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We only included all studies that examined the outcome of type 1 diabetes in relation to breastfeeding in developed countries. To be consistent with previous meta-analyses, articles were excluded if they only used surrogate markers for type 1 diabetes (e.g., the presence of islet cell antibodies). A total of six case-control studies were identified,91-96 The studies included 1,293 patients with type 1 diabetes and 3,262 control subjects. Five studies were conducted in Europe, and one in Taiwan. Four studies were rated grade B in methodological quality; two studies were rated grade C. Commonly considered confounders in these studies were family history of type 1 diabetes, neonatal illness, maternal age at birth, birth order, maternal/parental education, and type of delivery.

In four studies, the definition of type 1 diabetes cases was children with juvenile-onset diabetes (or developing diabetes before 17 years of age). In the other two studies, the cases were registered type 1 diabetes patients who were younger than 30 years of age and children with diabetes who were identified through hospital records. Matched controls were those without type 1 diabetes selected from various sources in the same population as the cases.

Three studies reported odds ratio of type 1 diabetes comparing subjects who were ever breastfed with those who were never breastfed. Two studies found a reduced risk of type 1 diabetes in

subjects who were ever breastfed (ORs 0.5695 and 0.7591), while the third study reported an increased risk (OR 2.4494).

Three studies compared subjects who were breastfed for more than 3 months or 6 months with those who were never breastfed. Two studies reported a reduced risk of type 1 diabetes in subjects who were breastfed for more than 3 or 6 months (adjusted OR 0.5796 and 0.2595, respectively). The third study94 _{reported an opposite finding (this was the same study that reported an increased risk}

with ever breastfed). A reduced risk of type 1 diabetes was found when comparing subjects who were never breastfed with those who were breastfed for more than 6 months (adjusted OR 0.36, 95%CI 0.14 - 0.94). The data also showed a slight increase in the risk of type 1 diabetes with longer duration of breastfeeding (1 month increment). The control subjects in this study were selected from children admitted to the same hospital as the cases, whether this explained the finding was unclear.

One study reported a reduced risk of type 1 diabetes comparing subjects who were initially exclusively breastfed with those who were not (adjusted OR 0.6, 95%CI 0.41 - 0.89).93 Another study found a small, but non-significant increased risk of type 1 diabetes with not breastfeeding at discharge (RR 1.33, 95%CI 0.76 - 2.31).92 This study was rated to have poor methodological quality because only univariate analysis was performed and potential confounders were not considered.

Conclusion

Our findings from the six additional case-control studies are similar to the findings from the two meta-analyses. However, the exclusivity of breastfeeding was not addressed in all studies, and the assessment of infant diet was based on long-term recall in five of six studies. We elected not to perform a meta-analysis, because it is unlikely to change the pooled estimates from the previous meta-analyses by adding additional three studies from the updates that compared subjects who were breastfed for more than 3 or 6 months with those who were never breastfed.

Two meta-analyses of moderate methodological quality reported statistically significant odds ratios of 1.23 and 1.43, respectively, for the risk of type 1 diabetes in subjects exposed to less than 3 months compared with more than 3 months of breastfeeding. Since case-control studies are prone to recall biases, Norris and Scott compared the odds ratios in studies relied on long-

term recall to assess infant diet with studies that did not. The results showed that studies using existing infant records to determine breastfeeding initiation and duration failed to show the associations reported in the studies relying on long-term recall for their exposure data. This suggests that subjects with type 1 diabetes were more likely to report shorter duration of breastfeeding than control subjects.

In conclusion, even though there is some evidence to suggest that breastfeeding for more than 3 months is associated with a reduced risk of type 1 diabetes, this evidence must be interpreted with caution because of the possibility of recall biases and suboptimal adjustments for potential confounders in the primary studies.

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Table 14. Summary of systematic reviews/meta-analyses on the relationship between breastfeeding and type 1 diabetes Author Year

Population Study description /Comparator Intervention Confounders considered Results Quality of SR/MA and limitations

Norris 1996

Case-control studies in which the neonatal feeding histories of patients with type 1 DM and individually matched non-DM control subjects were compared Cases: 4,656 Controls: 16,383 MA of 17 case- control studies published from 1966 to 1994. A=breastfeeding status (ever/never) B=total breastfeeding duration C=exposure to breast- milk substitutes D=exposure to cow’s milk-based substitutes Maternal education, maternal age at birth, birth order,

household income, race/ethnicity, social class

The summary OR for type 1 DM in patients who were never being breast-fed was 1.13 (95% CI 1.04-123).

The summary OR for type 1 DM in subjects who were breast-fed for < 3 mo compared with those who were breast-fed for at least 3 mo was 1.23 (95%CI 1.12-1.35).

