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Diabetologia

, Volume 51, Issue 5, pp 726–735 | Cite as

Caesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: a meta-analysis of observational studies

  • C. R. Cardwell
  • L. C. Stene
  • G. Joner
  • O. Cinek
  • J. Svensson
  • M. J. Goldacre
  • R. C. Parslow
  • P. Pozzilli
  • G. Brigis
  • D. Stoyanov
  • B. Urbonaitė
  • S. Šipetić
  • E. Schober
  • C. Ionescu-Tirgoviste
  • G. Devoti
  • C. E. de Beaufort
  • K. Buschard
  • C. C. Patterson
Meta Analysis
First Online:
Received:
Accepted:

Abstract

Aims/hypothesis

The aim of this study was to investigate the evidence of an increased risk of childhood-onset type 1 diabetes in children born by Caesarean section by systematically reviewing the published literature and performing a meta-analysis with adjustment for recognised confounders.

Methods

After MEDLINE, Web of Science and EMBASE searches, crude ORs and 95% CIs for type 1 diabetes in children born by Caesarean section were calculated from the data reported in each study. Authors were contacted to facilitate adjustments for potential confounders, either by supplying raw data or calculating adjusted estimates. Meta-analysis techniques were then used to derive combined ORs and to investigate heterogeneity between studies.

Results

Twenty studies were identified. Overall, there was a significant increase in the risk of type 1 diabetes in children born by Caesarean section (OR 1.23, 95% CI 1.15–1.32, p < 0.001). There was little evidence of heterogeneity between studies (p = 0.54). Seventeen authors provided raw data or adjusted estimates to facilitate adjustments for potential confounders. In these studies, there was evidence of an increase in diabetes risk with greater birthweight, shorter gestation and greater maternal age. The increased risk of type 1 diabetes after Caesarean section was little altered after adjustment for gestational age, birth weight, maternal age, birth order, breast-feeding and maternal diabetes (adjusted OR 1.19, 95% CI 1.04–1.36, p = 0.01).

Conclusions/interpretation

This analysis demonstrates a 20% increase in the risk of childhood-onset type 1 diabetes after Caesarean section delivery that cannot be explained by known confounders.

Keywords

Caesarean section Cesarean section Diabetes mellitus Epidemiology Type 1 
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Introduction

Although type 1 diabetes has an important genetic component [1], the marked increases in incidence rate observed among the under 15 age group in recent decades [2, 3] strongly suggest the role of environmental influences. Various observations have lead to speculation that Caesarean section delivery could be involved. Rapid increases in Caesarean section rates [4] have occurred in parallel with increasing diabetes rates. For example, rates of Caesarean section in England, Sweden and the USA have risen from 6%, 8% and 10% in 1975 [5] to 19%, 12% and 22% in 1999 [4], respectively. Animal models suggest a higher risk of diabetes after Caesarean section [6, 7]. Also, children delivered by Caesarean section have been shown to have altered gut microbiotic composition and immune function [8, 9, 10, 11], which could increase their risk of type 1 diabetes. Numerous studies have investigated Caesarean section and type 1 diabetes, but findings have been inconsistent, possibly as a result of inadequate size and limited power in some studies. In such a situation, meta-analysis is valuable in synthesising the available evidence [12].

The first aim of this study was to assess the evidence of an association between type 1 diabetes and Caesarean section by performing a meta-analysis. Previous studies have shown that various perinatal and early life factors are associated with type 1 diabetes, such as maternal age, birthweight and breastfeeding [13, 14, 15]. As such factors may differ in children born by Caesarean section, the second aim was to adjust the pooled estimate of the association between Caesarean section and type 1 diabetes for the influence of these potential confounders.

