Maria Christine Magnus

Delivery by Cesarean Section and Early Childhood Respiratory Symptoms and Disorders The Norwegian Mother and Child Cohort Study

Studies have indicated that children delivered by cesarean section are at an increased risk of developing wheezing and asthma. This could be the result of an altered immune system development due to delayed gut colonization or of increased neonatal respiratory morbidity. The authors examined the associations between delivery by cesarean section and the development of wheezing, asthma, and recurrent lower respiratory tract infections in children up to 36 months of age among 37,171 children in the Norwegian Mother and Child Cohort Study. Generalized linear models were used in the multivariable analysis. Children delivered by cesarean section had an increased likelihood of current asthma at 36 months of age (relative risk = 1.17, 95% confidence interval: 1.03, 1.32), and the association was stronger among children of nonatopic mothers (relative risk = 1.33, 95% confidence interval: 1.12, 1.58). No increased risk of wheezing or recurrent lower respiratory tract infections was seen among children delivered by cesarean section. Findings were similar among children delivered by acute and elective cesarean section. In conclusion, children delivered by cesarean section may have an increased risk of current asthma at 36 months, but residual confounding cannot be excluded. In future prospective studies, investigators should reexamine this association in different age groups.

Grandmother's smoking when pregnant with the mother and asthma in the grandchild: the Norwegian Mother and Child Cohort Study

Background A trans-generational influence of prenatal tobacco smoke exposure on asthma development has been proposed but the evidence remains sparse. Methods We examined the grandmothers smoking when pregnant with the mother in relation to asthma outcomes in the grandchild (current asthma at 36 months (N=53 169, cases=3013), current asthma at 7 years (N=25 394, cases=1265) and dispensed asthma medications at 7 years in the Norwegian Prescription Database (N=45 607, cases=1787)) within the Norwegian Mother and Child Cohort Study (MoBa). We calculated adjusted RR (adj. RR) and 95% CIs using log binomial regression. Results A total of 23.5% of mothers reported that their mother smoked when pregnant with them. The grandmothers smoking when pregnant with the mother was positively associated with asthma at 36 months (adj. RR 1.15 (95% CI 1.06 to 1.24)), asthma at 7 years (adj. RR 1.21 (95% CI 1.07 to 1.37)) and dispensed asthma medications at 7 years (adj. RR 1.15 (95% CI 1.04 to 1.26)). This positive association did not differ significantly by the mothers smoking status when pregnant with the child (p values for multiplicative interaction >0.1). Conclusions The grandmothers smoking when pregnant with the mother increased the risk of asthma in the grandchild independent of the mothers smoking status. However, given limited information on the grandmothers socioeconomic status, asthma status and other factors, unmeasured confounding may be present.

Prospective Study of Maternal Mid-Pregnancy 25-hydroxyvitamin D Level and Early Childhood Respiratory Disorders

BACKGROUND Studies suggest that prenatal vitamin D status may be inversely associated with lower respiratory tract infections (LRTIs) early in life. Studies of prenatal vitamin D status and development of asthma have inconsistent findings. METHODS We examined the associations of maternal mid-pregnancy 25-hydroxyvitamin D [25(OH)D] level with the frequency of LRTIs by 36 months and with current asthma at 36 months using the Norwegian Mother and Child Cohort Study. Maternal plasma 25(OH)D level was measured using liquid chromatography-tandem mass spectrometry. Respiratory disorders were evaluated by maternal report through questionnaires. LRTIs were analysed in a random sample of 1248 children. Asthma was analysed using a case-control design, including 489 cases and 1183 controls. Multivariable generalised linear models calculated adjusted measures of association. RESULTS The median gestational week of sample collection was 18 weeks (range 9, 35). The mean 25(OH)D level was 73.7 nmol/L (standard deviation 23.7). Higher maternal mid-pregnancy 25(OH)D level was associated with a reduced risk of three or more LRTIs by 36 months vs. none, adjusted risk ratio 0.74 [95% confidence interval (CI): 0.58, 0.93] per 20 nmol/L increase. Associations were similar when examining the frequency of LRTIs by 18 months, and the frequency of LRTIs between 18 and 36 months. Maternal mid-pregnancy 25(OH)D level was not significantly associated with current asthma at 36 months, adjusted odds ratio 0.91 [95% CI 0.81, 1.02] per 20 nmol/L increase. CONCLUSIONS Higher maternal mid-pregnancy 25(OH)D level was associated with a modestly reduced risk of recurrent LRTIs by 36 months, but was not associated with current asthma at 36 months.

