. The survey stratified patients by the following conditions: asthma, cystic fibrosis (CF), bronchopulmonary dysplasia (BPD) and other respiratory conditions.

Results: In total 174 centres responded to at least one survey. 80 centres reported no cases, whereas 94 entered data from 945 children with coronavirus disease 2019 (COVID-19). SARS-CoV-2 was isolated from 49 children with asthma of whom 29 required no treatment, 19 needed supplemental oxygen and four children required mechanical ventilation. Of the 14 children with CF and COVID-19, 10 required no treatment and four had only minor symptoms. Among the nine children with BPD and COVID-19, two required no treatment, five required inpatient care and oxygen and two were admitted to a paediatric intensive care unit (PICU) requiring invasive ventilation. Data were available from 33 children with other conditions and SARS-CoV-2 of whom 20 required supplemental oxygen and 11 needed noninvasive or invasive ventilation.

Conclusions: Within the participating centres, in children with asthma and CF, infection with SARS-CoV-2 was well tolerated, but a substantial minority of children with BPD and other conditions required ventilatory support indicating that these latter groups are at risk from SARS-CoV-2 infection.
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http://dx.doi.org/10.1183/23120541.00409-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682706PMC
October 2020

Parental psychological distress during pregnancy and the risk of childhood lower lung function and asthma: a population-based prospective cohort study.

Thorax 2020 12 12;75(12):1074-1081. Epub 2020 Oct 12.

Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus Medical Center, Rotterdam, The Netherlands

Background: Although maternal psychological distress during pregnancy is associated with increased risks of respiratory morbidity in preschool children, it is unknown whether this association persists into later childhood.

Objective: To examine the association between parental psychological distress during pregnancy and lung function and asthma in children of school age.

Methods: This study of 4231 children was embedded in a population-based prospective cohort. Parental psychological distress was assessed by the Brief Symptom Inventory during and 3 years after pregnancy, and in mothers also at 2 and 6 months after pregnancy. At age 10 years, lung function was obtained by spirometry and asthma by questionnaire.

Results: The prevalence of asthma was 5.9%. Maternal overall psychological distress during pregnancy was associated with a lower forced vital capacity (FVC) (z-score difference -0.10 (95% CI -0.20 to -0.01) per 1-unit increase), maternal depressive symptoms during pregnancy with a lower forced expiratory volume in the first second (FEV) and FVC (-0.13 (95% CI -0.24 to -0.01) and -0.13 (95% CI -0.24 to -0.02) when using clinical cut-offs) in their children. All maternal psychological distress measures during pregnancy were associated with an increased risk of asthma (range OR: 1.46 (95% CI 1.12 to 1.90) to 1.91 (95% CI 1.26 to 2.91)). Additional adjustment for paternal psychological distress during pregnancy and parental psychological distress after pregnancy did not materially change the associations. Paternal psychological distress during pregnancy was not associated with childhood respiratory morbidity.

Conclusion: Maternal, but not paternal, psychological distress during pregnancy is associated with an increased risk of asthma and partly lower lung function in children. This suggests intrauterine programming for the risk of later-life respiratory disease.
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http://dx.doi.org/10.1136/thoraxjnl-2019-214099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677473PMC
December 2020

Associations of Plasma Fatty Acid Patterns during Pregnancy with Respiratory and Allergy Outcomes at School Age.

Nutrients 2020 Oct 7;12(10). Epub 2020 Oct 7.

Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center, 3000 CA Rotterdam, The Netherlands.