Methods

Literature search

The main literature search was conducted using MEDLINE, through OVID ONLINE, with the following strategy: (‘Cesarean Section’ or ‘Delivery, Obstetric’ or cesarean or caesarean or mode of delivery) and (‘Diabetes Mellitus, Type 1’ or (diabetes and Type 1) or IDDM), using the terms in inverted commas as MEDLINE subject heading key words. Similar searches were conducted on Web of Science and EMBASE. To identify studies that investigated Caesarean section along with other risk factors, a more general search was conducted on MEDLINE using: (‘Diabetes Mellitus, Type 1’ and (‘Case–Control Studies’ or ‘Cohort Studies’)). The searches were limited to studies on humans, published before September 2007. Abstracts were screened independently by two investigators (C. R. Cardwell and C. C. Patterson) to establish if the studies were likely to provide relevant data based on the following inclusion criteria: (1) they identified a group with type 1 diabetes (containing more than 15 cases) and a group without type 1 diabetes, and (2) they determined the prevalence of delivery by Caesarean section in these groups. Citations generated from the more general MEDLINE search were initially screened to remove obviously irrelevant articles. Finally, the reference lists of all pertinent articles were examined.

Eligible studies were assessed independently by two reviewers (C. R. Cardwell and C. C. Patterson) to abstract information about the study (country, design and year of publication), participants with type 1 diabetes (source, age at onset), control participants (source) and mode of delivery (methods of ascertainment).

Attempts were made to contact the corresponding author of all eligible studies to facilitate adjustment for maternal age, birthweight, gestational age, birth order, breast-feeding and maternal diabetes. Authors were requested to provide raw data or to provide adjusted estimates of the association between Caesarean section and type 1 diabetes after conducting specified additional analyses.

Statistical analysis

ORs and SEs were calculated for the association between diabetes and Caesarean section for each study. Conditional logistic regression was used to calculate the ORs and SEs for the matched case–control studies. In cohort studies with varying duration of participant follow-up, rate ratios and their SEs were used instead of ORs, which were not directly calculable. As type 1 diabetes is a rare disease, these measures should be approximately equal [16]. Poisson regression was used to adjust these rate ratios for differences in the year of birth between cases and controls, a consequence of this study design [17, 18], by adding a year of birth and age term to the regression model in addition to Caesarean section. Tests for heterogeneity between studies were conducted, and random effects models used to calculate pooled ORs [19]. Random effects models were deemed more appropriate than fixed effects models because it was anticipated that there would be between study heterogeneity due to their observational nature. The I 2 statistic was calculated to quantify the degree of heterogeneity between studies [20]. This statistic measures the percentage of the total variation across studies that is due to heterogeneity. Study-specific weights in the random effects model were calculated and scaled to percentages. Publication/selection bias was investigated by checking for asymmetry in funnel plots of the study ORs against the SE of the logarithm of the ORs [21]. In the absence of publication/selection bias this graph should conform to a funnel shape, as the OR estimates from smaller studies (with larger SEs) show greater variation around the overall estimate than the OR estimates from larger studies (with smaller SEs). An identical approach was adopted to combine ORs for the association between type 1 diabetes and available confounders. To investigate the trend across categories for maternal age and birthweight, an OR (and SE) was calculated per increase in category using regression models appropriate to the design of the study, and then meta-analysis techniques were applied.

A two-stage technique was used to calculate pooled estimates of the association between Caesarean section and diabetes after adjustment for potential confounders [22]. First, adjusted estimates and SEs were calculated within each study using regression models appropriate to the study design (logistic regression for case–control studies, conditional logistic regression for matched case–control studies and Poisson regression for cohort studies) including diabetes as the outcome variable and Caesarean section and the potential confounder(s) of interest as explanatory variables. As explained previously, Poisson regression models additionally included terms to adjust for differences in year of birth between cases and controls in the cohort studies with varying participant follow-up. Meta-analysis techniques were then applied to these adjusted estimates.

Sensitivity analyses were conducted by subdividing studies by quality (whether population-based randomly selected controls were used) and using the Trim and Fill method to calculate pooled estimates after adjustment for any potential publication bias [23]. This method identifies funnel plot asymmetry and imputes study results, which are considered to have been conducted but not published, to create funnel plot symmetry. The overall combined estimate of the association is then based on the observed and imputed study results.

All statistical analyses were performed using STATA 9.0 software (STATA, College Station, TX, USA).

Results

The searches identified nine eligible articles using MEDLINE [15, 17, 24, 25, 26, 27, 28, 29, 30]; a further article was identified from Web of Science [31] and another from EMBASE [32]. The more general MEDLINE search identified a further eight articles [33, 34, 35, 36, 37, 38, 39, 40], and review of reference lists revealed another two articles [41, 42].