Effectiveness of Mammography Screening in Reducing Breast Cancer Mortality in Women Aged 39–49 Years: A Meta-Analysis

BACKGROUND Mammography screening of women >50 years of age significantly reduces breast cancer mortality in randomized controlled trials (RCTs). We sought to evaluate the effectiveness of mammography screening in women aged 39-49 years in reducing breast cancer mortality and to discuss previously published meta-analyses. METHODS PubMed/MEDLINE, OVID, COCHRANE, and Educational Resources Information Center (ERIC) databases were searched, and extracted references were reviewed. Dissertation abstracts and clinical trials databases available online were assessed to identify unpublished works. All assessments were independently done by two reviewers. All trials included were RCTs, published in English, included data on women aged 39-49, and reported relative risk (RR)/odds ratio (OR) or frequency data. RESULTS Nine studies were identified: the Kopparberg, Ostergotland (The Two-County study), Health Insurance Plan (HIP), Canada, Stockholm, Gothenburg, Edinburgh, Age, and Malmo trials. The individual trials were quality assessed, and the data were extracted using predefined forms. Using the DerSimonian and Laird random effects model, the results from the seven RCTs with the highest quality score were combined, and a significant pooled RR estimate of 0.83 (95% confidence interval [CI] 0.72-0.97) was calculated. Post hoc sensitivity analyses excluding studies with randomization before 1980 caused a loss of statistical significance (RR 0.87, 95% CI: 0.56, 1.13). CONCLUSIONS Mammography screenings are effective and generate a 17% reduction in breast cancer mortality in women 39-49 years of age. The quality of the trials varies, and providers should inform women in this age group about the positive and negative aspects of mammography screenings.

Decline in Early Childhood Respiratory Tract Infections in the Norwegian Mother and Child Cohort Study after Introduction of Pneumococcal Conjugate Vaccination

Background: The 7-valent pneumococcal conjugate vaccine (PCV7) was introduced into the Norwegian Childhood Immunization Program in 2006. A substantial effectiveness of PCV7 immunization against invasive pneumococcal disease has been demonstrated, whereas evidence of its impact on respiratory tract infections are less consistent. Methods: This study included children participating in the Norwegian Mother and Child Cohort Study, which recruited pregnant women between 1999 and 2008. Maternal report of acute otitis media (AOM), lower respiratory tract infections (LRTIs) and asthma in the child was compared by PCV7 immunization status, as obtained from the Norwegian Immunization Registry. Generalized linear models with the log-link function were used to report adjusted relative risks (RRs) and 95% confidence intervals (CIs). Results: For children who had received 3 or more PCV7 immunizations by 12 months of age, the adjusted RRs of AOM and LRTIs between 12 and 18 months were 0.86 (95% CI: 0.81, 0.91) and 0.78 (95% CI: 0.70, 0.87) respectively, when compared with nonimmunized children. A reduced risk of AOM, RR 0.92 (95% CI: 0.90, 0.94), and LRTIs, RR 0.75 (95% CI: 0.71, 0.80), between 18 and 36 months of age was also identified among children who had received 3 or more immunizations by 18 months of age. No association was seen between PCV7 immunization and asthma at 36 months of age. Conclusion: Reduced incidences of AOM and LRTIs before 36 months of age were observed among children immunized with PCV7 through the childhood immunization program.

Prenatal and infant paracetamol exposure and development of asthma: the Norwegian Mother and Child Cohort Study

BACKGROUND Paracetamol exposure has been positively associated with asthma development. The relative importance of prenatal vs infant exposure and confounding by indication remains elusive. We examined the association of prenatal and infant (first 6 months) paracetamol exposure with asthma development while addressing confounding by indication. METHODS We used information from the Norwegian Mother and Child Cohort Study, including 53169 children for evaluation of current asthma at 3 years, 25394 for current asthma at 7 years and 45607 for dispensed asthma medications at 7 years in the Norwegian Prescription Database. We calculated adjusted relative risks (adj. RR) and 95% confidence intervals (CI) using log-binomial regression. RESULTS There were independent modest associations between asthma at 3 years with prenatal paracetamol exposure (adj. RR 1.13; 95% CI: 1.02-1.25) and use of paracetamol during infancy (adj. RR 1.29; 95% CI: 1.16-1.45). The results were consistent for asthma at 7 years. The associations with prenatal paracetamol exposure were seen for different indications (pain, respiratory tract infections/influenza and fever). Maternal pain during pregnancy was the only indication that showed an association both with and without paracetamol use. Maternal paracetamol use outside pregnancy and paternal paracetamol use were not associated with asthma development. In a secondary analysis, prenatal ibuprofen exposure was positively associated with asthma at 3 years but not asthma at 7 years. CONCLUSIONS This study provides evidence that prenatal and infant paracetamol exposure have independent associations with asthma development. Our findings suggest that the associations could not be fully explained by confounding by indication.