Fatty acids might play a role in asthma and allergy development as they can modulate immune responses. We examined among 4260 mother-child pairs participating in a population-based cohort the associations of maternal plasma fatty acid patterns during pregnancy with a child's respiratory and allergy outcomes at school-age. In mid-pregnancy, 22 individual fatty acids were measured from maternal blood. Three patterns were previously identified by principal component analysis: A 'high n-6 polyunsaturated fatty acid (PUFA)', a 'monounsaturated and saturated fatty acid', and a 'high n-3 PUFA' pattern. At the age of 10 years, a child's lung function was assessed by spirometry, current asthma and physician-diagnosed inhalant allergy by questionnaire, and inhalant allergic sensitization by skin prick tests. A higher 'high n-6 PUFA' pattern was associated with a higher forced expiratory volume in 1 s/forced vital capacity and forced expiratory flow after exhaling 75% of forced vital capacity (Z-score difference (95% CI) 0.04 (0, 0.07) and 0.04 (0.01, 0.07), respectively, per SD increase in the fatty acid pattern). We observed no associations of maternal fatty acid patterns with a child's asthma or allergy outcomes. Our results showed limited associations of maternal patterns of high n-6 PUFA concentrations in pregnancy with a better lung function in school-aged children.
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http://dx.doi.org/10.3390/nu12103057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601105PMC
October 2020

Fetal exposure to phthalates and bisphenols and childhood general and organ fat. A population-based prospective cohort study.

Int J Obes (Lond) 2020 11 12;44(11):2225-2235. Epub 2020 Sep 12.

The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Objectives: Fetal exposure to phthalates and bisphenols might have long-lasting effects on growth and fat development. Not much is known about the effects on general and organ fat development in childhood. We assessed the associations of fetal exposure to phthalates and bisphenols with general and organ fat measures in school-aged children.

Methods: In a population-based, prospective cohort study among 1128 mother-child pairs, we measured maternal urinary phthalate metabolites and bisphenol concentrations in first, second, and third trimester. Offspring body mass index, fat mass index by dual-energy X-ray absorptiometry, and visceral and pericardial fat indices and liver fat fraction were measured by magnetic resonance imaging at 10 years.

Results: After adjustment for confounders and correction for multiple testing, an interquartile range increase in first trimester phthalic acid concentrations remained associated with a 0.14 (95% confidence interval: 0.05, 0.22) standard deviation score increase in pericardial fat index. We also observed tendencies for associations of higher maternal low molecular weight phthalate urinary concentrations in second trimester with childhood pericardial fat index, but these were not significant after adjustment for multiple testing. High molecular weight phthalate, di-2-ethylhexyl phthalate, and di-n-octyl phthalate concentrations were not associated with childhood outcomes. Maternal urinary bisphenol concentrations were not associated with childhood adiposity.

Conclusions: Maternal first trimester phthalic acid concentrations are associated with increased childhood pericardial fat index at 10 years of age, whereas maternal bisphenol concentrations are not associated with childhood adiposity. We did not find significant sex-specific effects. These findings should be considered as hypothesis generating and need further replication and identification of underlying mechanisms.
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http://dx.doi.org/10.1038/s41366-020-00672-7DOI Listing
November 2020

Fetal phthalates and bisphenols and childhood lipid and glucose metabolism. A population-based prospective cohort study.

Environ Int 2020 11 1;144:106063. Epub 2020 Sep 1.

Department of Paediatrics, New York University School of Medicine, New York City, NY 10016, USA; Department of Environmental Medicine, New York University School of Medicine, New York City, NY 10016, USA; Department of Population Health, New York University School of Medicine, New York City, NY, USA; New York University Wagner School of Public Service, New York City, NY 10016, USA; New York University College of Global Public Health, New York City, NY 10016, USA. Electronic address:

Background And Aims: Fetal exposure to endocrine disruptors such as phthalates and bisphenols may lead to developmental metabolic adaptations. We examined associations of maternal phthalate and bisphenol urine concentrations during pregnancy with lipids, insulin, and glucose concentrations at school age.

Methods: In a population-based, prospective cohort study among 757 mother-child pairs, we measured maternal phthalate and bisphenol urine concentrations in first, second and third trimester of pregnancy. We measured non-fasting lipids, glucose and insulin blood concentrations of their children at a mean age of 9.7 (standard deviation 0.2) years. Analyses were performed for boys and girls separately.

