[Skip to Content]
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Download PDF
Figure.
Formation of the Analysis Sample
Formation of the Analysis Sample

A, Children in the Norwegian Mother and Child Cohort Study (MoBa). In MoBa, a total of 2545 children were excluded because they were stillborn, were aborted, or had unknown birth outcome, and 3842 live-born children were excluded because they were from multiple births. B, Children in the Danish National Birth Cohort (DNBC). In DNBC, a total of 6303 children were excluded because they were stillborn, were aborted, or had unknown birth outcome, and 4163 live-born children were excluded because they were from multiple births.

Table 1.  
Distribution of Characteristics
Distribution of Characteristics
Table 2.  
Distribution of Anthropometric Measurements
Distribution of Anthropometric Measurements
Table 3.  
Association of Growth Between Birth and Age 12 Months With Development of Type 1 Diabetes
Association of Growth Between Birth and Age 12 Months With Development of Type 1 Diabetes
Table 4.  
Association of Growth During 2 Periods Between Birth and Age 12 Months With Development of Type 1 Diabetes
Association of Growth During 2 Periods Between Birth and Age 12 Months With Development of Type 1 Diabetes
1.
Harjutsalo  V, Sund  R, Knip  M, Groop  PH.  Incidence of type 1 diabetes in Finland. JAMA. 2013;310(4):427-428.
PubMedArticle
2.
Skrivarhaug  T, Stene  LC, Drivvoll  AK, Strøm  H, Joner  G; Norwegian Childhood Diabetes Study Group.  Incidence of type 1 diabetes in Norway among children aged 0-14 years between 1989 and 2012: has the incidence stopped rising? results from the Norwegian Childhood Diabetes Registry. Diabetologia. 2014;57(1):57-62.
PubMedArticle
3.
Patterson  CC, Gyürüs  E, Rosenbauer  J,  et al.  Trends in childhood type 1 diabetes incidence in Europe during 1989-2008: evidence of non-uniformity over time in rates of increase. Diabetologia. 2012;55(8):2142-2147.
PubMedArticle
4.
Stene  LC, Gale  EA.  The prenatal environment and type 1 diabetes. Diabetologia. 2013;56(9):1888-1897.
PubMedArticle
5.
Baum  JD, Ounsted  M, Smith  MA.  Letter: weight gain in infancy and subsequent development of diabetes mellitus in childhood. Lancet. 1975;2(7940):866.
PubMedArticle
6.
EURODIAB Substudy 2 Study Group.  Rapid early growth is associated with increased risk of childhood type 1 diabetes in various European populations. Diabetes Care. 2002;25(10):1755-1760.
PubMedArticle
7.
Hyppönen  E, Kenward  MG, Virtanen  SM,  et al; Childhood Diabetes in Finland (DiMe) Study Group.  Infant feeding, early weight gain, and risk of type 1 diabetes. Diabetes Care. 1999;22(12):1961-1965.
PubMedArticle
8.
Johansson  C, Samuelsson  U, Ludvigsson  J.  A high weight gain early in life is associated with an increased risk of type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1994;37(1):91-94.
PubMedArticle
9.
Ljungkrantz  M, Ludvigsson  J, Samuelsson  U.  Type 1 diabetes: increased height and weight gains in early childhood. Pediatr Diabetes. 2008;9(3, pt 2):50-56.
PubMedArticle
10.
Svensson  J, Carstensen  B, Mortensen  HB, Borch-Johnsen  K.  Growth in the first year of life and the risk of type 1 diabetes in a Danish population. Paediatr Perinat Epidemiol. 2007;21(1):44-48.
PubMedArticle
11.
Beyerlein  A, Thiering  E, Pflueger  M,  et al.  Early infant growth is associated with the risk of islet autoimmunity in genetically susceptible children. Pediatr Diabetes. 2014;15(7):534-542.
PubMedArticle
12.
Couper  JJ, Beresford  S, Hirte  C,  et al.  Weight gain in early life predicts risk of islet autoimmunity in children with a first-degree relative with type 1 diabetes. Diabetes Care. 2009;32(1):94-99.
PubMedArticle
13.
Lamb  MM, Yin  X, Zerbe  GO,  et al.  Height growth velocity, islet autoimmunity and type 1 diabetes development: the Diabetes Autoimmunity Study in the Young. Diabetologia. 2009;52(10):2064-2071.
PubMedArticle
14.