Perinatal Risk Factors for Development of Celiac Disease in Children, Based on the Prospective Norwegian Mother and Child Cohort Study

BACKGROUND & AIMS There have been inconsistent reports of prenatal and perinatal factors that affect risk for development of celiac disease. We assessed the association of fetal growth, birth weight, and mode of delivery with development of celiac disease within the Norwegian Mother and Child (MoBa) Cohort Study. METHODS The MoBa cohort contains pregnancy information on 95,200 women and data on their 114,500 children, which were collected in Norway from 1999 through 2008; it is linked to the Medical Birth Registry. Women and children with celiac disease were identified from the National Patient Registry and from womens responses to MoBa questionnaires. We calculated odds ratios (ORs) for celiac disease by using a multivariable logistic regression model, adjusting for maternal celiac disease, sex of children, and childrens age (model 1); in a second model, we adjusted for age of gluten introduction and duration of breastfeeding (model 2). RESULTS We identified 650 children with celiac disease and 107,828 controls in the MoBa database. We found no association between birth weight or height with celiac disease (born small for gestational age was not associated). Celiac disease was not associated with mode of delivery (cesarean section, model 1: OR, 0.84; 95% confidence interval [CI], 0.65-1.09, and model 2: OR, 0.83; 95% CI, 0.63-1.09). Maternal celiac disease, adjusted for age and sex of the children (OR, 12.45; 95% CI, 8.29-18.71) and type 1 diabetes (model 1: OR, 2.58; 95% CI, 1.19-5.53, and model 2: OR, 2.61; 95% CI, 1.14-5.98) were associated with development of celiac disease in children, whereas maternal type 2 diabetes and gestational diabetes were not. CONCLUSIONS On the basis of analysis of the Norwegian MoBa cohort, development of celiac disease in children is significantly associated with sex of the child, maternal celiac disease, and type 1 diabetes but not with intrauterine growth.

Peak Weight and Height Velocity to Age 36 Months and Asthma Development: The Norwegian Mother and Child Cohort Study

Background The immediate postnatal period is the period of the fastest growth in the entire life span and a critical period for lung development. Therefore, it is interesting to examine the association between growth during this period and childhood respiratory disorders. Methods We examined the association of peak weight and height velocity to age 36 months with maternal report of current asthma at 36 months (n = 50,311), recurrent lower respiratory tract infections (LRTIs) by 36 months (n = 47,905) and current asthma at 7 years (n = 24,827) in the Norwegian Mother and Child Cohort Study. Peak weight and height velocity was calculated using the Reed1 model through multilevel mixed-effects linear regression. Multivariable log-binomial regression was used to calculate adjusted relative risks (adj.RR) and 95% confidence intervals (CI). We also conducted a sibling pair analysis using conditional logistic regression. Results Peak weight velocity was positively associated with current asthma at 36 months [adj.RR 1.22 (95%CI: 1.18, 1.26) per standard deviation (SD) increase], recurrent LRTIs by 36 months [adj.RR 1.14 (1.10, 1.19) per SD increase] and current asthma at 7 years [adj.RR 1.13 (95%CI: 1.07, 1.19) per SD increase]. Peak height velocity was not associated with any of the respiratory disorders. The positive association of peak weight velocity and asthma at 36 months remained in the sibling pair analysis. Conclusions Higher peak weight velocity, achieved during the immediate postnatal period, increased the risk of respiratory disorders. This might be explained by an influence on neonatal lung development, shared genetic/epigenetic mechanisms and/or environmental factors.

Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium

&NA; Pre‐pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta‐analysed the association between pre‐pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother‐newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother‐child pairs), we meta‐analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10‐7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for acausal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well‐powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large‐scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.

Maternal Folate Intake during Pregnancy and Childhood Asthma in a Population-based Cohort

Rationale: A potential adverse effect of high folate intake during pregnancy on childrens asthma development remains controversial. Objectives: To prospectively investigate folate intake from both food and supplements during pregnancy and asthma at age 7 years when the diagnosis is more reliable than at preschool age. Methods: This study included eligible children born 2002‐2006 from the Norwegian Mother and Child Cohort Study, a population‐based pregnancy cohort, linked to the Norwegian Prescription Database. Current asthma at age 7 was defined by asthma medications dispensed at least twice in the year (1,901 cases; n = 39,846) or by maternal questionnaire report (1,624 cases; n = 28,872). Maternal folate intake was assessed with a food frequency questionnaire validated against plasma folate. We used log‐binomial and multinomial regression to calculate adjusted relative risks with 95% confidence intervals. Measurements and Main Results: Risk of asthma was increased in the highest versus lowest quintile of total folate intake with an adjusted relative risk of 1.23 (95% confidence interval, 1.06‐1.44) that was similar for maternally reported asthma. Mothers in the highest quintile had a relatively high intake of food folate (median, 308; interquartile range, 241‐366 &mgr;g/d) and nearly all took at least 400 &mgr;g/d of supplemental folic acid (median, 500; interquartile range, 400‐600 &mgr;g/d). Conclusions: In this large prospective population‐based cohort with essentially complete follow‐up, pregnant women taking supplemental folic acid at or above the recommended dose, combined with a diet rich in folate, reach a total folate intake level associated with a slightly increased risk of asthma in children.