Results: An interquartile range (IQR) higher natural log transformed third trimester maternal urine phthalic acid concentration was associated with a 0.20 (95% confidence interval (CI) 0.07-0.34) standard deviation score (SDS) higher triglycerides concentration among boys. Maternal bisphenol urine concentrations were not associated with non-fasting lipid concentrations during childhood. An IQR higher natural log transformed second trimester maternal high molecular weight phthalates (HMWP) and di-2-ethylhexylphthalate (DEHP) urine concentration were associated with a 0.19 (95% CI 0.31-0.07) respectively 0.18 (95% CI 0.31-0.06) SDS lower glucose concentration among boys. An IQR higher natural log transformed third trimester maternal bisphenol F urine concentration was associated with a 0.22 (95% CI 0.35-0.09) SDS lower non-fasting insulin concentration among boys.

Conclusions: Our results suggest potential persisting sex specific effects of fetal exposure to phthalates and bisphenols on childhood lipid concentrations and glucose metabolism. Future studies are needed for replication and exploring underlying mechanisms.
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http://dx.doi.org/10.1016/j.envint.2020.106063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572773PMC
November 2020

ERS International Congress, Madrid, 2019: highlights from the Paediatric Assembly.

ERJ Open Res 2020 Apr 20;6(2). Epub 2020 Jul 20.

Centre for Paediatrics, Queen Mary University London, London, UK.

In this article, the Group Chairs and the Early Career Members of the Paediatric Assembly of the European Respiratory Society (ERS) highlight some of the most interesting findings in the field of paediatrics presented at the 2019 ERS International Congress, which was held in Madrid, Spain. The main findings from each group are summarised at the end of each chapter.
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http://dx.doi.org/10.1183/23120541.00063-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369464PMC
April 2020

The LifeCycle Project-EU Child Cohort Network: a federated analysis infrastructure and harmonized data of more than 250,000 children and parents.

Eur J Epidemiol 2020 Jul 23;35(7):709-724. Epub 2020 Jul 23.

ISGlobal, Barcelona, Spain.

Early life is an important window of opportunity to improve health across the full lifecycle. An accumulating body of evidence suggests that exposure to adverse stressors during early life leads to developmental adaptations, which subsequently affect disease risk in later life. Also, geographical, socio-economic, and ethnic differences are related to health inequalities from early life onwards. To address these important public health challenges, many European pregnancy and childhood cohorts have been established over the last 30 years. The enormous wealth of data of these cohorts has led to important new biological insights and important impact for health from early life onwards. The impact of these cohorts and their data could be further increased by combining data from different cohorts. Combining data will lead to the possibility of identifying smaller effect estimates, and the opportunity to better identify risk groups and risk factors leading to disease across the lifecycle across countries. Also, it enables research on better causal understanding and modelling of life course health trajectories. The EU Child Cohort Network, established by the Horizon2020-funded LifeCycle Project, brings together nineteen pregnancy and childhood cohorts, together including more than 250,000 children and their parents. A large set of variables has been harmonised and standardized across these cohorts. The harmonized data are kept within each institution and can be accessed by external researchers through a shared federated data analysis platform using the R-based platform DataSHIELD, which takes relevant national and international data regulations into account. The EU Child Cohort Network has an open character. All protocols for data harmonization and setting up the data analysis platform are available online. The EU Child Cohort Network creates great opportunities for researchers to use data from different cohorts, during and beyond the LifeCycle Project duration. It also provides a novel model for collaborative research in large research infrastructures with individual-level data. The LifeCycle Project will translate results from research using the EU Child Cohort Network into recommendations for targeted prevention strategies to improve health trajectories for current and future generations by optimizing their earliest phases of life.
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http://dx.doi.org/10.1007/s10654-020-00662-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387322PMC
July 2020

during pregnancy and childhood asthma-related morbidity: a population-based prospective cohort.

Eur Respir J 2020 07 23;56(1). Epub 2020 Jul 23.