Magnus  P, Irgens  LM, Haug  K, Nystad  W, Skjaerven  R, Stoltenberg  C; MoBa Study Group.  Cohort profile: the Norwegian Mother and Child Cohort Study (MoBa). Int J Epidemiol. 2006;35(5):1146-1150.
PubMedArticle
15.
Nilsen  RM, Vollset  SE, Gjessing  HK,  et al.  Self-selection and bias in a large prospective pregnancy cohort in Norway. Paediatr Perinat Epidemiol. 2009;23(6):597-608.
PubMedArticle
16.
Nohr  EA, Frydenberg  M, Henriksen  TB, Olsen  J.  Does low participation in cohort studies induce bias? Epidemiology. 2006;17(4):413-418.
PubMedArticle
17.
Olsen  J, Melbye  M, Olsen  SF,  et al.  The Danish National Birth Cohort: its background, structure and aim. Scand J Public Health. 2001;29(4):300-307.
PubMedArticle
18.
Svensson  J, Lyngaae-Jørgensen  A, Carstensen  B, Simonsen  LB, Mortensen  HB; Danish Childhood Diabetes Registry.  Long-term trends in the incidence of type 1 diabetes in Denmark: the seasonal variation changes over time. Pediatr Diabetes. 2009;10(4):248-254.
PubMedArticle
19.
Pundziute-Lyckå  A, Persson  LA, Cedermark  G,  et al.  Diet, growth, and the risk for type 1 diabetes in childhood: a matched case-referent study. Diabetes Care. 2004;27(12):2784-2789.
PubMedArticle
20.
Blom  L, Persson  LA, Dahlquist  G.  A high linear growth is associated with an increased risk of childhood diabetes mellitus. Diabetologia. 1992;35(6):528-533.
PubMedArticle
21.
Bruining  GJ; Netherlands Kolibrie Study Group of Childhood Diabetes.  Association between infant growth before onset of juvenile type-1 diabetes and autoantibodies to IA-2. Lancet. 2000;356(9230):655-656.
PubMedArticle
22.
Kharagjitsingh  AV, de Ridder  MA, Roep  BO, Koeleman  BP, Bruining  GJ, Veeze  HJ.  Revisiting infant growth prior to childhood onset type 1 diabetes. Clin Endocrinol (Oxf). 2010;72(5):620-624.
PubMedArticle
23.
Larsson  HE, Hansson  G, Carlsson  A,  et al; DiPiS Study Group.  Children developing type 1 diabetes before 6 years of age have increased linear growth independent of HLA genotypes. Diabetologia. 2008;51(9):1623-1630.
PubMedArticle
24.
Júlíusson  PB, Roelants  M, Eide  GE,  et al.  Growth references for Norwegian children [in Norwegian]. Tidsskr Nor Laegeforen. 2009;129(4):281-286.
PubMedArticle
25.
Baird  J, Fisher  D, Lucas  P, Kleijnen  J, Roberts  H, Law  C.  Being big or growing fast: systematic review of size and growth in infancy and later obesity. BMJ. 2005;331(7522):929.
PubMedArticle
26.
Kharagjitsingh  A, de Ridder  M, Alizadeh  B,  et al.  Genetic correlates of early accelerated infant growth associated with juvenile-onset type 1 diabetes. Pediatr Diabetes. 2012;13(3):266-271.
PubMedArticle
27.
Peet  A, Hämäläinen  AM, Kool  P, Ilonen  J, Knip  M, Tillmann  V; DIABIMMUNE Study Group.  Early postnatal growth in children with HLA-conferred susceptibility to type 1 diabetes. Diabetes Metab Res Rev. 2014;30(1):60-68.
PubMedArticle
28.
Lambertini  L.  Genomic imprinting: sensing the environment and driving the fetal growth. Curr Opin Pediatr. 2014;26(2):237-242.
PubMedArticle
29.
Nerup  J, Mandrup-Poulsen  T, Mølvig  J, Helqvist  S, Wogensen  L, Egeberg  J.  Mechanisms of pancreatic beta-cell destruction in type I diabetes. Diabetes Care. 1988;11(suppl 1):16-23.
PubMed
30.
Atkinson  MA, Chervonsky  A.  Does the gut microbiota have a role in type 1 diabetes? early evidence from humans and animal models of the disease. Diabetologia. 2012;55(11):2868-2877.
PubMedArticle
31.
White  RA, Bjørnholt  JV, Baird  DD,  et al.  Novel developmental analyses identify longitudinal patterns of early gut microbiota that affect infant growth. PLoS Comput Biol. 2013;9(5):e1003042.
PubMedArticle
32.
Bluestone  JA, Herold  K, Eisenbarth  G.  Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature. 2010;464(7293):1293-1300.
PubMedArticle
33.
Cabrera  SM, Henschel  AM, Hessner  MJ.  Innate inflammation in type 1 diabetes [published online April 29, 2015]. Transl Res. doi:10.1016/j.trsl.2015.04.011.
Views 1,362
Citations 0
Original Investigation
December 7, 2015