Seven of the identified articles were excluded from further consideration. An earlier study [41] was excluded in favour of a larger study [42] that included all the participants enrolled in the former. Three articles [25, 26, 28] reported the same data. A study [33] was excluded because no raw data were presented in the paper or available from the authors. Another study was excluded as it contained fewer than 15 cases [29]. A meeting abstract [31] was replaced with the subsequently published article [43] and, after contact with authors, an earlier report from a cohort [35] was replaced with a later report [18].

The 16 remaining articles corresponded to 20 independent studies, because one study [15] provided data from eight centres, three of which were reported elsewhere [25, 27, 32], and another provided data from two centres [24], one of which was subsequently reported in a larger study [32]. Finally, to ensure two studies [17, 30] provided independent information, authors removed cases from one study [30] that were included in the other [17]. Study characteristics are summarised in Table 1.
Table 1

Characteristics of studies investigating the association between Caesarean section and type 1 diabetes, ordered by publication date

First author, yeara [reference]

Design

Country

Type 1 diabetes

Controls

Ascertainment of Caesarean section

Available confoundersb

Ascertainment method

Age at diagnosis

n

Source (matching criteria)

n

GA

MA

BW

BO

BF

MD

Dahlquist, 1992 [42]

C–C

Sweden

Swedish Childhood Diabetes Registry

0–14 years

2,757

Swedish Medical Birth Registry (year of birth, delivery unit)

8,271

Maternity record

 

 

 

 

 

 

Patterson, 1994 [24]

C–C

Scotland

Hospital admission / childhood diabetes register

0–14 years

271

Scottish maternal discharge records (age, sex and area)

1,355

Maternity record

✓

✓

✓

✓

 

✓

McKinney, 1997 [25]

C–C

England

Yorkshire Childhood Diabetes Register

0–15 years

220

General practitioner’s records (age and sex)

433

Questionnaire

✓

✓

✓

✓

✓

✓

Tai, 1998 [34]

C–C

China

Taipei type 1 Diabetes Registry

0–29 years (mean = 8 years)

117

Classmates or colleaguesc (age, sex, parental and individual education)

193

Questionnaire

 

 

 

 

 

 

Rami, 1999 [27]

C–C

Austria

Vienna type 1 diabetes register

0–14 years

114

Schools (age and sex)

495

Maternity record

✓

✓

✓

✓

✓

✓d

Bache, 1999 [36]

C–C

Denmark

Hospital admission

0–14 years

839

Medical birth register (age, sex and district)

1,687

Maternity record

 

 

 

 

 

 

 

C–C

Bulgaria

West Bulgaria type 1 diabetes register

0–14 years

176

Schools and policlinics (age)

562

Maternity record

✓

✓

✓

✓

✓

✓d

 

C–C

Latvia

Latvian type 1 diabetes register

0–14 years

143

Population register (age)

410

Maternity record

✓

✓

✓

✓

✓

✓d

EURODIAB, 1999 [15]

C–C

Lithuania

Lithuanian type 1 diabetes register

0–14 years

124

Policlinics (age)

369

Maternity record

✓

✓

✓

✓

✓

✓d

 

C–C

Luxembourg

Luxembourg type 1 diabetes register

0–14 years

59

Pre-schools and schools (age)

188

Maternity record

✓

✓

✓

✓

✓

✓d

 

C–C

Romania

Bucharest type 1 diabetes register

0–14 years

111

Pre-schools and schools (age)

342

Maternity record

✓

✓

✓

✓

✓

✓d

Visalli, 2003 [43]

C–C

Italy

Lazio type 1 diabetes register

0–14 years

150

Schools (age)

750

Questionnaire

✓

✓

✓

 

✓

✓

Stene, 2003 [17]

Cohort

Norway

Norwegian Childhood Diabetes Registry

0–14 years

1,824

Norwegian medical birth registry

1,380,778

Maternity record

✓

✓

✓

✓

 

✓

Stene, 2004 [30]

C–C

Norway

Norwegian Childhood Diabetes Registry

0–14 years

545

Norwegian population registry

1,668

Maternity record

✓

✓

✓

✓

✓

✓d

Cardwell, 2005 [32]

