Liesbeth Duijts

Prolonged and Exclusive Breastfeeding Reduces the Risk of Infectious Diseases in Infancy

OBJECTIVE: To examine the associations of duration of exclusive breastfeeding with infections in the upper respiratory (URTI), lower respiratory (LRTI), and gastrointestinal tracts (GI) in infancy. METHODS: This study was embedded in the Generation R Study, a population-based prospective cohort study from fetal life onward in the Netherlands. Rates of breastfeeding during the first 6 months (never; partial for <4 months, not thereafter; partial for 4–6 months; exclusive for 4 months, not thereafter; exclusive for 4 months, partial thereafter; and exclusive for 6 months) and doctor-attended infections in the URTI, LRTI, and GI until the age of 12 months were assessed by questionnaires and available for 4164 subjects. RESULTS: Compared with never-breastfed infants, those who were breastfed exclusively until the age of 4 months and partially thereafter had lower risks of infections in the URTI, LRTI, and GI until the age of 6 months (adjusted odds ratio [aOR]: 0.65 [95% confidence interval (CI): 0.51–0.83]; aOR: 0.50 [CI: 0.32–0.79]; and aOR: 0.41 [CI: 0.26–0.64], respectively) and of LRTI infections between the ages of 7 and 12 months (aOR: 0.46 [CI: 0.31–0.69]). Similar tendencies were observed for infants who were exclusively breastfed for 6 months or longer. Partial breastfeeding, even for 6 months, did not result in significantly lower risks of these infections. CONCLUSIONS: Exclusive breastfeeding until the age of 4 months and partially thereafter was associated with a significant reduction of respiratory and gastrointestinal morbidity in infants. Our findings support health-policy strategies to promote exclusive breastfeeding for at least 4 months, but preferably 6 months, in industrialized countries.

A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations

Asthma exacerbations are among the most frequent causes of hospitalization during childhood, but the underlying mechanisms are poorly understood. We performed a genome-wide association study of a specific asthma phenotype characterized by recurrent, severe exacerbations occurring between 2 and 6 years of age in a total of 1,173 cases and 2,522 controls. Cases were identified from national health registries of hospitalization, and DNA was obtained from the Danish Neonatal Screening Biobank. We identified five loci with genome-wide significant association. Four of these, GSDMB, IL33, RAD50 and IL1RL1, were previously reported as asthma susceptibility loci, but the effect sizes for these loci in our cohort were considerably larger than in the previous genome-wide association studies of asthma. We also obtained strong evidence for a new susceptibility gene, CDHR3 (encoding cadherin-related family member 3), which is highly expressed in airway epithelium. These results demonstrate the strength of applying specific phenotyping in the search for asthma susceptibility genes.

Breastfeeding protects against infectious diseases during infancy in industrialized countries. A systematic review

Firstly, this review was performed to assess the effect of breastfeeding on infections during infancy in industrialized countries. Secondly, the effect of duration and exclusiveness of breastfeeding were explored. Studies were identified using Medline, Cochrane Library, Science Citation Index and by a manual search from bibliographies of articles from August 1986 to January 2008. Follow-up, case-control and randomized controlled trial (RCT) studies performed in an industrialized country, published in English, with breastfeeding as a determinant, with overall infections, gastrointestinal or respiratory tract infections as a major outcome, and at least 40 participants in the study were included. Using Bauchners criteria published in a review in 1986, two reviewers and a peer reviewer assessed the internal validity of those studies. Twenty-one studies that met the inclusion and internal validity criteria were included. These included 16 follow-up and four case-control studies and one RCT. Four out of five studies observed decreased effects on overall infections in breastfed infants. With regard to gastrointestinal infections, six out of eight studies suggested that breastfeeding had a protective effect. Thirteen out of 16 studies concluded that breastfeeding protects infants against respiratory tract infections. Five studies combined duration and exclusiveness of breastfeeding. All studies observed a protective dose/duration-response effect on gastrointestinal or respiratory tract infections. These studies strongly suggest that breastfeeding protects infants against overall infections, gastrointestinal and respiratory tract infections in industrialized countries. The optimal duration of exclusive breastfeeding for protection against infectious diseases needs to be studied in more detail.

Fetal and infant origins of asthma

Previous studies have suggested that asthma, like other common diseases, has at least part of its origin early in life. Low birth weight has been shown to be associated with increased risks of asthma, chronic obstructive airway disease, and impaired lung function in adults, and increased risks of respiratory symptoms in early childhood. The developmental plasticity hypothesis suggests that the associations between low birth weight and diseases in later life are explained by adaptation mechanisms in fetal life and infancy in response to various adverse exposures. Various pathways leading from adverse fetal and infant exposures to growth adaptations and respiratory health outcomes have been studied, including fetal and early infant growth patterns, maternal smoking and diet, children’s diet, respiratory tract infections and acetaminophen use, and genetic susceptibility. Still, the specific adverse exposures in fetal and early postnatal life leading to respiratory disease in adult life are not yet fully understood. Current studies suggest that both environmental and genetic factors in various periods of life, and their epigenetic mechanisms may underlie the complex associations of low birth weight with respiratory disease in later life. New well-designed epidemiological studies are needed to identify the specific underlying mechanisms. This review is focused on specific adverse fetal and infant growth patterns and exposures, genetic susceptibility, possible respiratory adaptations and perspectives for new studies.