Infant Growth and Risk of Childhood-Onset Type 1 Diabetes in Children From 2 Scandinavian Birth Cohorts

Author Affiliations
  • 1Department of Chronic Diseases, Norwegian Institute of Public Health, Oslo, Norway
  • 2Centre for Fetal Programming, Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
  • 3Institute of Clinical Medicine, University of Oslo, Oslo, Norway
  • 4Department of Pediatrics, Oslo University Hospital, Oslo, Norway
  • 5Department of Pediatrics, Copenhagen University Hospital, Herlev, Denmark
  • 6Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
  • 7KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway
  • 8Institute Management and Staff, Norwegian Institute of Public Health, Oslo, Norway
  • 9Department of Pediatrics, Ostfold Hospital Trust, Fredrikstad, Norway
JAMA Pediatr. 2015;169(12):e153759. doi:10.1001/jamapediatrics.2015.3759
Abstract

Importance  Type 1 diabetes mellitus is one of the most common chronic diseases with onset in childhood, but environmental risk factors have not been convincingly established.

Objective  To test whether increased growth during the first year of life is associated with higher risk of childhood-onset type 1 diabetes.

Design, Setting, and Participants  This is a cohort study using information from 2 population-based cohort studies in Norway and Denmark, the Norwegian Mother and Child Cohort Study (MoBa) and the Danish National Birth Cohort (DNBC), of children born between February 1998 and July 2009. The current study was conducted between November 2014 and June 2015.

Exposures  Change in weight and length from birth to age 12 months.

Main Outcomes and Measures  Unadjusted and adjusted hazard ratios (HRs) of type 1 diabetes, classified based on nationwide childhood diabetes registers, obtained using Cox proportional hazards regression.

Results  A total of 99 832 children were included in the study, with 59 221 in MoBa (51.2% boys and 48.8% girls; mean age at end of follow-up, 8.6 years [range, 4.6-14.2 years]) and 40 611 in DNBC (50.6% boys and 49.4% girls; mean age at end of follow-up, 13.0 years [range, 10.4-15.7 years]). The incidence rate of type 1 diabetes from age 12 months to the end of follow-up was 25 cases per 100 000 person-years in DNBC and 31 cases per 100 000 person-years in MoBa. The change in weight from birth to 12 months was positively associated with type 1 diabetes (pooled unadjusted HR = 1.24 per 1-SD increase; 95% CI, 1.11-1.39; pooled adjusted HR = 1.24 per 1-SD increase; 95% CI, 1.09-1.41). There was no significant association between length increase from birth to 12 months and type 1 diabetes (pooled unadjusted HR = 1.06 per 1-SD increase; 95% CI, 0.93-1.22; pooled adjusted HR = 1.06 per 1-SD increase; 95% CI, 0.86-1.32). The associations were similar in both sexes.

Conclusions and Relevance  This is the first prospective population-based study, to our knowledge, providing evidence that weight increase during the first year of life is positively associated with type 1 diabetes. This supports the early environmental origins of type 1 diabetes.

Introduction

Type 1 diabetes mellitus is among the most common chronic diseases with onset in childhood, and the Nordic countries have the highest disease burden.13 Despite the well-known role of genetic susceptibility, a changing incidence during the past decades suggests a role for environmental factors in development of type 1 diabetes.1 While no single environmental factor has been established as a risk factor for type 1 diabetes, it is proposed that environmental factors might operate early in life.4

In 1975, Baum et al5 reported that children with type 1 diabetes had a higher weight at age 12 months compared with a group of children without type 1 diabetes. Since then, a few other studies have reported similar findings, but these studies varied in the age at anthropometric measurements and were retrospective case-control studies.610

Prospective cohort studies are less susceptible to selection and information bias compared with case-control studies. A few cohort studies of genetically susceptible children have reported associations between growth and islet autoimmunity.1113 However, associations identified in high-risk populations are not necessarily transferable to the general population. The previous studies are briefly summarized in eTable 1 in the Supplement.

We aimed to test whether increased growth during the first year of life predicts higher risk of childhood-onset type 1 diabetes in 2 Scandinavian birth cohorts, the Norwegian Mother and Child Cohort Study (MoBa) and the Danish National Birth Cohort (DNBC), which are 2 of the largest birth cohorts in the world.

Box Section Ref ID

At a Glance

  • Previous studies indicate that growth during early childhood might be associated with type 1 diabetes, but most studies have been retrospective or restricted to genetically high-risk populations.

  • Results in the current study from 2 large birth cohorts indicate a consistent positive association between increase in weight from birth to age 12 months and subsequent diagnosis of type 1 diabetes (pooled adjusted hazard ratio = 1.24 per 1-SD increase; 95% CI, 1.09-1.41).

  • No significant association was observed between the increase in length from birth to age 12 months and subsequent diagnosis of type 1 diabetes.

  • This is the first prospective population-based study providing evidence that weight increase during the first year of life is positively associated with type 1 diabetes. This supports the early environmental origins of type 1 diabetes.

Methods
Study Population

The MoBa is a population-based birth cohort administered by the Norwegian Institute of Public Health.14,15 This cohort study recruited pregnant women across Norway between June 1999 and December 2008, at approximately 18 gestational weeks, where 40% of eligible women participated. We used data available in March 2014, comprising 95 267 mothers and 114 761 children, and information from questionnaires administered at 18 gestational weeks and when the child was aged 6, 18, and 36 months. The Norwegian Data Inspectorate and the Regional Ethics Committee for Medical Research of South East Norway approved this study. All participants provided written informed consent.

