In this large cohort study including over 60 years of pregnancy data linked to the national diabetes dataset we found that, for pregnant women, being overweight or obese was associated with an increased incidence of type 2 diabetes in the offspring. This association with type 2 diabetes may lie on the causal pathway to explain the link between being overweight or obese during pregnancy and offspring cardiovascular disease and mortality rates [2, 3], and it highlights a potential target for intervention.
Our finding of a link between being overweight or obese and type 2 diabetes in the offspring is in accord with previous observations of associations of pregnant women being overweight and higher maternal weight with increased incidence of type 2 diabetes in the offspring [11, 12], and of maternal obesity with markers in the offspring of increased insulin resistance in childhood [18] and young adulthood [5, 11, 19]; it is also consistent with the findings of increased diabetes risk in offspring born to overweight mothers in the Helsinki Birth Cohort Study [3]. Although the latter study could not distinguish between types of diabetes, the association between being overweight and risk of diabetes was stronger in women than in men, as observed in our dataset. The reasons for a sex difference in the findings are unknown but are possibly related to the smaller pancreatic volume [20], and hence beta cell reserve, in women compared with men, potentially programmed in utero [21], and the findings are consistent with those of other studies suggesting women may be more vulnerable to adverse metabolic programming influences [22, 23]. Evidence suggests increasing incidence of type 1 diabetes in children born between 1989 and 2003 [24], a time when rates of maternal obesity were dramatically rising, as also observed in our dataset. Associations between maternal obesity and childhood-onset type 1 diabetes have been reported in some studies [6,7,8] but not others [9, 10]. Notably, two studies from Sweden observed an increased incidence of childhood type 1 diabetes in obese mothers without diabetes [6, 8]. We were unable to replicate this finding in our dataset. Reasons for the differences between the Swedish and Aberdeen cohorts are unknown and we only found an association of maternal obesity with offspring type 1 diabetes when we restricted the cohort to individuals who had at least 35 years of follow-up.
The underlying mechanisms linking mothers being overweight/obese to type 2 diabetes in the offspring are not known. The fetal overnutrition hypothesis suggests that the adverse in utero environment associated with maternal obesity, including high circulating levels of glucose, insulin and NEFA, programmes adverse offspring outcomes [25]. In addition, obesity in pregnancy is associated with complex neuroendocrine, metabolic and immune/inflammatory changes which likely impact on fetal hormonal exposure and nutrient supply [26, 27]. It is also thought that epigenetic factors in the intrauterine environment of obese mothers may initiate beta cell stress, metabolic dysregulation and earlier onset of type 2 diabetes and cardiometabolic risk [28]. Further, although we adjusted for both prenatal and postnatal environmental influences in our statistical analyses, it is extremely likely that there will be residual confounding by environmental factors that we were unable to measure. The Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) study showed an association between increased maternal BMI and fetal hyperinsulinaemia, independently of maternal glycaemia [29], supporting an intrauterine influence of maternal obesity on glucose metabolism in the offspring. Others reported that rapid growth in the postnatal environment from birth onwards, rather than during fetal life, was associated with higher insulin levels in childhood [30]. Further studies are needed to understand the contribution of pre- and postnatal mechanisms linking maternal obesity with type 2 diabetes in the offspring.
The strengths of our study include the large sample size and the detailed quality of the antenatal records, including maternal history of type 1 diabetes. Our findings remained similar if we adjusted for maternal diabetes prior to pregnancy in the analyses or excluded women with a history of diabetes both prior to and after pregnancy from the analyses. In addition, we used national population-based health data for diagnosed diabetes (SCI-Diabetes), which allowed us to examine outcomes of both type 2 and type 1 diabetes in the same dataset. A further major strength of our study is that we included outcome data for offspring from birth to age 62 years, which allowed us to explore outcomes across the lifespan. Scottish Diabetes Survey data indicate that type 2 diabetes prevalence increases with age to about 11% for 55- to 59-year-olds (i.e. the oldest age group in this study) [13]. To our knowledge, there are no other databases worldwide that would allow such linkage between maternal obesity records in pregnancy and confirmed diagnosis of diabetes in the offspring. The main limitation is that as only maternal history of type 1 diabetes is recorded in the AMND, we were not able to use ‘gestational diabetes’ or ‘type 2 diabetes’ as covariates to determine whether there was a difference in offspring outcomes of mothers who were obese but did not have diabetes during pregnancy or who were both obese and had gestational or type 2 diabetes. However, we believe the number of women with pre-existing type 2 diabetes in this dataset would be negligible, particularly for mothers who were pregnant in the 1950s and 1960s. In addition, the definition of gestational diabetes has changed over the study period and more detailed measurements of glucose levels taken during pregnancy would be required to generate a comparable definition. As hypertension is part of the metabolic syndrome, we included history of hypertension in our models as a proxy for insulin resistance. Data on maternal gestational weight gain were not available, although a recent study found no evidence that gestational weight gain influenced risk of childhood type 1 diabetes [8]. A further limitation of our study is that we did not have data for all offspring on BMI or lifestyle factors (e.g. diet, exercise) that are known to increase the risk of type 2 diabetes. Indeed, it is plausible that our observations were due to increased BMI in the child, either through prenatal programming of BMI or through shared lifestyle of mother and child. In either case, our observations are important, as pregnancy represents a potential time to intervene with health advice for the family.
In conclusion, we showed that, in pregnant women, being overweight or obese was associated with increased type 2 diabetes incidence in the offspring, independently of perinatal and sociodemographic covariates and maternal history of diabetes. With the rising prevalence of being overweight/obese in women of childbearing age (for example, recent data indicated that over 60% of women in the USA were overweight or obese at the time of conception [4]), our findings have profound public health implications. There is an urgent need to establish effective approaches to prevention of obesity and diabetes among mothers and their offspring.