Jorma Toppari

Background: Daycare attendance and breastfeeding have been associated with asthma risk. However, it remains unclear whether the association between breastfeeding and asthma risk depends on daycare attendance. We investigated whether daycare attendance acts as a modifier in the relationship between breastfeeding and asthma risk. Methods: We included 72,558 children from the MoBa and 3015 children from the DIPP studies. Current asthma at age 7 years in MoBa and time to asthma by the age 5 years in DIPP were analyzed. Results: In both cohorts, approximately 4% of participants were diagnosed with asthma. In MoBa, breastfeeding was associated with lower risk of overall asthma (adjusted risk ratio, aRR 0.99 [95% CI, 0.98–1.00]) and nonatopic asthma (aRR 0.97 [95% CI, 0.96–0.99]) in children who had attended daycare by the age of 18 months, and it was associated with higher overall asthma (aRR 1.01 [95% CI, 1.00–1.02]) and atopic asthma risk (aRR 1.03 [95% CI, 1.01–1.06]) in children who had not attended daycare by that age (all interaction p values ≤.05). In DIPP, the duration of breastfeeding was inversely associated with risk of atopic asthma only in an exploratory analysis in those who had started daycare by the age of 12 months (adjusted hazard ratio, aHR 0.75 [95% CI, 0.59–0.95]) but not in children who had started daycare at the age of 13–24 months (adjusted hazard ratio, aHR 1.03 [95% CI, 0.96–1.10]) or had not started daycare by the age of 24 months (adjusted hazard ratio, aHR 1.00 [95% CI, 0.94–1.06]) (interaction p value .04). Conclusions: While the primary analysis in the MoBa study suggested that age at daycare entry might mildly modify the association of breastfeeding with asthma risk, in the DIPP study an interaction only appeared in an exploratory analysis with limited atopic asthma cases. Consequently, these findings represent inconsistent evidence. image

Background: Declining fertility rates are typically linked to socioeconomic changes and later childbearing, but changes in fecundity may also contribute. As fecundity is difficult to measure in populations, rates of unassisted pregnancies, including prior induced abortions among women who later experience infertility, can serve as useful indicators. We previously examined trends in unassisted pregnancies in Denmark using the Comprehensive Unassisted Pregnancy Rate (CUPR), defined as number of live births excluding those following medically assisted reproduction (MAR), plus induced abortions.Methods: This Nordic registry-based study analyzed data from Finland, Norway, Sweden, and Denmark on births, induced abortions, and MAR among women born 1966–1999. We calculated cumulative live births and CUPR up to age 45 where possible. Linear regression estimated combined and country-specific CUPR and total birth rates (TBR), comparing slopes with 95% CIs. In Danish data, age-specific induced abortion rates before first MAR were compared between women with MAR births and women without MAR births.Findings: CUPR declined across all countries and birth cohorts. In combined analysis, it fell by 0.0138 pregnancies per woman per year, compared to a 0.0051 decline in TBR, with a slope difference of -0.0087 (95% CI -0.0115 to -0.0060), showing a steeper decline in unassisted pregnancies than in births. Later cohorts had fewer unassisted pregnancies at all ages. Among completed-fertility cohorts, induced abortion rates declined, and MAR birth rates increased, but not enough to offset the decrease. In Denmark, women with MAR births had lower prior induced abortion rates than those without.Interpretation: Unassisted pregnancy rates, reflected by the CUPR, declined progressively and similarly across all four Nordic countries. The overall decline in CUPR and lower rates of prior induced abortion at younger ages among women who later received MAR suggest that reduced fecundity may contribute to fewer unassisted pregnancies beyond the effects of delayed childbearing.

Background: The external environment, including toxicants, remains largely unexplored in celiac disease (CeD). Some of the per- and polyfluoroalkyl substances (PFAS) have immune-toxic properties and may play a role in the development of autoimmune diseases.Methods: In case-control studies nested in the Norwegian MoBa and the Finnish DIPP cohorts, children with CeD were identified by case-finding (n=349, MoBa) or screening with clinical ascertainment (n=129, DIPP). Cohort controls were randomly selected (n=324, MoBa) or matched by age, sex and place of birth (n=273, DIPP). Blood samples were collected at birth (cord blood, MoBa) or at the age of 6 months (DIPP) and 15 PFAS compounds were measured using liquid chromatography mass spectrometry. The sum of four common PFASs (PFOS + PFOA + PFHxS + PFNA = PFAS4) were the primary exposure in logistic regression models, adjusted for parity, maternal education, breastfeeding (DIPP) and other covariates.Findings: The cord blood PFAS4 concentration in MoBa was similar between cases (mean 8·47 ng/mL; SD 3·60) and controls (8·63; 4·21), and the adjusted odds ratio for CeD per unit increase was 0·99 (95% CI 0·95–1·04). In DIPP, the serum PFAS4 concentration at the age of 6 months was also similar between cases (13·30 ng/mL; SD 10·47) and controls (13·61; SD 10·29), and the adjusted odds ratio per unit increase was 1·00 (0·97–1·03). None of the specific PFASs (PFOS, PFOA, PFHxS, PFNA) were associated with CeD in MoBa or DIPP. The PFAS4 concentrations were significantly lower by increasing birth year and parity.Interpretation: The findings suggest that pre- and postnatal exposure to the environmental toxicant PFAS does not contribute to the risk of CeD in childhood. The findings were robust across cohorts and exposure pathways. Funding Funded by a grant from EU Horizon 2020.