The DNBC is a population-based birth cohort administered by the Statens Serum Institut in Denmark.16,17 Pregnant women were recruited at their first antenatal visit across Denmark between January 1996 and October 2002, and 60% of eligible women participated. The cohort consists of 91 745 mothers and 103 118 children. We used information gathered through telephone interviews at 18 and 30 gestational weeks and when the child was aged 6 and 18 months. Data collection in the DNBC is approved by the Danish National Ethics Board. All participants provided written informed consent.

In both cohorts, additional information was obtained from national birth registers and disease registers. The current study was conducted between November 2014 and June 2015.

Main Exposure

In MoBa and DNBC, birth weight and length were collected from the medical birth registers. Through the MoBa questionnaires, the mothers reported anthropometric measurements from their child’s health records. These were recorded at 6 weeks and 3, 6, 8, 12, 15 through 18, 18, 24, and 36 months. In DNBC, the mothers reported the child’s weight and length from their child’s health records at 5 and 12 months.

The a priori–specified primary exposures were absolute change in weight and length from birth to 12 months. Secondary exposures included change in weight and length from birth to age 5 or 6 months, change in weight and length from ages 5 or 6 months to 12 months, and absolute body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) at age 5 or 6 months and age 12 months. Because additional anthropometric measurements were available in MoBa, we explored absolute change in weight and length from 12 to 24 months, absolute change in weight and length from 24 to 36 months, peak weight and length velocity by 36 months, and age at peak BMI (eAppendix in the Supplement).

Outcome

The outcome was clinical diagnosis of type 1 diabetes, defined as the first day of insulin treatment in accordance with the EURODIAB criteria.3 This information was obtained from the Norwegian Childhood Diabetes Registry2 and the Danish Childhood Diabetes Registry.18 For the MoBa participants, additional linkage to the Norwegian Patient Register was done. Details of the registers are described in the eAppendix in the Supplement.

Covariates

Characteristics that might influence both postnatal growth and risk of type 1 diabetes were included as potential confounders. These included the child’s sex, birth weight and length, breastfeeding duration, maternal age, maternal parity, maternal education, maternal smoking during pregnancy, maternal height, maternal prepregnancy BMI, paternal height, paternal BMI, and maternal diabetes (maternal type 1 diabetes in MoBa and all types of diabetes in DNBC). Data on paternal type 1 diabetes were available in MoBa.

Statistical Analysis

We used Cox proportional hazards regression to examine the associations of absolute change in weight and length from birth to age 12 months with diagnosis of type 1 diabetes, reporting hazard ratios (HRs) and 95% confidence intervals. Participants were followed up from the day the child turned 1 year of age until diagnosed as having type 1 diabetes or the end of follow-up (April 2, 2014, for MoBa and October 31, 2013, for DNBC). We tested for nonlinearity of the associations by evaluating second-order terms. Because we found no indication of nonlinear associations, the exposures were standardized to examine the association per 1-SD increase. The proportional hazards assumption was evaluated by examination of Schoenfeld residuals, which indicated no deviations from this model assumption. Because some participants were siblings, we used robust cluster variance estimation. We adjusted the multivariable models for all of the covariates selected a priori based on a plausible association with both infant growth and development of type 1 diabetes. Results from the 2 cohorts were combined using a random-effects model by the inverse variance method implemented in the metan function in Stata (StataCorp LP). Heterogeneity of associations between the 2 cohorts was examined using the I2 statistic.

We explored a number of sensitivity analyses. The main results presented are from complete case analyses. Approximately 10% to 15% of the observations had missing covariate information in the multivariable analyses. Missing covariate information was therefore imputed using the multivariate normal distribution in DNBC and chained equations in MoBa, generating a total of 20 imputed data sets. Second, we conducted sensitivity analyses excluding children of mothers with diabetes, children of mothers who reported smoking during pregnancy, children with celiac disease, and children who were preterm (born at <37 gestational weeks).

In the secondary analysis of growth between 12 and 24 months, follow-up started when the child was aged 24 months. For growth between ages 24 and 36 months, peak weight and length velocity by age 36 months, and age at peak BMI by age 36 months, follow-up started when the child was aged 36 months.

A 95% confidence interval for the hazard ratio excluding 1.00 was considered statistically significant. The analysis was conducted using SAS version 9.4 (SAS Institute, Inc) and Stata version 13 (StataCorp LP) statistical software.

Results

For the primary analysis of growth from birth to age 12 months, data were available for 99 832 children (Figure). Maternal education tended to be higher, smoking less common, and parity lower among mothers of children with sufficient follow-up information to be included in the primary analysis (eTable 2 in the Supplement). However, the risk of type 1 diabetes was similar (eFigure 1 in the Supplement).

The children in the analysis were born between February 1998 and July 2009 (Table 1). The mean age at the end of follow-up in the study sample was 8.6 years (range, 4.6-14.2 years) in MoBa and 13.0 years (range, 10.4-15.7 years) in DNBC. The children diagnosed as having type 1 diabetes during the first year of life were excluded from the primary analyses (5 children in MoBa and 1 child in DNBC). The incidence rate of type 1 diabetes from age 12 months to the end of follow-up was 25 cases per 100 000 person-years in DNBC and 31 cases per 100 000 person-years in MoBa.