Fetal and infant growth and asthma symptoms in preschool children: The generation R study

RATIONALE Low birth weight is associated with an increased risk of wheezing in childhood. OBJECTIVES We examined the associations of longitudinally measured fetal and infant growth patterns with the risks of asthma symptoms in preschool children. METHODS This study was embedded in a population-based prospective cohort study among 5,125 children. Second- and third-trimester fetal growth characteristics (head circumference, femur length, abdominal circumference, and weight) were estimated by repeated ultrasounds. Infant growth (head circumference, length, and weight) was measured at birth and at the ages of 3, 6, and 12 months. Parental report of asthma symptoms until the age of 4 years was yearly obtained by questionnaires. MEASUREMENTS AND MAIN RESULTS Both fetal restricted and accelerated growth, defined as a negative or positive change of more than 0.67 standard deviation score, were not associated with asthma symptoms until the age of 4 years. Accelerated weight gain from birth to 3 months following normal fetal growth was associated with increased risks of asthma symptoms (overall odds ratio for wheezing: 1.44 [95% confidence interval: 1.22, 1.70]; shortness of breath: 1.32 [1.12, 1.56]; dry cough: 1.16 [1.01, 1.34]; persistent phlegm: 1.30 [1.07, 1.58]), but not with eczema (0.95 [0.80, 1.14]). These associations were independent of other fetal growth patterns and tended to be stronger for children of atopic mothers than for children of nonatopic mothers. CONCLUSIONS Weight-gain acceleration in early infancy was associated with increased risks of asthma symptoms in preschool children, independent of fetal growth. Early infancy might be a critical period for the development of asthma.

Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns

Folate is vital for fetal development. Periconceptional folic acid supplementation and food fortification are recommended to prevent neural tube defects. Mechanisms whereby periconceptional folate influences normal development and disease are poorly understood: epigenetics may be involved. We examine the association between maternal plasma folate during pregnancy and epigenome-wide DNA methylation using Illuminas HumanMethyl450 Beadchip in 1,988 newborns from two European cohorts. Here we report the combined covariate-adjusted results using meta-analysis and employ pathway and gene expression analyses. Four-hundred forty-three CpGs (320 genes) are significantly associated with maternal plasma folate levels during pregnancy (false discovery rate 5%); 48 are significant after Bonferroni correction. Most genes are not known for folate biology, including APC2, GRM8, SLC16A12, OPCML, PRPH, LHX1, KLK4 and PRSS21. Some relate to birth defects other than neural tube defects, neurological functions or varied aspects of embryonic development. These findings may inform how maternal folate impacts the developing epigenome and health outcomes in offspring.

DNA methylation mediates the effect of maternal smoking during pregnancy on birthweight of the offspring

Background: We examined whether the effect of maternal smoking during pregnancy on birthweight of the offspring was mediated by smoking-induced changes to DNA methylation in cord blood. Methods: First, we used cord blood of 129 Dutch children exposed to maternal smoking vs 126 unexposed to maternal and paternal smoking (53% male) participating in the GECKO Drenthe birth cohort. DNA methylation was measured using the Illumina HumanMethylation450 Beadchip. We performed an epigenome-wide association study for the association between maternal smoking and methylation followed by a mediation analysis of the top signals [false-discovery rate (FDR) < 0.05]. We adjusted both analyses for maternal age, education, pre-pregnancy BMI, offspring’s sex, gestational age and white blood cell composition. Secondly, in 175 exposed and 1248 unexposed newborns from two independent birth cohorts, we replicated and meta-analysed results of eight cytosine-phosphate-guanine (CpG) sites in the GFI1 gene, which showed the most robust mediation. Finally, we performed functional network and enrichment analysis. Results: We found 35 differentially methylated CpGs (FDR < 0.05) in newborns exposed vs unexposed to smoking, of which 23 survived Bonferroni correction (P < 1 × 10-7). These 23 CpGs mapped to eight genes: AHRR, GFI1, MYO1G, CYP1A1, NEUROG1, CNTNAP2, FRMD4A and LRP5. We observed partial confirmation as three of the eight CpGs in GFI1 replicated. These CpGs partly mediated the effect of maternal smoking on birthweight (Sobel P < 0.05) in meta-analysis of GECKO and the two replication cohorts. Differential methylation of these three GFI1 CpGs explained 12–19% of the 202 g lower birthweight in smoking mothers. Functional enrichment analysis pointed towards activation of cell-mediated immunity. Conclusions: Maternal smoking during pregnancy was associated with cord blood methylation differences. We observed a potentially mediating role of methylation in the association between maternal smoking during pregnancy and birthweight of the offspring. Functional network analysis suggested a role in activating the immune system.