Dept of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

Introduction: is the most commonly reported sexually transmitted disease and although infection during pregnancy is associated with neonatal complications, long-term respiratory consequences are unknown. We aimed to determine whether infection during pregnancy is associated with asthma-related symptoms across childhood METHODS: This study among 2475 children and their mothers was embedded in a population-based prospective cohort study. Maternal urine samples were tested for infection during pregnancy. Questionnaires provided information on childhood physician-attended lower respiratory tract infections and wheezing, and current asthma at age 10 years. Lung function was measured by spirometry at age 10 years.

Results: The prevalence of infection during pregnancy was 3.2% (78 out of 2475). infection during pregnancy was not associated with lower respiratory tract infections until age 6 years, but was associated with a higher odds of wheezing in children until age 10 years (OR 1.50 (95% CI 1.10-2.03)). infection during pregnancy was associated with an increased odds of asthma (OR 2.29 (95% CI 1.02-5.13)), and with a lower forced expiratory volume in 1 s/forced vital capacity and forced expiratory flow at 75% of forced vital capacity (z-score difference -0.28 (95% CI -0.52- -0.04) and -0.24 (95% CI -0.46- -0.01), respectively) in children at age 10 years. The observed associations were only partly explained by mode of delivery, gestational age at birth or birthweight.

Conclusions: infection during pregnancy is associated with increased odds of wheezing, asthma and impaired lung function. The causality of the observed associations and potential underlying mechanisms need to be explored.
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http://dx.doi.org/10.1183/13993003.01829-2019DOI Listing
July 2020

Airway bacterial carriage and childhood respiratory health: A population-based prospective cohort study.

Pediatr Allergy Immunol 2020 10 30;31(7):774-782. Epub 2020 Jun 30.

Division of Respiratory Medicine and Allergology, Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: Airway bacterial carriage might play a role in respiratory disease. We hypothesize that nasal carriage with Staphylococcus aureus or nasopharyngeal carriage with Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae predisposes individuals to adverse respiratory health.

Objective: To examine the association of early-life airway bacterial carriage with respiratory tract infections and vice versa, and of early-life airway bacterial carriage with wheezing, lung function, and asthma in later childhood.

Methods: We collected upper airway swabs for bacterial culturing for S aureus, H influenzae, M catarrhalis, and H influenzae at six timepoints between the ages of 6 weeks and 6 years among 945 children participating in a population-based prospective cohort study. Information on respiratory tract infections and wheezing until age 6 years, and asthma at age 10 years was obtained by questionnaires. Lung function at age 10 years was measured by spirometry. We tested possible bidirectional associations between airway bacterial carriage and respiratory tract infections by cross-lagged models, and associations of repeatedly measured airway bacterial carriage with wheezing, lung function, and asthma by generalized estimating equations models and regression models.

Results: Cross-lagged modeling showed that early-life airway bacterial carriage was not consistently associated with upper and lower respiratory tract infections or vice versa. Nasopharyngeal carriage with any bacteria in infancy was associated with an increased risk of wheezing (OR [95% CI]: 1.66 [1.31, 2.10]). Airway bacterial carriage was not consistently associated with school-age lung function or asthma.

Conclusion: Nasopharyngeal carriage with any bacteria is associated with wheezing, but not respiratory tract infections, asthma, or lung function.
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http://dx.doi.org/10.1111/pai.13310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587008PMC
October 2020

Sociodemographic factors, current asthma and lung function in an urban child population.

Eur J Clin Invest 2020 Oct 11;50(10):e13277. Epub 2020 Aug 11.

Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands.

Background: We aimed to assess which sociodemographic factors are associated with current asthma and indicators of lung function in 10-year-old children.

