Influence of maternal age at delivery and birth order on risk of type 1 diabetes in childhood: prospective population based family study.(Statistical Data Included)

Abstract

Objectives To examine the influence of parental age at delivery and birth order on subsequent risk of childhood diabetes.

Design Prospective population based family study.

Setting Area formerly administered by the Oxford Regional Health Authority.

Participants 1375 families in which one child or more had diabetes. Of 3221 offspring, 1431 had diabetes (median age at diagnosis 10.5 years, range 0.4-28.5) and 1790 remained non-diabetic at a median age of 16.1 years.

Main outcome measures Disease free survival and hazard ratios for the development of type 1 diabetes in all offspring, assessed by Cox proportional hazard regression.

Results Maternal age at delivery was strongly related to risk of type 1 diabetes in the offspring; risk increased by 25% (95% confidence interval 17% to 34%) for each five year band of maternal age, so that maternal age at delivery of 45 years or more was associated with a relative risk of 3.11 (2.07 to 4.66) compared with a maternal age of less than 20 years. Paternal age was also associated with a 9% (3% to 16%) increase for each five year increase in paternal age. The relative risk of diabetes, adjusted for parental age at delivery and sex of offspring, decreased with increasing birth order; the overall effect was a 15% risk reduction (10% to 21%) per child born.

Conclusions A strong association was found between increasing maternal age at delivery and risk of diabetes in the child. Risk was highest in firstborn children and decreased progressively with higher birth order. The fetal environment seems to have a strong influence on risk of type 1 diabetes in the child. The increase in maternal age at delivery in the United Kingdom over the past two decades could partly account for the increase in incidence of childhood diabetes over this period.

Introduction

Type 1 diabetes develops against a background of genetic susceptibility and is mediated by immune mechanisms activated many years before clinical onset of the disease. Studies of the appearance of autoantibodies in the offspring or siblings of individuals with type 1 diabetes suggest that autoimmune responses to islet antigens are generally well established by age 3-5 years, even though the disease may not develop until adult life.[1] As in type 2 diabetes, prenatal and early postnatal factors are known to influence subsequent risk of type 1 diabetes.[2] These include intrauterine exposure to viral infection with rubella or enterovirus and birth weight.[3-7] Additionally, several studies have reported that high maternal age at delivery increases the risk of type 1 diabetes in the child.[8-13] Studies of birth order have produced inconsistent results.[12 13] We therefore examined the influence of parental age at delivery and birth order on subsequent risk of diabetes in the child in a large population based family cohort.

Participants and methods

The Bart's-Oxford family study

The Bart's-Oxford (BOX) family study of childhood diabetes is a prospective population based study, which since 1985 has recruited more than 90% of the families of children who have developed type 1 diabetes under the age of 21 in the former Oxford Regional Health Authority area. This area has a population of 2.6 million, including 730 000 people under the age of 21 years. Ascertainment of new cases is more than 95%, and incidence up to age 15 over the period 1985-95 averaged 18.6 (95% confidence interval 17.4 to 19.8) cases per 100 000/year.[14] Data, including dates of birth and history of diabetes, are collected during home visits, and further contact with the families is maintained by visits and telephone calls from the field workers, supplemented by annual postal questionnaires. More than 90% of those recruited remain under regular follow up. Diabetes is defined according to World Health Organization criteria, and cases of secondary diabetes or maturity onset diabetes of the young are excluded by examination of the clinical records.

Our analysis included 3221 offspring from 1375 families. A further 91 offspring from 49 families were excluded because the date of birth of the father or mother, or both, was unavailable. The median age of mothers at delivery of the included offspring was 27 years (range 16-45) and the median age of fathers was 29 years (range 16-74). The analysis included 1294 firstborn children, 1177 second children, 516 third children, 171 fourth children, 41 fifth children, and 22 children who were sixth or more in the birth order. Of the 1790 offspring who…