Weight in the First Year of Life and Risk of Type 1 Diabetes

The mean (SD) change in weight from birth to age 12 months was just over 6 (1) kg (Table 2). The change in weight from birth to 12 months was positively associated with type 1 diabetes (pooled unadjusted hazard ratio [HR] = 1.24 per 1-SD increase; 95% CI, 1.11-1.39; pooled adjusted HR = 1.24 per 1-SD increase; 95% CI, 1.09-1.41), with no evidence of heterogeneity between the cohorts (Table 3). The multiple imputation analysis yielded results similar to those of the complete case analysis (Table 3). While there was no significant association between birth weight and type 1 diabetes, the absolute weight at age 12 months also significantly predicted type 1 diabetes with a similar adjusted HR of 1.26 per 1-SD increase (95% CI, 1.10-1.44).

Length in the First Year of Life and Risk of Type 1 Diabetes

The mean (SD) change in length from birth to age 12 months was about 25 (3) cm (Table 2). There was no significant association between length increase the first year of life and type 1 diabetes (pooled unadjusted HR = 1.06 per 1-SD increase; 95% CI, 0.93-1.22; pooled adjusted HR = 1.06 per 1-SD increase; 95% CI, 0.86-1.32) (Table 3).

Sensitivity Analyses

There were no significant differences in the associations by sex (eFigure 2 in the Supplement). Similar results were found when excluding children who were preterm, children of mothers who smoked during pregnancy, children of mothers with diabetes, and children with celiac disease (data not shown). We explored the potential effect of the slight variation in exact age at anthropometric measurements by analyzing growth measures as age- and sex-specific z scores in the MoBa cohort, and this produced unchanged results (data not shown). Further adjustment for the child’s year of birth or for cesarean delivery also did not change the observed associations (data not shown). Finally, excluding children of parents with a native language other than Norwegian in the MoBa cohort did not change the results (data not shown).

Secondary Analyses

Growth from birth to age 5 months (DNBC) or 6 months (MoBa) showed results similar to those for growth in the first 12 months of life, whereas growth during the second half year of life was not significantly associated with type 1 diabetes after adjustment for growth in the first half year of life (Table 4). The child’s BMI at both age 5 or 6 months and age 12 months was positively associated with type 1 diabetes (eFigure 3 in the Supplement).

Analyses in MoBa showed that after adjustment for previous growth (up to age 12 or 24 months), there was no significant association between increase in weight or length between ages 12 and 24 months with development of type 1 diabetes, while change in weight and length from ages 24 to 36 months showed a tendency for a positive association (eTable 3 in the Supplement). Peak weight velocity was also not significantly associated with type 1 diabetes. Peak length velocity (mean [SD], 62.9 [15.4] cm/y) occurred at an average of 7 days. Each 1-SD increase in peak length velocity was associated with an adjusted HR of 1.31 (95% CI, 1.08-1.60) (eTable 3 in the Supplement). There was a tendency for a decreased risk in development of type 1 diabetes with increasing age at peak BMI, but the results did not indicate a linear decrease in the risk of type 1 diabetes and were not statistically significant (eTable 3 in the Supplement).

Discussion

In this analysis of 2 large Scandinavian birth cohorts, we found that weight increase in the first year of life was positively associated with subsequent risk of type 1 diabetes during childhood.

Strengths and Limitations

Strengths of this study include the large size, the prospective data collection, inclusion of 2 relatively homogeneous populations, adjustment for a number of potential confounding factors not included in previous studies, and linkage to nationwide registers with a high level of case ascertainment.2,3 However, as in any observational study, confounding from unmeasured factors may be present. We also cannot exclude the possibility of a selection bias due to the initial participation rate in the cohorts or due to loss to follow-up. A number of associations were found to be similar among eligible pregnant women and participating women in both cohorts by using nationwide registers.15,16 Furthermore, the observed incidence of type 1 diabetes among these cohorts was similar to that reported for the general population.2,18 Using maternal report of the child’s anthropometric measurements might have resulted in misclassification, but the prospective design implies that such misclassification is unlikely to be differential and therefore most likely would attenuate the observed association. By asking the mother to refer to the child’s health records, we attempted to minimize misclassification.

