Discussion
In this large cohort study, we found that maternal diabetes before or during pregnancy was associated with an increased risk of FED in offspring. Children of mothers with pregestational diabetes (type 1 or type 2 diabetes) had varied increased risks (1.73 for type 1; 2.53 for type 2) than those of mothers without diabetes, which were higher than that in children of mothers with GDM only. The highest risk of FED was observed among offspring of mothers with diabetic complications. Mediation analyses further indicated that adverse birth outcomes could only explain a very small proportion of the overall effects.
Our findings are, in general, consistent with previous studies on the association between maternal pregestational diabetes and neurodevelopmental disorders in childhood or adolescence,14 15 18–20 37 38 but it is new to observe the elevated risk in infancy and early childhood. We further observed that the associations of type 1 and type 2 diabetes with FED might vary in magnitude. The variations in the magnitude of the FED risk in offspring by subtypes of maternal diabetes could be due to the different pathophysiological mechanisms underlying subtypes of diabetes,39 which warrants further investigations.
Regarding GDM, a meta-analysis of both prospective and cross-sectional studies reported that GDM was associated with ASD in offspring.40 However, a large population-based study in the USA found that only GDM diagnosed before 26 weeks was significantly associated with risk for ASD.19 Our stratified analyses found that children exposed to GDM diagnosed before 26 weeks had a similar HR, compared with children exposed to GDM at any time. Several register-based studies have suggested that the association between GDM and neurodevelopmental disorders in offspring was only observed in children of parents with lower socioeconomic position or of mothers with obesity.14 18 41–43 These discrepancies might be explained by different screening procedures, diagnostic criteria, and treatment guidelines for GDM, or measurements for offspring neurodevelopment.40
Potential biological mechanisms linking maternal diabetes during pregnancy and FED risk in offspring may involve multiple pathways. During diabetic pregnancies, maternal hyperglycemia may predispose fetuses to a proinflammatory state with fetal hyperinsulinemia,44 increased oxidative stress,45 chronic inflammation,11 and hypoxia,46 which in turn could interfere with brain development during the critical period and lead to subsequently neurobehavioral disorders in later life.12 47 Previous studies have established that the development of neurons and brain circuits, that is, proliferation, migration, differentiation, is an array of complex processes, and are more susceptible to environmental insults during early pregnancy.48 49 During this period, maternal hyperglycemia may play a more critical role in the etiology of neurodevelopment disorders.50 51 Maternal hyperglycemia has also been associated with epigenetic modifications which potentially mediate the link between maternal diabetes and FED risk in offspring.52 Experimental studies in rats have suggested that epigenetic modifications of neocortical neurogenesis due to alterations in the hyperglycemic intrauterine environment increased the susceptibility to neurodevelopment disorders in later life.16 In addition, infants born to mother with diabetes have higher serum leptin and Mendelian randomization supports the causal relationship between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns.53 Leptin, one of the anorexigenic neurotransmitters, may restrain the feeding behavior by restricting the availability or counteracting the orexigenic effect of neuropeptide Y,54 which may partly explain the disturbed feeding behaviors in offspring of mothers with diabetes.
It is noteworthy that children of mothers with diabetic complications have the highest risk of FED. Diabetic complications are closely correlated with insulin resistance and may reflect the severity of pregestational diabetes and poor glycemic control.55 Similarly, previous studies have found a higher risk of genital anomalies and cardiovascular diseases in offspring of mothers with diabetic complications.21 33 Maternal poor glycemic control in pregnancy may exert potential implications in offspring for behavioral and emotional problems.56 57
Strengths and limitations of this study
This study has several strengths. First, methodological strengths of this study include its use of the Danish register data, which provide a large and representative sample with more than 1 million children. Second, in this study, we have used Cox proportional hazards model. This statistical model can take into consideration of time until FED occur and compare the incidence rate of events over time for different groups, while adjusting for various potential confounders. Third, the data used in this study were extracted from national registers which have been proved to be reliable and of high quality.24 25 28 Furthermore, the data are prospectively collected, so the possibility of recall bias could be ruled out.
Our study also had several limitations. First, the FED treated in private clinics could not be included. However, misclassification of FED might be expected to be non-differential by maternal diabetes and therefore are more likely to influence our results toward the null. Second, the potential misclassification bias might also remain for maternal diabetes. Before 1986, type 1 and type 2 diabetes were recorded using the same ICD-8 codes.28 We further validated the diagnosis by using the specific register information for diabetes later and previous studies have indicated the high validity of Danish diabetic diagnosis in epidemiological studies. Third, although we adjusted for relevant confounders, as in other observational studies, we cannot completely rule out the possibility of residual confounding by unmeasured confounders. However, the cosibling analyses showed that they were not explained by unmeasured shared familial factors. In addition, no significant association between paternal diabetes further suggested the findings are unlikely to be explained by the uncontrolled confounding completely. Lastly, pregestational diabetes with complications could indicate severity of diabetes, poor glycemic control or duration of exposure to hyperglycemia. However, due to lack of detailed information on these factors, we could not explore further on this issue and further research is warranted.