Several studies have shown that the risk of type 1 diabetes increases with high maternal age. These studies have generally compared cases with controls or census data. Flood et al studied 580 children or adolescents with diabetes and compared maternal age at delivery with data from a census bureau.10
The comparison showed fewer than expected births to mothers aged less than 25 and more than expected births to mothers aged more than 30. A previous study from the United Kingdom, again using census data for comparison, showed that mothers of diabetic children were significantly older at delivery than mothers in the general population.11
A population based Swedish study found no difference in mean maternal age at delivery between children with diabetes and referent children, but the proportion of mothers aged more than 35 years at delivery was higher for children with diabetes.9
Similar population based case-control studies found an increased risk of diabetes among children born to older mothers in Scotland but not in Northern Ireland, and a Danish study found a linear risk of diabetes with increasing maternal age for males but not for females.8,12
One case-control study found no association with maternal age.16
We studied the effect of parental age and risk of diabetes within a large population based cohort of children with diabetes and their siblings. This cohort is larger than the studies described above and has the additional advantage that probands are compared with siblings rather than unrelated controls. Survival analysis was therefore performed within a group in which genetic susceptibility to type 1 diabetes was increased and can be assumed to be independent of parental age at delivery. Our major finding was that increasing maternal age at delivery was associated with a log linear increase in risk of diabetes in the offspring. There was also a weaker association between risk and the father's age at delivery. The most comparable study to ours was that from Pittsburgh, which examined just over a thousand families and showed a significant association between a maternal age of more than 35 years and the cumulative frequency of diabetes in children. No trend was found in younger maternal age groups.13
The observation that children of older mothers have an increased risk of diabetes seems reasonably secure. We have extended this observation by showing a log linear relation throughout reproductive life sufficiently powerful to influence the overall rate of diabetes within a population.
Whereas most studies on maternal age at birth and risk of type 1 diabetes have had consistent results, the literature on birth order is conflicting.12,13
Our study, based on multivariate analysis, may help to explain this. We found that univariate analysis showed no association with birth order, but after adjustment for maternal age, an inverse association with birth order was apparent. In other words, later offspring have a higher risk of diabetes associated with maternal age but are also relatively protected compared with firstborn children. The combined effect of low birth order and high maternal age is such that risk of diabetes will be highest in firstborn children of mothers who start their families late.
The incidence of childhood diabetes has increased in many parts of the world since the 1950s. Studies from Finland, which has the highest incidence of childhood diabetes in the world, have shown that the incidence is now about four times as high as in 1953, when the first nationwide study was performed, with a linear trend over nearly 40 years.17
The increase in incidence has been most noticeable in developed countries, which have shown an increasing maternal age at first childbirth over a similar period.18
In the United Kingdom, for example, there are now fewer mothers in the 20-24 year age band and more in the 30-34 year age band (Figure ). We estimate that changes in the distribution of maternal age at delivery could account for an 11% increase in the cumulative incidence of diabetes between 1970 and 1996.
The incidence of type 1 diabetes in childhood has increased rapidly in the population we are studying, with an annual increase of 4% from 1985 to 1996.14
Increasing maternal age at delivery can only partly explain an increase of this magnitude, and other as yet unknown factors must be involved. A trend to earlier onset of disease has also been observed in our area, as in Finland.14,19
The weak inverse correlation between maternal age at birth and age at diagnosis in the child shown in our present study and also in Pittsburgh13
would be expected to have a small influence on this trend.
What is already known on this topic
Several studies have shown that children born to older mothers have an increased risk of type 1 diabetes
Most studies have compared cases with census data or controls and therefore have not matched for genetic susceptibility
Most reports suggest that increased risk is limited to the offspring of mothers aged more than 35 years at delivery. Conflicting reports exist concerning birth order and subsequent risk of type 1 diabetes
What this study adds
A strong log linear inverse relation was found between maternal age at delivery and risk of diabetes, equivalent to a 25% increase in risk for each 5 year rise in maternal age
Multivariate analysis showed that risk, adjusted for the effects of parental age at delivery and sex of the offspring, is highest in firstborn children and decreased progressively with higher birth order
Increasing maternal age at delivery of the first child may have contributed to the rising incidence of childhood diabetes
Why should maternal age influence risk of type 1 diabetes? An acquired genetic abnormality seems unlikely because, although parental age is associated with several genetic disorders due to aneuploidy—most notably Down's syndrome20
—no chromosomal abnormality is present in type 1 diabetes. Intrauterine viral infection can influence subsequent risk of diabetes in the child and might account for the higher risk in firstborn children, but it would not explain the effect of increasing maternal age.4,5
An alternative possibility, prompted by epidemiological observations in atopic conditions, including asthma, is that maturation of the immune system may be influenced by maternal age. Atopic disease is thought to be mediated via a predominant Th2 (T helper) lymphocyte response, whereas type 1 diabetes and other autoimmune diseases are mediated via Th1 responses. This is reflected in the clinical observation that children with type 1 diabetes have a lower prevalence of asthmatic symptoms than controls.21
Studies in asthma and other atopic disorders have shown that these Th2 mediated diseases are associated with low maternal age.22,23,24
We would therefore speculate that factors associated with higher maternal age influence maturation of the immune system in the offspring; possibly increasing predisposition to type 1 diabetes in later life by shifting the balance towards Th1 responses.
High maternal age—and possibly high paternal age—increases the risk of type 1 diabetes in offspring. Additionally, risk increases in a log linear fashion throughout the maternal age range. Higher maternal age at birth is associated with younger age of onset of type 1 diabetes in the child. Firstborn children are at greater risk than children of higher birth order. These observations, if confirmed, could account in part for the increasing incidence of diabetes and for the trend towards younger age at diagnosis. The fetal origins of type 2 diabetes, an aetiologically distinct disorder, are now well established.2
Fetal or neonatal influences could prove equally important in type 1 diabetes.