Background: Little is known about the relative contribution of genetic and environmental factors on male reproductive function. Objectives: We studied in a cross‐sectional setting, whether testicular function and genital size correlate in father–son pairs. The study included young men from a prospective Finnish–Danish Boy cohort study and their fathers. Materials and Methods: We collected data on young men born between 1997 and 2002 at Turku University Hospital, Finland, and at the University Hospital of Copenhagen, Denmark. These young men were invited for an adult follow‐up visit at 18–23 years together with their fathers. Altogether 38 Finnish and 79 Danish father–son pairs participated in the study. The study visits included analysis of a semen sample, measurement of serum reproductive hormones and genital size (testes, penis, anogenital distance [AGD]). Intraclass correlation coefficients (ICCs) were used to evaluate familial resemblance between fathers and sons. Results: In the adjusted analyses, weak significant positive correlations between fathers and sons were observed in testicular volume measured by ultrasonography (ICC 0.30), concentrations of inhibin B (ICC 0.25), FSH (ICC 0.24), LH (ICC 0.22), and SHBG (ICC 0.26), sperm concentration (ICC 0.21), and anopenile distance (ICC 0.19). Penile width (ICC 0.23) showed significant father–son correlation, but it was of borderline statistical significance when pairs with cryptorchidism that had required surgical correction ( n = 5) were excluded. Father–son correlation for testicular size based on orchidometer (ICC 0.16) was statistically significant only when excluding pairs with a history of cryptorchidism (ICC 0.18). Conclusion: In conclusion, while genetics contributes to reproductive health, the studied reproductive variables showed rather weak correlations between fathers and sons.

Aim: To study how pubertal timing associates with cardiometabolic measures in puberty and young adulthood. Methods: Cardiovascular risk factors, anthropometry and pubertal development were regularly studied in STRIP study subjects until age 26 years. The study participants were divided into tertiles (early, average, and late) according to the age at the beginning of breast/testicular growth, menarche in females, and end of testicular growth in males. Differences in cardiometabolic variables between tertiles were analysed using one‐way ANOVA. Results: Earlier breast development was associated with higher body mass index (BMI), waist circumference (WC), and blood pressure (BP) in adulthood compared to the late group. Earlier age at menarche was associated with higher BMI and WC in adulthood. Earlier beginning of testicular enlargement was associated with higher insulin and insulin resistance at 26 years when compared to the late group. Earlier end of testicular growth tended to have higher insulin values and insulin resistance at 26 years than the average group. Conclusions: Early pubertal development in females is associated with higher BMI and WC. In males, early pubertal development is associated with increased insulin levels and insulin resistance. More research is needed to study whether these metabolic differences build up a cumulative burden.

Background: The urbanization of African populations adopting Westernized lifestyles might be connected to changes in microbial exposure and immune system activity that are harmful to health and increase the risk of non-communicable diseases, such as immune-mediated diseases. The study aims to compare microbial exposure, immune system markers, and gut microbiota between rural African and Westernized Northern European children to delineate whether there are differences present in these factors in early childhood. Methods: We compared innate immune cytokines in plasma (IL-10, IL-6, IL-1β, and TNF-α) using Luminex, gut microbiota using 16S rRNA sequencing, and microbial infections using qPCR in early childhood longitudinal sample series of children from rural Africa (participants from the iLINS-DYAD-M study conducted in Malawi) and from Northern Europe (participants from the DIPP study conducted in Finland) to identify differences which could be associated with negative health outcomes in Westernized societies. Results: Here, we show that the levels of plasma cytokines and frequency of stool pathogen positivity are substantially higher in Malawian than in Finnish children and that some of the cytokines differ in their longitudinal pattern between the two groups. Also, the diversity and composition of gut microbiota differ between the groups at the age of 6 months and diverge more with increasing age. Conclusions: These results highlight the early emergence of differences in the immune system and gut microbiota between children living in extremities of the microbial exposure gradient. These differences add to the existing knowledge of possible factors contributing to increasing prevalence of chronic inflammatory diseases in African societies shifting towards more Westernized lifestyle.