Methods: We analysed data of 5237 children (Mean age: 9.7, SD: 0.3) from the Generation R Study (2012-2016), a population-based cohort study in the Netherlands. Indicators of sociodemographic factors included parental educational level, net household income, financial difficulties, parental employment status and child ethnic background. Current asthma (yes/no) was defined as ever doctor-diagnosed-asthma combined with wheezing symptoms or asthma-medication use in the past 12 months. Lung function was measured by spirometry and included forced expiratory volume in 1 second (FEV ), forced vital capacity (FVC), FEV /FVC, and forced expiratory flow after exhaling 75% of FVC (FEF ). Within-study sex-, height- and age-adjusted lung function measurements' z-scores were converted.

Results: After adjustment for all sociodemographic factors, an independent association was observed between ethnic background with current asthma and lung function. Compared with children with a Dutch background, children with a nonwestern ethnic background had a higher odds of having current asthma (OR: 1.61, 95% CI: 1.02, 2.53), lower FVC z-score (-0.25, 95% CI: -0.35, -0.14), higher FEV /FVC z-score (0.26, 95% CI: 0.14, 0.37) and higher FEF z-score (0.15, 95% CI: 0.04, 0.25).

Conclusions: Among 10-year-old children, ethnic background was associated with current asthma and lung function after adjusting for a wide range of sociodemographic factors. No associations were found between socioeconomic status indicators and current asthma. Explanations for these associations such as language barriers, suboptimal care or pathophysiological differences require further investigation.
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http://dx.doi.org/10.1111/eci.13277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539956PMC
October 2020

Associations of maternal age at the start of pregnancy with placental function throughout pregnancy: The Generation R Study.

Eur J Obstet Gynecol Reprod Biol 2020 Aug 20;251:53-59. Epub 2020 May 20.

The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands. Electronic address:

Objective: To examine the associations of maternal age at the start of pregnancy across the full range with second and third trimester uterine and umbilical artery flow indices, and placental weight.

Study Design: In a population-based prospective cohort study among 8271 pregnant women, we measured second and third trimester uterine artery resistance and umbilical artery pulsatility indices and the presence of third trimester uterine artery notching using Doppler ultrasound.

Results: Compared to women aged 25-29.9 years, higher maternal age was associated with a higher third trimester uterine artery resistance index (difference for women 30-34.9 years was 0.10 SD (95% Confidence Interval (CI) 0.02 to 0.17), and for women aged ≥40 years 0.33 SD (95% CI 0.08 to 0.57), overall linear trend 0.02 SD (95% CI 0.01 to 0.03) per year). Compared to women aged 25-29.9 years, women younger than 20 years had an increased risk of third trimester uterine artery notching (Odds Ratio (OR) 1.97 (95% CI 1.30-3.00)). A linear trend was present with a decrease in risk of third trimester uterine artery notching per year increase in maternal age (OR 0.96 (95% CI 0.94 to 0.98)). Maternal age was not consistently associated with umbilical artery pulsatility indices or placental weight.

Conclusions: Young maternal age is associated with higher risk of third trimester uterine artery notching, whereas advanced maternal age is associated with a higher third trimester uterine artery resistance index, which may predispose to an increased risk of pregnancy complications.
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http://dx.doi.org/10.1016/j.ejogrb.2020.04.055DOI Listing
August 2020

Cord blood DNA methylation reflects cord blood C-reactive protein levels but not maternal levels: a longitudinal study and meta-analysis.

Clin Epigenetics 2020 04 30;12(1):60. Epub 2020 Apr 30.

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 6710B Rockledge Dr, MSC 7004, Bethesda, MD, 20817, USA.

Background: Prenatal inflammation has been proposed as an important mediating factor in several adverse pregnancy outcomes. C-reactive protein (CRP) is an inflammatory cytokine easily measured in blood. It has clinical value due to its reliability as a biomarker for systemic inflammation and can indicate cellular injury and disease severity. Elevated levels of CRP in adulthood are associated with alterations in DNA methylation. However, no studies have prospectively investigated the relationship between maternal CRP levels and newborn DNA methylation measured by microarray in cord blood with reasonable epigenome-wide coverage. Importantly, the timing of inflammation exposure during pregnancy may also result in different effects. Thus, our objective was to evaluate this prospective association of CRP levels measured during multiple periods of pregnancy and in cord blood at delivery which was available in one cohort (i.e., Effects of Aspirin in Gestation and Reproduction trial), and also to conduct a meta-analysis with available data at one point in pregnancy from three other cohorts from the Pregnancy And Childhood Epigenetics consortium (PACE). Secondarily, the impact of maternal randomization to low dose aspirin prior to pregnancy on methylation was assessed.