Cohort

Northern Ireland

Northern Ireland type 1 diabetes register

0–14 years

991

Northern Ireland Child Health Register

447,633

Maternity record

✓

✓

✓

✓

✓

✓

Šipetić, 2005 [38]

C–C

Serbia

Belgrade Hospital admission

0–16 years

105

Hospital outpatients with skin diseasec (age, sex and area)

210

Questionnaire

✓

✓

✓

✓

✓

✓d

Svensson, 2005 [37]

C–C

Denmark

Danish register of childhood diabetes

0–14 years

490

Danish population register (age and sex)

696

Questionnaire

✓

✓

✓

✓

✓

✓

Malcova, 2006 [39]

C–C

Czech Republic

Czech Childhood Diabetes Register

0–14 years

868

School friendsc

1,466

Questionnaire

✓

✓

✓

✓

✓

✓

Tenconi, 2007 [40]

C–C

Italy

Pavia type 1 Diabetes Registry

0–14 years

159

Hospital patientsc (age and sex)

318

Questionnaire

 

✓

 

✓

✓

 

Ievins, 2007 [18]

Cohort

England

Hospital admission (ICD code for diabetes)

0–14 years

411

Oxfordshire and West Berkshire maternity records

292,845

Maternity record

✓

✓

✓

✓

✓

✓

aYear of publication

bTick denotes data recorded in study and available for analysis

cNot randomly selected or not population-based

dMaternal type 1 diabetes used in analyses

BF, Breast-feeding; BO, birth order; BW, birthweight; C–C, case–control; GA, gestational age; MA, maternal age; MD, maternal diabetes

The unadjusted association between Caesarean section and childhood-onset type 1 diabetes for all 20 studies, including 9,938 cases, is shown in Fig. 1. Overall, there was a significant increase (p < 0.001) in the risk of type 1 diabetes after Caesarean section delivery, with an OR of 1.23 (95% CI 1.15–1.32). There was little evidence of heterogeneity between the study estimates (I 2 = 0%, 95% CI 0–48%; χ 2 = 17.70, df 19, p = 0.54). A funnel plot, shown in Fig. 2, roughly conformed to the expected funnel shape, providing little evidence of asymmetry and therefore little evidence of publication bias. Similarly, the Trim and Fill method, which attempts to adjust for any publication bias by imputing possible unpublished studies, produced estimates that were unaltered (OR 1.23), suggesting that any effect of publication bias was negligible. Further analysis in the subgroup of 16 studies judged to have used randomly selected population-based controls produced a similar pooled estimate (OR 1.24, 95% CI 1.13–1.35).
Fig. 1

Meta-analysis of studies of Caesarean section and type 1 diabetes (including 9,938 cases) using the random effects model, studies ordered by publication date. Reference numbers are provided in Table 1. aTest for heterogeneity χ 2 = 17.70, df 19, p = 0.54; I 2 = 0% (95% CI 0–48%); test for overall effect Z = 5.70, p ≤ 0.001; badjusted for year of birth and age group, as explained in Statistical analysis; capproximated from person years. DM, diabetes mellitus; ED, EURODIAB

Fig. 2

Funnel plot of studies of Caesarean section and type 1 diabetes, labelled by reference number

Adjustment for potential confounders was possible in 17 studies. Fifteen authors provided raw data, and two calculated adjusted estimates. Raw data from two studies were not available [36, 42] and one author could not be contacted [34].

