Prognosis for the child
Intrauterine hyperglycaemia has long-lasting adverse effects on offspring health. The underlying pathogenetic pathways are only partly understood, but may involve epigenetic changes. Understanding the adverse consequences of intrauterine programming may be of vital importance to future management of gestational diabetes mellitus (GDM), since the prevalence of this condition is rapidly increasing all over the world. Animal studies have shown that exposure to intrauterine hyperglycaemia increases the risk that the offspring will become overweight and develop diabetes, GDM or cardiovascular disease. Furthermore, these metabolic and phenotypic changes are associated with structural changes in the hypothalamus. These changes in experimental models are not only inducible but preventable. Human studies also demonstrate consistent associations between exposure to maternal diabetes during pregnancy and subsequent excess weight gain, type 2 diabetes and cardiovascular disease in the offspring. Other studies have found that offspring risk increases with increasing maternal glucose values during pregnancy. Randomised controlled studies have yet to demonstrate that such long-term effects can be prevented by more intensive treatment of maternal hyperglycaemia. Future research should focus on pathogenetic mechanisms, long-term follow-up of randomised controlled studies in humans and animal intervention studies evaluating potential dose-dependent effects.
The negative long-term effects of GDM upon offspring health raise great concerns from a global perspective. These health consequences are not only a threat to the individual but also a challenge to health costs, since the prevalence of GDM is rapidly increasing.
Sophisticated animal studies have been performed using streptozotocin-induced diabetes in rat models. Studies in Belgium followed the effect of intrauterine hyperglycaemia through several generations, and found that mild intrauterine hyperglycaemia was associated with macrosomia and reduced insulin secretion in the offspring, whereas severe hyperglycaemia was associated with microsomia, hyperinsulinaemia and increased prevalence of cardiovascular risk factors. Both mild- and severe intrauterine hyperglycaemia were associated with increased risk of GDM in the offspring, thus creating a vicious cycle by which adverse effects were transferred from one generation to the other via a non-genetic pathway. Interestingly, these adverse effects could be prevented by correcting maternal hyperglycaemia before the last stage of pregnancy.
Studies from Germany made similar observations regarding metabolic and phenotypic changes, and further found that the offspring had neuro-anatomical changes in the hypothalamus, which is the centre for regulation of food-intake, weight and insulin-secretion. In line with the Belgian study, they found that both metabolic and neuro-anatomical changes were preventable. Furthermore, they found that by implanting insulin-plaques in the hypothalamus of new-born rats, they could induce both anatomical and functional changes in the offspring.
Recent decades have provided rather convincing evidence from human studies - covering cohorts from very different ethnic groups - that offspring exposed to GDM have an increased risk of overweight in childhood, adolescence and adult life.
Findings from these cohort studies have been confirmed in sibling studies demonstrating an increased prevalence of overweight in siblings born after the diagnosis of maternal type 2 diabetes as compared with siblings born before the diagnosis – an association which could not be found in relation to paternal type 2 diabetes. The findings are further supported by studies which have shown that the risk of offspring overweight increases with increasing metabolic dysfunction in the mother (HbA1c, fasting blood glucose, 2-hour glucose, free fatty acids and ketonaemia).
In line with the findings concerning overweight, the risk of prediabetes/type 2 diabetes is increased in offspring exposed to GDM, and several studies have found that the higher the maternal glucose or other measures of deranged maternal metabolism, the higher the risk for the progeny.
It has further been shown that offspring genetically predisposed to maturity-onset diabetes of the young (MODY, with mutations in the HNF-1a gene) who had been exposed to intrauterine hyperglycaemia developed MODY at an earlier age than offspring that had not been exposed to a hyperglycaemic intrauterine environment.
This effect was not observed in offspring of fathers with MODY diagnosed either before or after pregnancy. The authors concluded that intrauterine hyperglycaemia increases the penetrance of the HNF-1a gene via non-genetic effects. However, both the risk of type 2 diabetes and the age at diagnosis of MODY could be predicted and modulated by polygenic gene-variants that predispose to type 2 diabetes.
