📘 Perinatal risk factors for type 1 diabetes mellitus

Higher birth weight (over 4000 g) slightly increases the risk of developing type 1 diabetes in childhood. Newborns weighing over 4 kg have an approximately 17% higher risk, with a linear increase of about 3-4% for every additional 500 g [1]. Unlike type 2 diabetes, where both low and high birth weight increase the risk, in the case of type 1 diabetes low birth weight (under 2,500 g) even appears to be protective.

The proposed mechanism is related to the accelerator hypothesis, which states that a heavier newborn has a higher insulin demand, which overloads the pancreatic beta cells, making them more visible to the immune system. Although the effect is modest, it is one of the best replicated findings in the research on perinatal factors for type 1 diabetes.

Caesarean delivery has been associated with an approximately 20% higher risk for the child to develop type 1 diabetes, compared with vaginal delivery [2]. The main hypothesis is that newborns delivered by caesarean section are not exposed to the mother's vaginal and intestinal microbiota, which alters early intestinal colonisation, with reduced levels of Bacteroides and Bifidobacterium.

However, recent studies have considerably weakened the causal argument [3]. For example, the prospective TEDDY study (very well designed) did not find an association between caesarean section and the subsequent development of type 1 diabetes-specific autoimmunity in the child. Currently, this association is considered possible, but various confounding factors could explain part of the additional risk.

Yes, breastfeeding appears to offer a moderate protective effect against type 1 diabetes. Prolonged breastfeeding (at least 6-12 months) reduces the risk of type 1 diabetes by 61%, and exclusive breastfeeding for at least 2-3 months reduces the risk by 32%. Compared with prolonged breastfeeding (over 6 months), the absence of breastfeeding is associated with an approximately 2.5-fold higher risk of type 1 diabetes [4]. The critical threshold for defining the risk of type 1 diabetes appears to be any breastfeeding versus no breastfeeding.

The protective mechanisms of breastfeeding include the transfer of immunoglobulins (type A, which protect the intestinal mucosa), the promotion of beneficial bacteria (Bifidobacterium), the strengthening of the intestinal barrier and the delay of exposure to complex foods. However, avoiding cow's milk proteins through hydrolysed formulas does not reduce the risk of type 1 diabetes.

The timing of solid food introduction appears to matter, and evidence suggests an optimal window between 4 and 6 months of age. According to the Lampousi 2021 meta-analysis, introducing gluten at 3-6 months (compared with before 3 months) is associated with a significant reduction in type 1 diabetes risk [4]. Some observational studies have suggested that very late introduction of gluten (after 9 months) could increase the risk, but this has not been confirmed by the only available randomised study (BABYDIET).

However, the only randomised study on this topic, BABYDIET, did not show a risk for type 1 diabetes from delaying gluten introduction from 6 to 12 months in 150 children at increased risk [5]. The amount of gluten-containing cereals consumed may matter, not just the timing of introduction. The biological explanation centres on the maturation of the intestinal immune system. In the 4-6 month window, the gut-associated lymphoid tissue learns to tolerate foods, and introducing them too early (immature barrier) or too late (missed learning window) may favour immune activation rather than tolerance.

The hypothesis that early introduction of cow's milk in the diet could trigger type 1 diabetes dominated research for decades. Early observational studies showed significant associations. The molecular mimicry hypothesis proposed that bovine serum albumin (BSA) causes cross-reactions with a beta-cell autoantigen. A 2021 meta-analysis actually showed that later introduction of cow's milk (after 2-3 months) is associated with a lower risk of type 1 diabetes [4].

Extensively hydrolysed casein formula was compared with conventional cow's milk formula over a median follow-up of 11.5 years. The incidence of type 1 diabetes was similar, a clearly negative result [6]. If intact cow's milk proteins had been a major trigger, the hydrolysed formula should have reduced the incidence, but it did not. The BSA antibody cross-reactivity with a specific pancreatic beta-cell antigen has never been proven at the molecular level. Therefore, cow's milk exposure remains at most a minor modulating factor, and its avoidance cannot be recommended as a prevention strategy for type 1 diabetes.

Overall, preterm birth (before 37 weeks) is associated with a slightly increased risk of type 1 diabetes. Extreme prematurity (23-27 weeks) is associated with a reduced risk, while late prematurity (34-36 weeks) increases the risk [3]. However, there is a numerical predominance of late preterm births.

Children born extremely preterm have a very immature immune system at birth, and their exposure to glucocorticoids (administered to mothers for lung maturation) and differences in pancreatic beta-cell development may explain the protective (apparently paradoxical) effect.