We aimed to determine if thyroid autoimmunity is associated with a child’s risk for subsequent development of islet or celiac autoantibodies. Children at high genetic risk of type 1 diabetes were followed for thyroid autoimmunity (thyroid peroxidase antibodies [TPOAb] and thyroglobulin antibodies [TGAb]), islet autoimmunity (IA), and celiac disease autoimmunity (CDA) in The Environmental Determinants of Diabetes in the Young study. Out of 5482 children tested for thyroid autoimmunity, IA, and CDA, 39% developed at least one autoantibody. At age 14 years, thyroid autoimmunity co-occurred with IA in 59 children (15 more cases than expected by chance alone, P = 0.02) and with CDA in 125 children (26 cases above expected, P = 0.01). The risk of developing IA or CDA after thyroid autoimmunity varied by which thyroid autoantibody appeared first: TPOAb-first was associated with both IA (HR 1.92, 95% CI, 1.09-3.40) and CDA (1.69, 95% CI, 1.03-2.76), whereas TGAb-first was not associated with the risk of either. Islet autoimmunity and CDA are frequently found in connection to thyroid autoimmunity in children and young adolescents. The relationships of thyroid autoimmunity with IA and CDA depend on which thyroid autoantibody appears first.

Aims/hypothesis: In this prospective birth cohort study, we examined whether the dietary intake of A, B, C, D and E vitamins is associated with the risk of islet autoimmunity or type 1 diabetes in children who are genetically at risk for type 1 diabetes. Methods: Data on vitamin intakes in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) cohort study were available for 5674 children born between September 1996 and September 2004 in Oulu University Hospital or Tampere University Hospital. Diet was assessed using 3-day food records at the age of 3 and 6 months, and annually from 1 to 6 years. The primary outcomes were: (1) islet autoimmunity defined as repeated positivity for islet cell autoantibodies and at least one out of three type 1 diabetes-related biochemical autoantibodies or a diagnosis of type 1 diabetes; and (2) a diagnosis of type 1 diabetes. Results: During the 6-year follow-up, 247 children (4.4%) developed islet autoimmunity and 94 (1.7%) developed type 1 diabetes. When adjusted for total energy intake, sex, HLA genotype and family history of diabetes, the intakes of retinol (HR 0.91; 95% credible interval [CrI] 0.86, 0.97 per 10 µg/MJ increase in intake), vitamin C (HR 0.70; 95% CrI 0.54, 0.90 per 10 µg/MJ) and vitamin E (HR 0.93; 95% CrI 0.89, 0.97 per 0.1 mg/MJ) were associated with decreased risk of islet autoimmunity and also with the risk of type 1 diabetes (retinol: HR 0.83; 95% CrI 0.74, 0.96 per 10 µg/MJ; vitamin C: HR 0.45; 95% CrI 0.23, 0.84 per 10 µg/MJ; vitamin E: HR 0.89; 95% CrI 0.80, 0.99 per 0.1 mg/MJ). The associations remained statistically significant after multiple testing correction for the risk of islet autoimmunity but not for type 1 diabetes. The association between retinol intake and islet autoimmunity risk was not significant when the 3-month age point, during which the child is primarily breastfed, was excluded. We observed a weak inverse association for vitamin D and islet autoimmunity, and no associations for B vitamins. Conclusions/interpretation: High intake of vitamin C and vitamin E was associated with a decreased risk of islet autoimmunity. Graphical

Objective: Clinical autoimmune thyroid disease (AITD), presenting as either hypo‐ or hyperthyroidism, can occur at any age. Autoantibodies against thyroid peroxidase or thyroglobulin precede the onset of clinical AITD. We aimed to assess factors associated with AITD in children and determine if risk factors for AITD differ among the subset who have developed thyroid autoantibodies. Design: Prospective cohort study. Patients: The TEDDY Study is a cohort of 8676 children with increased genetic susceptibility for type 1 diabetes, followed to age 15 years. Measurements: Hypothyroidism and hyperthyroidism clinical diagnoses as well as medications used for treating AITD were reported to study staff at every visit, 2 to 4 times per year. Children were screened for thyroid autoantibodies at ages 9 and 14, and if positive, previously collected samples were retrospectively analyzed to determine the age when autoantibodies first appeared. Results: Of 5203 children screened for thyroid autoantibodies, 99 were diagnosed with AITD. Female sex, human leukocyte antigen (HLA) haplogenotype, and family history of hypothyroidism, hyperthyroidism, type 1 diabetes, and celiac disease were associated with risk of AITD. Among the 575 children positive for thyroid autoantibodies, HLA remained associated with AITD, while the estimates for family history were attenuated, and no association was present for sex. Conclusions: Female sex, family history of autoimmune disease, and HLA haplogenotype are risk factors for AITD in genetically high‐risk children, but these trends differ for progression from thyroid autoimmunity to AITD.