Table 2 summarises the crude association between childhood-onset type 1 diabetes and potential confounders. Overall, there was an increase in the risk of diabetes with increasing birthweight (combined OR per category increase 1.05, p = 0.006) and little heterogeneity between studies (I 2 = 25, p = 0.17). There was evidence (p = 0.02) of a reduction in risk of diabetes with longer gestation. The pooled risk of diabetes in children born later than 42 weeks was 0.84 times that of children born 38–41 weeks, and was similar across studies (I 2 = 10, p = 0.34). There was evidence of an increase in diabetes risk with maternal age (combined OR per category increase 1.08, p = 0.001) but there was considerable heterogeneity between studies (I 2 = 50, p = 0.01). Overall, there was some evidence that children second born (OR 1.12, p = 0.03) or third or later born (OR 1.08, p = 0.17) had a slightly higher risk of type 1 diabetes than first born children, but these associations were also subject to considerable heterogeneity (I 2 = 45, p = 0.03 and I 2 = 25, p = 0.17, respectively). Children whose mother had diabetes (OR 4.92, p < 0.001) or, specifically, type 1 diabetes (OR 4.03, p = 0.001) had a higher risk of type 1 diabetes, and these associations were fairly consistent across studies (I 2 = 0, p = 0.49 and I 2 = 0, p = 0.88, respectively). Finally, there was some indication that children who were breastfed, or breastfed for a longer duration, had a slightly lower risk of diabetes than children who were not breastfed, or breastfed for a shorter duration, (OR 0.84, p = 0.02). This association was subject to marked heterogeneity (I 2 = 61, p = 0.001)—perhaps due in part to the different categorisations used in each study—and should therefore be carefully interpreted.
Table 2

Pooled analysis of the association between potential confounders and type 1 diabetes

Potential confounder

Number of studies

Heterogeneity

Combined OR (95% CI)

p value

χ 2

p value

I 2 (95%CI)

Birthweight (g)

16

     

 <2,500

 

21.05

0.14

29 (0–61)

0.87 (0.71–1.07)

0.18

 2,500–2,999

 

11.15

0.74

0 (0–52)

0.93 (0.86–1.02)

0.14

 3,000–3,499

    

1.00 (Ref. cat.)

–

 3,500–3,999

 

10.77

0.77

0 (0–52)

1.03 (0.97–1.10)

0.33

 ≥4,000

 

11.24

0.74

0 (0–52)

1.12 (1.02–1.21)

0.01

 Trend across categories

 

20.10

0.17

25 (0–59)

1.05 (1.02–1.09)

0.006

Gestational age (weeks)

16

     

 ≤37

 

8.56

0.86

0 (0–54)

1.01 (0.91–1.11)

0.87

 38–41

    

1.00 (Ref. cat.)

–

 ≥42

 

16.67

0.34

10 (0–47)

0.84 (0.73–0.97)

0.02

Maternal age (years)

17

     

 <20

 

29.54

0.02

46 (4–69)

0.84 (0.68–1.04)

0.10

 20–24

 

19.11

0.26

16 (0–52)

0.90 (0.83–0.98)

0.01

 25–29

    

1.00 (Ref. cat.)

–

 30–34

 

17.94

0.32

11 (0–48)

1.03 (0.95–1.13)

0.47

 ≥35

 

14.01

0.59

0 (0–51)

1.11 (1.01–1.23)

0.04

 Trend across categories

 

32.22

0.01

50 (13–72)

1.08 (1.03–1.13)

0.001

Birth order

16

     

 First born

    

1.00 (Ref. cat.)

–

 Second born

 

27.29

0.03

45 (1–69)

1.12 (1.02–1.24)

0.03

 Third or later born

 

20.05

0.17

25 (0–59)

1.08 (0.97–1.19)

0.17

Maternal diabetesa

      

 No

8

   

1.00 (Ref. cat.)

–

 Yes

 

6.42

0.49

0 (0–68)

4.92 (3.93–6.16)

<0.001

Maternal type 1 diabetesa

      

 No

8

   

1.00 (Ref. cat.)

–

 Yes

 

3.05

0.88

0 (0–68)

4.03 (1.76–9.20)

0.001

Breast-feedingb

      

 No or short period

15

   

1.00 (Ref. cat.)