Comparison With Previous Studies

The main result from our cohort study is in line with a few previous case-control studies.510 A Danish study reported a nonsignificant 9% increase in the odds of type 1 diabetes per 1-kg increase in weight at age 12 months, which translates to an odds ratio of 1.22 per 1-SD increase.10 The mean difference in weight at age 11 months was reported to be 204 g between cases with type 1 diabetes and controls in a Finnish study,7 while a mean difference of 160 g at age 12 months was reported in a Swedish study.9 This is comparable to a mean difference of 240 g in MoBa and 270 g in DNBC at age 12 months. Notably, a larger mean difference of approximately 700 g at age 12 months was reported in the initial study by Baum et al.5

The lack of association with length increase in the first year of life in our study is in line with 1 previous case-control study.19 In contrast, several studies of length increase and type 1 diabetes indicated a positive association.6,9,10,2023 Two previous studies explored a sibling comparison, both reporting a positive association between length increase in the first 3 to 4 years of life and type 1 diabetes.21,22 Our secondary results on length increase in the third year of life, albeit not statistically significant, suggested a positive association between length increase in the third year of life and risk of type 1 diabetes. However, the analysis of growth after the first year of life in MoBa likely had lower statistical power due to the smaller number of study participants with the necessary follow-up information for this analysis.

Although few studies have reported weight at age 12 months in relation to type 1 diabetes, other studies of anthropometric measurements and islet autoimmunity or type 1 diabetes have been published. The previous cohort studies of genetically susceptible children generally included relatively few cases, with islet autoimmunity as the end point, and anthropometric measurements from age 2 years or older.1113 Our findings indicated a tendency for a positive association between peak length velocity and type 1 diabetes, while there was no association with peak weight velocity. Results on BMI from other studies have been mixed, but overall they indicate a positive association in line with our findings. Furthermore, our results indicate no significant association between age at peak BMI and diagnosis of type 1 diabetes.

Potential Implications

It has been hypothesized that childhood overweight is a risk factor and explains the temporal changes in incidence of type 1 diabetes. Our results may be taken as support for the hypothesis that weight gain explains at least some of the long-term temporal changes in incidence of type 1 diabetes. However, there is limited evidence for changes in infant weight in the short term, in line with a plateau in the incidence of type 1 diabetes.2 We observed no time trends in anthropometric measurements during the first year of life in our 2 cohorts (data not shown), and Norwegian growth data for children at birth to age 4 years indicated little or no change in weight (or length) between 1982-1984 and 2003-2006.24

It should be noted that our observed association was linear across the range of weight increase, with no indication of a threshold for overweight infants. While we decided a priori to focus on growth to age 12 months, infant growth is shown in other studies to be associated with obesity later in life.25 Furthermore, our results suggested that weight change early in infancy (age <6 months) was more important for type 1 diabetes risk than was subsequent weight change.

Potential Mechanisms

Genetic variants may in theory explain our findings, if the same variants are associated with increased risk of type 1 diabetes and increased infant weight gain. Furthermore, either such variants must be very common or there must be a very large number of different rare variants with these properties. This is not likely to be the case. If anything, variants known to influence type 1 diabetes risk seem to be associated with less weight gain in the first 2 years of life.26,27

Similarly, epigenetic mechanisms may in theory explain the link between infant weight gain and type 1 diabetes, but only if the same pathways influencing infant growth also influence type 1 diabetes. Current evidence does not support the latter.28

Maternal type 1 diabetes is known to be associated with infant weight gain and increased risk of type 1 diabetes, but this is too uncommon in the population to explain our finding, as indicated by the robustness of our results to adjustment for or exclusion of children whose mothers had diabetes. Furthermore, infant feeding and a number of other environmental factors that could potentially explain an association between infant weight gain and risk of type 1 diabetes were also adjusted for in our analysis and are therefore unlikely to be major explanatory mechanisms.

A general mechanism that may plausibly explain our findings is that rapid growth increases the demand on β cells to secrete insulin, and it has been shown that β cells actively secreting insulin are more susceptible to cytokine damage in vitro.29 We can also speculate that perhaps gut microbiota30,31 or inflammation32,33 may be involved in relevant pathways to explain our findings.

Conclusions

In conclusion, our study is the first prospective population-based study, to our knowledge, providing evidence that weight increase during the first year of life is positively associated with type 1 diabetes. This supports the early environmental origins of type 1 diabetes.

Back to top
Article Information

Corresponding Author: Maria C. Magnus, PhD, Department of Chronic Diseases, Norwegian Institute of Public Health, PO Box 4404, Nydalen, N-0403 Oslo, Norway (maria.christine.magnus@fhi.no).

Accepted for Publication: October 7, 2015.

Published Online: December 7, 2015. doi:10.1001/jamapediatrics.2015.3759.

Author Contributions: Dr M. C. Magnus had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: M. C. Magnus, Joner, Skrivarhaug, Johannesen, Njølstad, Størdal, Stene.

Acquisition, analysis, or interpretation of data: M. C. Magnus, Olsen, Granström, Skrivarhaug, Svensson, Johannesen, Njølstad, P. Magnus, Stene.

Drafting of the manuscript: M. C. Magnus, Skrivarhaug, Johannesen.

Critical revision of the manuscript for important intellectual content: Olsen, Granström, Joner, Skrivarhaug, Svensson, Johannesen, Njølstad, P. Magnus, Størdal, Stene.

Statistical analysis: M. C. Magnus, Granström.

Obtained funding: Olsen, Skrivarhaug, Njølstad, P. Magnus, Stene.