The metabolic syndrome and cardiovascular risk factors
An increased risk of the metabolic syndrome has been found in the offspring of mothers with GDM, both in childhood and as young adults. Furthermore, several other studies have found that the offspring have an increased prevalence of risk markers for cardiovascular disease. It remains unclear whether this increase in risk is mediated by increased birth weight.
Studies in relation to pre-gestational type 1 diabetes indicate that maternal hyperglycaemia may affect certain cognitive domains including working memory, and that the deleterious effects may be mediated through preterm delivery.
Studies concerning the adverse effects of mild hyperglycaemia in GDM have produced conflicting results. Findings have ranged from neutral to both negative and positive effects of GDM on offspring cognitive function. Some studies indicate that GDM, may only have adverse effects in socially deprived families, reflecting either that adverse effects of GDM could be reversed after birth or that socially deprived mothers have a more pronounced metabolic derangement.
The findings of positive as well as negative associations between estimates of maternal metabolism and offspring outcome may reflect residual confounding and permit no firm conclusions. There are no animal studies to elucidate the question further.
Exposure to GDM induces a vicious cycle by which an increased risk of GDM is passed on to the next generation – a risk which goes through the maternal line and is not explained by genetic predisposition. The more specific pathogenetic mechanisms leading from intrauterine hyperglycaemia to long-term adverse outcome in the offspring are poorly understood, and most probably reflects a very complex interaction between several different mechanisms and risk factors.
According to the “Joergen-Pedersen hypothesis”, maternal glucose passes freely through the placental barrier to produce intrauterine hyperglycaemia and fetal hyperinsulinaemia. Glucose in high doses induces oxidative stress, and this may result in altered gene expression, vascular changes and accelerated apoptosis. Insulin, which is a potent growth-factor, induces hypertrophy of most fetal organs (heart, liver, adipose tissue, pancreas, muscles). These changes - directly caused by peripheral effects of hyperglycaemia and hyperinsulinaemia - may permanently affect organ function. Furthermore, Animal studies strongly indicate that pathogenetic mechanisms also involve pathological changes in the hypothalamus and centrally induced insulin resistance.
Many factors other than hyperglycaemia and hyperinsulinaemia affect offspring risk of overweight, type 2 diabetes and cardiovascular disease. Other hormones, like cortisol, adipokines and cytokines, produce their effects both centrally and in the periphery. Free fatty acids and other maternal metabolites have known effects on offspring growth and probably also have long-term effects. And finally, genetic pre-disposition, breastfeeding, lifestyle behaviour and many other risk-factors will strongly affect offspring risk, and probably also modulate the potential effects of intrauterine hyperglycaemia.
Are epigenetic factors involved?
Epigenetic changes may turn out to be the missing link between intrauterine hyperglycaemia, altered gene expression and altered phenotype in the progeny. It has been proposed that different intrauterine environmental factors e.g. intrauterine growth retardation, maternal smoking, stress and hyperglycaemia may produce very similar epigenetic changes.
Some of these epigenetic changes are stable, resulting in comparable phenotypic traits transferred through the maternal line irrespective of the primary intrauterine stimulus. However, these epigenetic changes may not only affect the index child – germ cell lines are also susceptible to persistent epigenetic changes thereby potentially enabling a trans-generational inheritance of environmental factors without changing the DNA sequence. Studies are needed to further elucidate whether exposure to GDM is associated with altered gene- and protein expression as well as changes in relation to epigenetic markers such as DNA-methylation, histone complex modifications and non coding RNA.
Summary and perspectives
Overall, there seems no doubt that gestational diabetes mellitus increases offspring risk of overweight, type 2 diabetes and cardiovascular disease. The pathogenic pathways leading up to this are only partly understood. This vicious cycle is likely to be enhanced by an increased prevalence of GDM in the next generation, but may also be accelerated by trans-generationally inherited epigenetic changes, which are induced by intrauterine hyperglycemia.
Whether GDM influences offspring cognitive function is still an open question.
Furthermore, it is not known whether intensified treatment during or after pregnancy has the potential to prevent adverse outcome in the offspring.
Future research should focus on pathogenetic mechanisms including gene expression and epigenetic changes, long-term follow-up of randomised controlled studies and finally animal intervention studies evaluating potential dose-dependent adverse effects of hyperglycaemia on offspring outcome, especially offspring cognitive function.
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