–

 Yes or long period

 

36.25

0.001

61 (32–78)

0.84 (0.72–0.98)

0.02

aStudies recording maternal diabetes and maternal type 1 diabetes are shown in Table 1

bBreast-feeding was categorised as breast-feeding at discharge from hospital [18, 32], any breast-feeding [15, 25, 27], breast-feeding for approximately 3 months or more [30, 40, 43] and breast-feeding for approximately 4 months or more [37, 38, 39]

Ref. cat., reference category

Table 3 shows the association between Caesarean section and type 1 diabetes after adjustment for confounders. The crude association between Caesarean section delivery and type 1 diabetes was little altered after adjustment for birthweight (OR 1.24, p < 0.001), gestational age (OR 1.19, p < 0.001), maternal age (OR 1.19, p < 0.001), birth order (OR 1.21, p < 0.001), maternal diabetes (OR 1.17, p = 0.003), breast-feeding (OR 1.26, p < 0.001) or all of these confounders (OR 1.19, p = 0.01).
Table 3

Pooled analysis of the association between Caesarean section and type 1 diabetes after adjustment for various potential confounders

Adjusted potential confounder(s)a

No. of studies

No. of cases

Heterogeneity

Adjusted combined OR (95% CI)

p value

χ 2

p value

I 2 (95%CI)

None

20

9,938

17.70

0.54

0 (0–48)

1.23 (1.15–1.32)

<0.001

Birthweight

16

6,138

13.55

0.56

0 (0–52)

1.24 (1.13–1.35)

<0.001

Gestational age

16

6,005

14.10

0.52

0 (0–52)

1.19 (1.09–1.31)

<0.001

Maternal age

17

6,246

16.04

0.45

0 (0–51)

1.19 (1.09–1.30)

<0.001

Birth order

16

6,029

16.19

0.37

7 (0–43)

1.21 (1.10–1.34)

<0.001

Maternal diabetes

16

6,150

16.79

0.33

11 (0–48)

1.17 (1.05–1.29)

0.003

Breastfeeding

15

3,874

9.00

0.83

0 (0–54)

1.26 (1.12–1.42)

<0.001

Birthweight, gestational age, maternal age and birth order

15

5,791

11.30

0.66

0 (0–54)

1.17 (1.06–1.28)

0.001

Birthweight, gestational age, maternal age, birth order and breastfeeding

13

3,444

7.86

0.80

0 (0–57)

1.21 (1.06–1.38)

0.005

Birthweight, gestational age, maternal age, birth order, breastfeeding and maternal diabetes

13

3,424

9.16

0.69

0 (0–57)

1.19 (1.04–1.36)

0.01

aAdjustments were made for potential confounders using broadly the categories shown in Table 2

Discussion

This meta-analysis demonstrates a consistent increase, of around 20%, in the risk of type 1 diabetes in children delivered by Caesarean section. This observed increase in diabetes risk after Caesarean section delivery could not be explained by the confounding influence of birthweight, gestational age, maternal age, birth order, maternal diabetes or breastfeeding.

The main finding was observed consistently across studies, conferring a level of robustness to this result. Importantly, using individual patient data, or adjusted estimates, we were able to demonstrate that the increased risk of diabetes after Caesarean section delivery could not be explained by known confounding factors. However, as this meta-analysis was based upon observational studies, it is impossible to rule out the influence of unrecorded confounders, although any such confounder would have to operate similarly across all studies. Social class is a possibility, as it may be associated with the likelihood of delivery by Caesarean section, but as the association between social class and type 1 diabetes is inconsistent [24, 44, 45, 46] it seems unlikely that it could exert the necessary confounding influence. Gestational diabetes is another possibility, but the proportion of mothers with gestational diabetes in these European populations is likely to be small [47], reducing the likelihood of marked confounding, and adjustment for gestational diabetes in seven of the studies [15, 25, 27] revealed little evidence of confounding. A further weakness of this study was that the reason for Caesarean section could not be investigated, as this was not available in the majority of studies, and therefore we were unable to confirm a report suggesting that any increased risk of type 1 diabetes after Caesarean section was most marked after elective procedures [24].

The explanation for the observed increase in the risk of type 1 diabetes in children born by Caesarean section is unknown, but various theories are plausible. The gut microbiota are thought to play an important role in stimulating the development of the immune system [48]. Recent studies have shown that the gut microbiotic composition differ in children born by Caesarean section compared with vaginally born children [8, 9, 10, 11], perhaps because such children are first exposed postpartum to bacteria originating from the hospital environment rather than to maternal bacteria [11]. This difference in gut microbiotic composition could increase the risk of type 1 diabetes. Similarly, the hygiene hypothesis suggests that children with reduced or delayed exposure to infection in early life may have an increased risk of type 1 diabetes [49]. According to this hypothesis, as children born by Caesarean section may have a reduced exposure to infections compared with children born vaginally, this could increase their diabetes risk. Alternatively, a previous study [42] speculated that any increased risk of diabetes after Caesarean section could be caused by non-specific perinatal stress.