Results: Maternal CRP levels were not associated with newborn DNA methylation regardless of gestational age of measurement (i.e., CRP at approximately 8, 20, and 36 weeks among 358 newborns in EAGeR). There also was no association in the meta-analyses (all p > 0.5) with a larger sample size (n = 1603) from all participating PACE cohorts with available CRP data from first trimester (< 18 weeks gestation). Randomization to aspirin was not associated with DNA methylation. On the other hand, newborn CRP levels were significantly associated with DNA methylation in the EAGeR trial, with 33 CpGs identified (FDR corrected p < 0.05) when both CRP and methylation were measured at the same time point in cord blood. The top 7 CpGs most strongly associated with CRP resided in inflammation and vascular-related genes.

Conclusions: Maternal CRP levels measured during each trimester were not associated with cord blood DNA methylation. Rather, DNA methylation was associated with CRP levels measured in cord blood, particularly in gene regions predominately associated with angiogenic and inflammatory pathways.

Trial Registration: Clinicaltrials.gov, NCT00467363, Registered April 30, 2007, http://www.clinicaltrials.gov/ct2/show/NCT00467363.
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http://dx.doi.org/10.1186/s13148-020-00852-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193358PMC
April 2020

Timing- and Dose-Specific Associations of Prenatal Smoke Exposure With Newborn DNA Methylation.

Nicotine Tob Res 2020 10;22(10):1917-1922

The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Introduction: Fetal changes in DNA methylation may underlie associations of maternal smoking during pregnancy with adverse outcomes in children. We examined critical periods and doses of maternal smoking during pregnancy in relation to newborn DNA methylation, and associations of paternal smoking with newborn DNA methylation.

Aims And Methods: This study was embedded in the Generation R Study, a population-based prospective cohort study from early pregnancy onwards. We assessed parental smoking during pregnancy using questionnaires. We analyzed associations of prenatal smoke exposure with newborn DNA methylation at 5915 known maternal smoking-related cytosine-phosphate-guanine sites (CpGs) in 1261 newborns using linear regression. Associations with false discovery rate-corrected p-values < .05 were taken forward.

Results: Sustained maternal smoking was associated with newborn DNA methylation at 1391 CpGs, compared with never smoking. Neither quitting smoking early in pregnancy nor former smoking was associated with DNA methylation, compared with never smoking. Among sustained smokers, smoking ≥5, compared with <5, cigarettes/d was associated with DNA methylation at seven CpGs. Paternal smoking was not associated with DNA methylation, independent of maternal smoking status.

Conclusions: Our results suggest that CpGs associated with sustained maternal smoking are not associated with maternal smoking earlier in pregnancy or with paternal smoking. Some of these CpGs show dose-response relationships with sustained maternal smoking. The third trimester may comprise a critical period for associations of smoking with newborn DNA methylation, or sustained smoking may reflect higher cumulative doses. Alternatively, maternal smoking limited to early pregnancy and paternal smoking may be associated with DNA methylation at specific other CpGs not studied here.

Implications: Our results suggest that quitting maternal smoking before the third trimester of pregnancy, and possibly lowering smoking dose, may prevent differential DNA methylation in the newborns at CpGs associated with sustained smoking. If the relevance of DNA methylation for clinical outcomes is established, these results may help in counseling parents-to-be about quitting smoking.
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http://dx.doi.org/10.1093/ntr/ntaa069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542646PMC
October 2020
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