The first instance of diabetes in a child with congenital rubella was mentioned in passing in 1949 , but the association between congenital rubella and diabetes came to general recognition via a single case from the Australian ‘Gregg cohort’ , to which four other cases were soon added [19, 20].
Twenty published cases were identified by a search of the literature [19–29] and are listed in Table 1. Of these, nine were diagnosed between the ages of 12–48 months; six presented in ketoacidosis, and most required insulin therapy. Two autopsies were performed. One, of a boy aged 14 months who died in ketoacidosis, showed insulitis , and the second, of an 11-year-old girl who died in ketoacidosis 7 years after diagnosis, showed atrophic islets considered typical of long-term type 1 diabetes .
The most detailed longitudinal study is based on long-term follow-up of cases diagnosed by Gregg in New South Wales. A survey of children with hearing difficulties identified 48 patients born after the outbreak of 1940–1941, and to these were added cases recruited from other sources, including the wedding list of one of the participants . A total of 50 individuals who were willing and able to participate were considered to have a definite diagnosis of congenital rubella; these were examined and studied in more detail. None was known to have diabetes before the initial examination in 1967, but one 24-year-old man was found at that time to have undiagnosed diabetes, with a routine blood glucose of 33 mmol/l.
A notice placed in the Medical Journal of Australia in 1968 resulted in a publication describing this patient plus another member of the Gregg cohort, diagnosed by OGTT, together with three reports from other centres . A total of 44 members of the Gregg cohort were subsequently tested by OGTT, in a survey that is widely misquoted as having shown that nine of the 44 (20%) had diabetes. It is therefore important to appreciate that the criteria used to diagnose diabetes were a 1 h glucose value of >8.9 mmol/l (160 mg/dl) or a 2 h value of >6.7 mmol/l (120 mg/dl). On this basis, five individuals were said to have diabetes. As described above, one had overt diabetes and a second had a diabetic OGTT, but the other three would not be considered to have diabetes by current criteria. Four others had stimulated glucose values below these levels but were deemed to have ‘latent diabetes’ by criteria that are now obsolete, such as a mismatch of glucose and insulin peaks. The average birthweight of the nine patients was 2.5 kg (range 1,985–3,435 g). Maternal infection had occurred from 4–16 weeks of gestation in all cases; all were deaf, two had cataracts, two had rubella chorioretinopathy and one had pulmonary stenosis. None of the nine required insulin, although six were treated with oral agents .
The members of this cohort were studied again after 50  and 60  years. Seven of the 50 had died by 50 years, including one with a diagnosis of diabetes. Follow-up glucose tolerance tests are not reported, but diabetes is said to have persisted in four out of five of those with abnormal tests; one required insulin and two were on tablets, but none had developed late complications of diabetes. One additional patient developed diabetes in the interim, but no further details were provided. When studied after 60 years, 40 of the originals were still alive, and seven were considered to have type 2 diabetes (none had a diagnosis of type 1). Of these, three were on insulin (two had developed retinopathy and were also found to have high levels of GAD antibodies), one other was on oral medication and the remaining three were on diet alone. The prevalence of type 2 diabetes was 22% compared with a background prevalence in that age group of 13.1% . In summary, this cohort study found a high prevalence of type 2 diabetes and two cases suggestive of latent autoimmune diabetes in adults (LADA) but no single instance of typical type 1 diabetes.
The rubella epidemic of 1964–1966 is estimated to have resulted in some 600 children with the congenital rubella syndrome in New York alone. Of these (and including children born outside this time-frame), 173, and subsequently 242 affected individuals, were identified for study via the Developmental Disabilities Center at St Luke’s-Roosevelt Hospital or the Pediatric Diabetes Clinic at Mount Sinai Hospital [32, 33]. Forty per cent of the children were Hispanic, 25% black and 30% of European extraction. The diagnosis of congenital rubella was based on isolation of rubella virus from the newborn (present in 16%), serological confirmation by detection of rubella-specific antibodies in the newborn (41%) and/or clinical stigmata plus positive serology not obtained in the immediate postnatal period. Given the interest of the investigators, the sample may have included a disproportionate number of children with diabetes. Of these, there were 21/173 in the initial study (mean age 14 years, range 6 months to 24 years) satisfying National Diabetes Data Group criteria (fasting blood glucose ≥ 6.7 mmol/l; 2 h blood glucose ≥ 10 mmol/l), and 16 had experienced ketoacidosis and were on insulin. An expanded group of 242 children was subsequently examined (mean age 17 years); of these, 15 required continuous insulin therapy, one had received insulin intermittently and 14 had abnormal glucose tolerance . Some of the latter, unexpectedly, showed distinctly elevated insulin levels during the OGTT , a finding also described but not commented on in an earlier series . The New York studies are remarkable for the very high number of individuals with diabetes, and it is therefore particularly disappointing that individual patient details are summarised but not reported in detail.
A second US study described a cohort of 201 adolescents meeting diagnostic criteria for the congenital rubella syndrome, 152 of whom were born in 1964–1965; all attended institutions for the deaf in Maryland or Virginia. Of these, two had overt diabetes (treatment not specified) and two others were considered to have diabetes on the basis of oral glucose tolerance testing. Overall, 22% were judged to have abnormal tests, using 1979 National Institutes of Health criteria for children plus some added categories devised by the authors—thus making comparison with other series impossible .
The National Congenital Rubella Surveillance Programme identified 482 children with confirmed or suspected congenital rubella in 1971–1977; two cases listed in Table 1 come from this registry . These two cases are presumably the same as those described in a long-term follow-up study of 616 UK children exposed to rubella in pregnancy. Since three cases of diabetes were reported in 605 controls, this later survey showed no excess of diabetes . Follow-up data on this cohort are unfortunately not available (P. Tookey, personal communication).
An epidemic outbreak of rubella occurred in 1964–1965, and 280 individuals with cataracts, sensory deafness and/or heart disease were studied 40 years later. Of these, three had developed diabetes, two presented in diabetic ketoacidosis at the ages of 13 and 18 (Table 1) and required insulin immediately, and another, asymptomatic, individual was picked up by screening and required insulin therapy later in life 
The Canadian Deafblind and Rubella Association maintains an active website (http://www.cdbra.ca/) and issues questionnaires from time to time. Its website lists 100 respondents with date of birth ranging back to the 1950s. Of these, four developed diabetes at the ages of >2, 9, 14 and 19 years, and another eight are listed with onset between the ages of 21 and 53 years; only seven of the 12 required medication .