Yes, advanced maternal age is associated with a slightly increased risk of type 1 diabetes in the child. The relationship appears to be linear, with a 5-10% increase in risk for every five additional years of maternal age, with no plateau at any particular age. The association persists even after adjustment for birth weight, gestational age, birth order, maternal diabetes and breastfeeding [7]. Paternal age has shown no clear association with the risk of type 1 diabetes.

Proposed mechanisms include the accumulation of environmental exposure over the mother's lifetime, age-related epigenetic changes, increasing maternal body mass index with advancing age, and possible alterations of immune function. Your risk of having a child with type 1 diabetes should not cause you additional concern solely on the basis of your age, as the effect is a modest one.

Certain maternal infections during pregnancy can increase the child's risk of type 1 diabetes, but the effect varies considerably depending on the type of infection. Overall, maternal infections during pregnancy increase the risk by 31%, with a more pronounced effect for enterovirus infections (54% increased risk) [8]. The strongest established association is with congenital rubella. Approximately 12-20% of children with congenital rubella syndrome develop diabetes, and over 40% have impaired glucose tolerance [9].

Maternal cytomegalovirus infection has been associated with an approximately fourfold higher risk, but the data are limited. One study suggested that respiratory infections in the first trimester might be associated with subsequent development of type 1 diabetes in the child, but this association has not been confirmed at the level of a recent meta-analysis. Regarding COVID-19, there is not yet sufficient evidence concerning maternal infection during pregnancy.

Yes, maternal gestational diabetes is associated with a nearly twofold risk of type 1 diabetes in the child. According to a recent meta-analysis, gestational diabetes increases the child's risk of type 1 diabetes by approximately 94% (OR 1.94) [10]. Pre-existing maternal type 1 diabetes increases the risk even more (estimates range between 3 and 11 times, depending on the study).

The accelerator hypothesis states that intrauterine hyperglycaemia programmes insulin resistance in the child, increasing the metabolic stress on beta cells and subsequently accelerating autoimmune destruction. The second proposed mechanism is epigenetic programming, whereby gestational diabetes would induce DNA methylation changes in cord blood, and exposed children thus exhibit accelerated epigenetic ageing. The third implicated mechanism is that the mother's genetic susceptibility to type 1 diabetes is transmitted to the child, and the mother may even subsequently develop autoimmune diabetes herself.

First-born children appear to have a slightly higher risk of type 1 diabetes compared with younger siblings, but the effect is small and inconsistently found across studies. The effect is more pronounced and more consistently found in studies during the first five years of the child's life and then decreases with age [11].

As a possible explanation, the hygiene hypothesis assumes that first-born children have lower early microbial exposure than children with older siblings, which could affect the development of immune tolerance. The evidence currently available is not sufficient to support the hygiene hypothesis in the development of type 1 diabetes. Therefore, you have no reason for additional concern based on the order in which your children were born.

There is suggestive but not definitive evidence that antibiotics administered repeatedly in the first year of life are associated with a slightly increased risk of type 1 diabetes. The risk is higher in children born by caesarean section. It appears that only broad-spectrum antibiotics administered in the first year of life have been associated with a higher risk of type 1 diabetes, while narrow-spectrum antibiotics had no effect in this regard [12].

It appears that it is not the antibiotics themselves that are to blame for this association, but rather the reason for which they were prescribed. The most recent studies, which attempt to account for this, have not found significant causal associations. The proposed mechanism is disruption of the gut microbiome [13].

Neonatal jaundice was historically associated with a slightly increased risk of type 1 diabetes, but this association has faded considerably at present. Large recent studies have no longer found an association between phototherapy and type 1 diabetes [14].

The association appears present only in older birth cohorts (1973-1982) and absent in recent decades, likely reflecting changes in Rh incompatibility prophylaxis and phototherapy practices [3]. Bilirubin at moderate concentrations actually has antioxidant properties and could theoretically protect beta cells.

Blood group itself is not a risk factor for type 1 diabetes. Blood group incompatibility between mother and child was historically associated with an increased risk of type 1 diabetes. This association no longer exists in modern birth cohorts, the reason being advances in Rh prophylaxis with anti-D immunoglobulin and improvements in the management of haemolytic disease [3, 15].

It is interesting that the HLA-DR3 variant (a risk factor for type 1 diabetes) is over-represented both in children with blood group incompatibility with their mother and in those with type 1 diabetes. This shared genetic susceptibility may explain the epidemiological association without implying a direct causal link.