Our study also allowed the documentation of pooled estimates of the crude risk associated with various perinatal factors. Although not the result of a systematic review of the literature for each perinatal factor, there is no obvious reason why this selection of studies would not be representative. To our knowledge, this is the largest selection of studies that have been combined to investigate associations with birthweight, gestational age, maternal age, birth order and maternal diabetes. These analyses indicated that children who are heavier at birth, have a shorter gestation and whose mother has diabetes have a greater risk of type 1 diabetes. Although there was also evidence of an increased risk of type 1 diabetes with greater maternal age and later birth order, these associations varied considerably between studies and should be interpreted more cautiously. The findings for breast-feeding, of a slight reduction in type 1 diabetes risk, although broadly similar to that observed in two previous meta-analyses [50, 51], were subject to considerable heterogeneity, perhaps reflecting differences in the recording of breast-feeding in the individual studies.

In conclusion, our study detected a small but significant and consistent increase in the risk of type 1 diabetes after Caesarean section, which could reflect differences in exposure to bacteria in early life.

Notes

Acknowledgements

The authors acknowledge support from the following: the Czech Republic Ministry of Education (grant MSM 0021620814), the NHS National Coordinating Centre for Research Capacity Development UK, the Research Council of Norway, Diabetes UK and the Northern Ireland Department of Health and Social Services. Finally, thanks are also due to G. Soltész and G. Dahlquist, EURODIAB Substudy 2 co-ordinators.

Duality of Interest

The authors declare that there is no duality of interest associated with this manuscript.

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • C. R. Cardwell
    • 1
  • L. C. Stene
    • 2
    • 3
  • G. Joner
    • 3
    • 4
  • O. Cinek
    • 5
  • J. Svensson
    • 6
  • M. J. Goldacre
    • 7
  • R. C. Parslow
    • 8
  • P. Pozzilli
    • 9
  • G. Brigis
    • 10
  • D. Stoyanov
    • 11
  • B. Urbonaitė
    • 12
  • S. Šipetić
    • 13
  • E. Schober
    • 14
  • C. Ionescu-Tirgoviste
    • 15
  • G. Devoti
    • 16
  • C. E. de Beaufort
    • 17
  • K. Buschard
    • 18
  • C. C. Patterson
    • 1
  1. 1.Department of Epidemiology and Public Health, School of Medicine and DentistryQueen’s University BelfastBelfastUK
  2. 2.Division of EpidemiologyNorwegian Institute of Public HealthOsloNorway
  3. 3.Diabetes Research CentreAker and Ullevål University HospitalsOsloNorway
  4. 4.Faculty of MedicineUniversity of OsloOsloNorway
  5. 5.Second Medical SchoolCharles UniversityPragueCzech Republic
  6. 6.Steno Diabetes CentreGentofteDenmark
  7. 7.Department of Public HealthOxford UniversityOxfordUK
  8. 8.Paediatric Epidemiology GroupUniversity of LeedsLeedsUK
  9. 9.University Campus Bio-MedicoRomeItaly
  10. 10.Department of Public Health and EpidemiologyRiga Stradins UniversityRigaLatvia
  11. 11.Children’s Diabetic CentreSofiaBulgaria
  12. 12.Institute of EndocrinologyKaunas University of MedicineKaunasLithuania
  13. 13.Institute of Epidemiology, School of MedicineBelgrade UniversityBelgradeSerbia
  14. 14.Department of PaediatricsMedical University of ViennaViennaAustria
  15. 15.Nutrition and Metabolic Diseases Clinic, ‘N. Paulescu’ Institute of DiabetesBucharestRomania
  16. 16.Department of Social Sciences and CommunicationUniversity of LecceLecceItaly
  17. 17.Clinique Pédiatrique LuxembourgLuxembourgLuxembourg
  18. 18.Bartholin Institutett, RigshospitaletCopenhagenDenmark

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