Childhood Cardiometabolic Outcomes of Maternal Obesity During Pregnancy The Generation R Study

Maternal prepregnancy obesity is associated with impaired cardiometabolic health in offspring. Whether these associations reflect direct intrauterine causal mechanisms remains unclear. In a population-based prospective cohort study among 4871 mothers, fathers, and their children, we examined the associations of both maternal and paternal prepregnancy body mass index (BMI) with childhood body fat distribution and cardiometabolic outcomes and explored whether any association was explained by pregnancy, birth, and childhood factors. We measured childhood BMI, total body and abdominal fat distribution, blood pressure, and blood levels of lipids, insulin, and C-peptide at the age of 6 years. We observed that higher maternal and paternal prepregnancy BMI were associated with higher childhood BMI, total body and abdominal fat mass measures, systolic blood pressure, and insulin levels and lower high-density lipoprotein cholesterol levels (P<0.05). Stronger associations were present for maternal than paternal BMI, with statistical support for heterogeneity between these associations. The associations for childhood fat mass and cardiometabolic outcomes attenuated after adjustment for childhood current BMI. Compared with children from normal-weight mothers, those from obese mothers had increased risks of childhood overweight (odds ratio, 3.84 [95% confidence interval, 3.01–4.90]) and clustering of cardiometabolic risk factors (odds ratio, 3.00 [95% confidence interval, 2.09–4.34]). Smaller effect estimates for these outcomes were observed for paternal obesity. In conclusion, higher maternal and paternal prepregnancy BMI were associated with an adverse cardiometabolic profile in offspring, with stronger associations present for maternal prepregnancy BMI. These findings suggest that maternal prepregnancy BMI may influence the cardiometabolic health of offspring through direct intrauterine mechanisms.

Breast-feeding and growth in children until the age of 3 years: the Generation R Study

Breast-feeding has been suggested to be associated with lower risks of obesity in older children and adults. We assessed whether the duration and exclusiveness of breast-feeding are associated with early postnatal growth rates and the risks of overweight and obesity in preschool children. The present study was embedded in a population-based prospective cohort study from early fetal life onwards, among 5047 children and their mothers in The Netherlands. Compared with children who were breast-fed, those who were never breast-fed had a lower weight at birth (difference 134 (95 % CI - 190, - 77) g). No associations between breast-feeding duration and exclusivity with growth rates before the age of 3 months were observed. Shorter breast-feeding duration was associated with an increased gain in age- and sex-adjusted standard deviation scores for length, weight and BMI (P for trend < 0·05) between 3 and 6 months of age. Similar tendencies were observed for the associations of breast-feeding exclusivity with change in length, weight and BMI. Breast-feeding duration and exclusivity were not consistently associated with the risks of overweight and obesity at the ages of 1, 2 and 3 years. In conclusion, shorter breast-feeding duration and exclusivity during the first 6 months tended to be associated with increased growth rates for length, weight and BMI between the age of 3 and 6 months but not with the risks of overweight and obesity until the age of 3 years.

Early origins of chronic obstructive lung diseases across the life course

Chronic obstructive lung diseases, like asthma and chronic obstructive pulmonary disease, have high prevalences and are a major public health concern. Chronic obstructive lung diseases have at least part of their origins in early life. Exposure to an adverse environment during critical periods in early life might lead to permanent developmental adaptations which results in impaired lung growth with smaller airways and lower lung volume, altered immunological responses and related inflammation, and subsequently to increased risks of chronic obstructive lung diseases throughout the life course. Various pathways leading from early life factors to respiratory health outcomes in later life have been studied, including fetal and early infant growth patterns, preterm birth, maternal obesity, diet and smoking, children’s diet, allergen exposure and respiratory tract infections, and genetic susceptibility. Data on potential adverse factors in the embryonic and preconception period and respiratory health outcomes are scarce. Also, the underlying mechanisms how specific adverse exposures in the fetal and early postnatal period lead to chronic obstructive lung diseases in later life are not yet fully understood. Current studies suggest that interactions between early environmental exposures and genetic factors such as changes in DNA-methylation and RNA expression patterns may explain the early development of chronic obstructive lung diseases. New well-designed epidemiological studies are needed to identify specific critical periods and to elucidate the mechanisms underlying the development of chronic obstructive lung disease throughout the life course.