Administrative, technical, or material support: Granström, Skrivarhaug, Svensson, Njølstad, P. Magnus, Stene.

Study supervision: Olsen, Johannesen, Størdal, Stene.

Conflict of Interest Disclosures: None reported.

Funding/Support: The Norwegian Mother and Child Cohort Study is supported by grants UO1 NS 047537-01 and UO1 NS 047537-06A1 from the National Institutes of Health and grant 151918/S10 from the Norwegian Research Council/FUGE. The substudy PAGE (Prediction of Autoimmune Diabetes and Celiac Disease in Childhood by Genes and Perinatal Environment), based on MoBa, is supported by grant 2210909/F20 from the Norwegian Research Council (Dr Stene). Dr M. C. Magnus is supported by grant 2011.2.0218 from the Norwegian Extra Foundation for Health and Rehabilitation. Dr Størdal is supported by an unrestricted grant from the Oak Foundation. The Danish National Birth Cohort is supported by the March of Dimes Birth Defects Foundation, the Danish Heart Association, the Danish National Research Foundation, the Danish Pharmaceutical Association, the Ministry of Health, and the National Board of Health. The cooperation between the 2 cohorts was supported by EARNEST EU FP6 Integrated Project contract 007036 with the European Commission (Dr Olsen was leader of a work package comparing the 2 databases), grant 09-067124 of the Innovation Fund Denmark from the Centre for Fetal Programming, and the Danish Cancer Union.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Inger Johanne Bakken, PhD, Norwegian Institute of Public Health, Oslo, Norway, provided guidance in the use of data from the Norwegian Patient Register; she received no compensation. We are grateful to all families participating in the Norwegian Mother and Child Cohort Study and the Danish National Birth Cohort and for the administrative staff surrounding these 2 cohorts.