Stratified analyses of studies were performed by prevalent vs. incident case-control study design, adequate vs. inadequate response rates of the cases and controls, the breastfeeding prevalence in the background population, the type 1 DM risk in the background population, and retrospective vs. concurrent infant diet assessment. All of these factors had impacts on the summary ORs for the risk of type 1 DM associated with infant diet exposures.

B Only unadjusted ORs were combined

although some primary studies had

adjustments for potential confounding

Gerstein 1994 Case-control studies in which the neonatal feeding histories of patients with type 1 DM and individually matched non-DM control subjects were compared

Cases: 3,708 Controls: 20,340

A SR review of 3 ecological and time- series studies, 13 case-control studies, one cohort study, and one case series. MA was performed for the case-control studies.

Cow’s milk exposure (and therefore non- exclusive breastfeeding) vs. Cow’s milk avoidance (and therefore

breastfeeding)

ND Results from the 13 case-control studies were mixed. The combined OR for type 1 DM in patients exposed to < 3 mo of breastfeeding was 1.38 (95% CI 1.22-1.53; p=0.11 for homogeneity).

An analysis of 2 cohorts of children born in the UK in 1958 and 1970 followed for 16 and 10 yr, respectively, failed to show any association between breastfeeding for < 1 mo and type 1 DM.

None of the 13 case-control studies fulfilled all six methodological criteria. Four case-control studies (31%) fulfilled five out of the six criteria (considered high quality)

B Combine both crude and adj. ORs without

performing sensitivity analyses

on potential confounding or study

quality

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Table 15. Summary of case-control studies on the relationship between breastfeeding and type 1 diabetes OR* (95% CI) Author year Country Cases (N) Control (N) Definition of type 1 DM Mean Age at Dx (year) Breastfeeding group Comparator

group Crude Adjust

Potential confounders adjusted Quality and Limitations EURODIAS 2002 Europe 610 1616 Onset < 15 yr in 1989- 1995 ND Ever BF Never BF 0.75 (0.58-0.96) (0.35-0.97) 0.59 Ht SDS, Wt SDS, maternal age, jaundice, RTI, Vit D suppl, asthma

B No demographic data; No adj. for SES McKinney 1999 UK 196 325 Onset < 16 yr in 1993- 1994 0-15 Initial exclusive

BF exclusive BF Initial not p=0.04 0.68 (0.41-0.89) 0.60

[Sex, age]a_{, maternal age,} maternal type 1 DM, preeclampsia, C-section,

neonatal illnesses

B No adj. for SES Ever BF Never BF _(0.40-1.2) 0.56 BF < 6 mo _(0.47-1.42) 0.82 _(0.45-1.59) 0.84 Tai 1998 Taiwan 177 193 Registered type 1 DM, age < 30 yr, born in 1984-1993 8.3 BF ≥ 6 mo Never BF _0.39 (0.16-0.94) (0.09-0.69) 0.25

[Age, sex, parental education]a_{, birth order,} paternal age, GA, type of

delivery, BW, monthly family income B Inconsistent methods for ascertainment of BF exposure Ever BF Never BF _(1.10-7.14) 2.44 BF 3-5 mo _(0.37-1.92) 0.85 BF > 6 mo BF 1-2 mo _(0.18-5.26) 2.08 BF 0 mo _(1.06-7.14) 2.78 Meloni 1997 Italy 100 100 Onset < 17 yr in 1983- 1994 6 (1-15) BF as continuous coefficient (1 mo increment) (0.99-1.22) 1.10

[Age, sex]a_{, mother’s} education, number of siblings B Hospital controls Visalli 2003 Italy 150 750 Onset < 15 yr, born in1977- 1989 ND BF ≥ 3 mo BF < 3 mo _(0.31-0.72) 0.47 _(041-0.74) 0.57

[Age]a_{, family history of} type 1 DM, infectious disease during pregnancy,

eczema C Inadequate response rate (>20%); No adj. For SES Jones, 1998 UK 60 458 Dx at discharge, born in 1976-1986

ND _discharge BF at _discharge Not BF at _(0.43-1.32) 0.75 [Age, sex]a

C Poor adj. for confounding

Dx, diagnosis; BF, breastfeeding; SR, systematic review; MA, meta-analysis; SDS, standard deviation score; Ht, height; Wt, weight; RTI, respiratory infection; Vit D suppl, Vitamin D supplementation; C-section, delivery by cesarean section; GA, gestational age; BW, birth weight; LTC, long-term recalls; adj, adjustment; SES, socioeconomic status

*Odds ratio of type 1 DM, compared the breastfeeding group to the comparator group (or the reference group), unless noted a

Relationship between Type 2 Diabetes and Breastfeeding