Caesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: a meta-analysis of observational studies
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DOI: 10.1007/s00125-008-0941-z
- Cite this article as:
- Cardwell, C.R., Stene, L.C., Joner, G. et al. Diabetologia (2008) 51: 726. doi:10.1007/s00125-008-0941-z
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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 1Introduction
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 I2 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].
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 |
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|
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 |
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|
|
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 |
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| 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 | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ |
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 χ2 = 17.70, df 19, p = 0.54; I2 = 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
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].
Pooled analysis of the association between potential confounders and type 1 diabetes
Potential confounder | Number of studies | Heterogeneity | Combined OR (95% CI) | p value | ||
|---|---|---|---|---|---|---|
χ2 | p value | I2 (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 | |
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 | ||
|---|---|---|---|---|---|---|---|
χ2 | p value | I2 (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 |
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.
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.