References
1.
Harjutsalo  V, Sund  R, Knip  M, Groop  PH.  Incidence of type 1 diabetes in Finland. JAMA. 2013;310(4):427-428.
PubMedArticle
2.
Skrivarhaug  T, Stene  LC, Drivvoll  AK, Strøm  H, Joner  G; Norwegian Childhood Diabetes Study Group.  Incidence of type 1 diabetes in Norway among children aged 0-14 years between 1989 and 2012: has the incidence stopped rising? results from the Norwegian Childhood Diabetes Registry. Diabetologia. 2014;57(1):57-62.
PubMedArticle
3.
Patterson  CC, Gyürüs  E, Rosenbauer  J,  et al.  Trends in childhood type 1 diabetes incidence in Europe during 1989-2008: evidence of non-uniformity over time in rates of increase. Diabetologia. 2012;55(8):2142-2147.
PubMedArticle
4.
Stene  LC, Gale  EA.  The prenatal environment and type 1 diabetes. Diabetologia. 2013;56(9):1888-1897.
PubMedArticle
5.
Baum  JD, Ounsted  M, Smith  MA.  Letter: weight gain in infancy and subsequent development of diabetes mellitus in childhood. Lancet. 1975;2(7940):866.
PubMedArticle
6.
EURODIAB Substudy 2 Study Group.  Rapid early growth is associated with increased risk of childhood type 1 diabetes in various European populations. Diabetes Care. 2002;25(10):1755-1760.
PubMedArticle
7.
Hyppönen  E, Kenward  MG, Virtanen  SM,  et al; Childhood Diabetes in Finland (DiMe) Study Group.  Infant feeding, early weight gain, and risk of type 1 diabetes. Diabetes Care. 1999;22(12):1961-1965.
PubMedArticle
8.
Johansson  C, Samuelsson  U, Ludvigsson  J.  A high weight gain early in life is associated with an increased risk of type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1994;37(1):91-94.
PubMedArticle
9.
Ljungkrantz  M, Ludvigsson  J, Samuelsson  U.  Type 1 diabetes: increased height and weight gains in early childhood. Pediatr Diabetes. 2008;9(3, pt 2):50-56.
PubMedArticle
10.
Svensson  J, Carstensen  B, Mortensen  HB, Borch-Johnsen  K.  Growth in the first year of life and the risk of type 1 diabetes in a Danish population. Paediatr Perinat Epidemiol. 2007;21(1):44-48.
PubMedArticle
11.
Beyerlein  A, Thiering  E, Pflueger  M,  et al.  Early infant growth is associated with the risk of islet autoimmunity in genetically susceptible children. Pediatr Diabetes. 2014;15(7):534-542.
PubMedArticle
12.
Couper  JJ, Beresford  S, Hirte  C,  et al.  Weight gain in early life predicts risk of islet autoimmunity in children with a first-degree relative with type 1 diabetes. Diabetes Care. 2009;32(1):94-99.
PubMedArticle
13.
Lamb  MM, Yin  X, Zerbe  GO,  et al.  Height growth velocity, islet autoimmunity and type 1 diabetes development: the Diabetes Autoimmunity Study in the Young. Diabetologia. 2009;52(10):2064-2071.
PubMedArticle
14.
Magnus  P, Irgens  LM, Haug  K, Nystad  W, Skjaerven  R, Stoltenberg  C; MoBa Study Group.  Cohort profile: the Norwegian Mother and Child Cohort Study (MoBa). Int J Epidemiol. 2006;35(5):1146-1150.
PubMedArticle
15.
Nilsen  RM, Vollset  SE, Gjessing  HK,  et al.  Self-selection and bias in a large prospective pregnancy cohort in Norway. Paediatr Perinat Epidemiol. 2009;23(6):597-608.
PubMedArticle
16.
Nohr  EA, Frydenberg  M, Henriksen  TB, Olsen  J.  Does low participation in cohort studies induce bias? Epidemiology. 2006;17(4):413-418.
PubMedArticle
17.
Olsen  J, Melbye  M, Olsen  SF,  et al.  The Danish National Birth Cohort: its background, structure and aim. Scand J Public Health. 2001;29(4):300-307.
PubMedArticle
18.
Svensson  J, Lyngaae-Jørgensen  A, Carstensen  B, Simonsen  LB, Mortensen  HB; Danish Childhood Diabetes Registry.  Long-term trends in the incidence of type 1 diabetes in Denmark: the seasonal variation changes over time. Pediatr Diabetes. 2009;10(4):248-254.
PubMedArticle
19.
Pundziute-Lyckå  A, Persson  LA, Cedermark  G,  et al.  Diet, growth, and the risk for type 1 diabetes in childhood: a matched case-referent study. Diabetes Care. 2004;27(12):2784-2789.
PubMedArticle
20.
Blom  L, Persson  LA, Dahlquist  G.  A high linear growth is associated with an increased risk of childhood diabetes mellitus. Diabetologia. 1992;35(6):528-533.
PubMedArticle
21.
Bruining  GJ; Netherlands Kolibrie Study Group of Childhood Diabetes.  Association between infant growth before onset of juvenile type-1 diabetes and autoantibodies to IA-2. Lancet. 2000;356(9230):655-656.
PubMedArticle
22.
Kharagjitsingh  AV, de Ridder  MA, Roep  BO, Koeleman  BP, Bruining  GJ, Veeze  HJ.  Revisiting infant growth prior to childhood onset type 1 diabetes. Clin Endocrinol (Oxf). 2010;72(5):620-624.
PubMedArticle
23.
Larsson  HE, Hansson  G, Carlsson  A,  et al; DiPiS Study Group.  Children developing type 1 diabetes before 6 years of age have increased linear growth independent of HLA genotypes. Diabetologia. 2008;51(9):1623-1630.
PubMedArticle
24.
Júlíusson  PB, Roelants  M, Eide  GE,  et al.  Growth references for Norwegian children [in Norwegian]. Tidsskr Nor Laegeforen. 2009;129(4):281-286.
PubMedArticle
25.
Baird  J, Fisher  D, Lucas  P, Kleijnen  J, Roberts  H, Law  C.  Being big or growing fast: systematic review of size and growth in infancy and later obesity. BMJ. 2005;331(7522):929.
PubMedArticle
26.
Kharagjitsingh  A, de Ridder  M, Alizadeh  B,  et al.  Genetic correlates of early accelerated infant growth associated with juvenile-onset type 1 diabetes. Pediatr Diabetes. 2012;13(3):266-271.
PubMedArticle
27.
Peet  A, Hämäläinen  AM, Kool  P, Ilonen  J, Knip  M, Tillmann  V; DIABIMMUNE Study Group.  Early postnatal growth in children with HLA-conferred susceptibility to type 1 diabetes. Diabetes Metab Res Rev. 2014;30(1):60-68.
PubMedArticle
28.
Lambertini  L.  Genomic imprinting: sensing the environment and driving the fetal growth. Curr Opin Pediatr. 2014;26(2):237-242.
PubMedArticle
29.
Nerup  J, Mandrup-Poulsen  T, Mølvig  J, Helqvist  S, Wogensen  L, Egeberg  J.  Mechanisms of pancreatic beta-cell destruction in type I diabetes. Diabetes Care. 1988;11(suppl 1):16-23.
PubMed
30.
Atkinson  MA, Chervonsky  A.  Does the gut microbiota have a role in type 1 diabetes? early evidence from humans and animal models of the disease. Diabetologia. 2012;55(11):2868-2877.
PubMedArticle
31.
White  RA, Bjørnholt  JV, Baird  DD,  et al.  Novel developmental analyses identify longitudinal patterns of early gut microbiota that affect infant growth. PLoS Comput Biol. 2013;9(5):e1003042.
PubMedArticle
32.
Bluestone  JA, Herold  K, Eisenbarth  G.  Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature. 2010;464(7293):1293-1300.
PubMedArticle
33.
Cabrera  SM, Henschel  AM, Hessner  MJ.  Innate inflammation in type 1 diabetes [published online April 29, 2015]. Transl Res. doi:10.1016/j.trsl.2015.04.011.
×