Maternal weight and gestational diabetes impacts on child health

Abstract

Purpose of review

To review recent evidence linking maternal body mass index and gestational diabetes with offspring health outcomes.

Recent findings

It is now established that the rising prevalences of maternal obesity and gestational diabetes are both making substantial contributions to the growing burden of childhood obesity and associated disorders. Strengthening evidence also links maternal obesity with increased offspring risks of cardiovascular disease, non-alcoholic fatty liver disease, lower respiratory tract infections during infancy, wheezing illnesses, asthma and attention deficit hyperactivity disorder during childhood, and with higher risks of psychiatric disorders and colorectal cancer in adulthood. Gestational diabetes has been associated with increased offspring risks of cardiovascular disease, childhood wheeze/asthma (but not allergic sensitization), and with high refractive error, attention deficit hyperactivity and psychiatric disorders from childhood onwards.

Summary

The long-term consequences of maternal obesity and gestational diabetes for the offspring in childhood and later adult life present major challenges for public health across the life course and for future generations. Tackling these challenges requires a systems-based approach to support achieving a healthy weight in young people prior to conception, alongside new insights into population based preventive measures against gestational diabetes.

Introduction

Rates of maternal obesity are increasing worldwide. This global increase in maternal obesity is of particular concern as obesity is associated with inflammation, hyperinsulinemia, insulin resistance and mitochondrial dysfunction, such that women with a high BMI during their reproductive years are more likely to be insulin resistant before conception. To facilitate glucose transfer to the developing fetus, metabolic adaptations during normal pregnancy increase insulin resistance, and many women are unable to maintain normal glycaemia during pregnancy as a consequence of combined insulin resistance and insufficient insulin secretion, resulting in the development of gestational diabetes (GDM). This is now reported in around 9-25% of pregnancies, depending on the population studied and definition applied [1,2]. Across ethnicities mothers with a higher body mass index are at greater risk of developing GDM [3], compared to their healthy weight counterparts. This is reflected in particularly high rates of GDM amongst women with a BMI ≥30kg/m² [4].

Maternal obesity and GDM are associated with a range of adverse pregnancy outcomes for the mother and infant [5,6]. In the mother herself, gestational obesity and GDM are both associated with increased risks of later type 2 diabetes and cardiovascular disease [7]. The high global prevalence of maternal obesity and GDM are increasingly recognised as a global health priority as substantial clinical [8] and experimental [9*] evidence indicate that both also have long-term implications for the offspring. As set out below, a growing body of evidence from epidemiological studies has unequivocally reported associations between high maternal weight and/or GDM and adverse childhood health outcomes.

Impact on childhood obesity and metabolic outcomes

Newborn infants born to women with a higher pre-pregnancy BMI are more likely to be macrosomic at birth and to have an increase in body fat percentage [10], with these associations extending into later infancy and childhood [11,12]. Thus, a meta-analysis of 37 cohorts, including 160,757 mother-child dyads, investigated the relationship between pre-pregnancy BMI and childhood overweight or obesity, concluding that maternal BMI ≥30kg/m² increased the risk of offspring obesity; odds ratios of childhood obesity in early, mid and late childhood were 2.43 [95% confidence interval (CI) 2.24, 2.64], 3.12 [2.98, 3.27] and 4.47 [3.99, 5.23] respectively [13]. The strongest effects were found at later ages in childhood. In studies where genotyping data is also available this suggests that the mother-offspring adiposity relationships more reflect environmental variation than genetic variation [14].

A strong relationship is also generally found between GDM in pregnancy and increased birthweight [15]. The mechanism thought to underlie this association is that maternal hyperglycaemia leads to hyperglycaemia in the fetus as glucose is freely transferred across the placenta by facilitated diffusion. This results in an increase in insulin secretion by the fetal pancreatic islet cells, and the increase in insulin stimulates fetal growth. There is preliminary evidence suggesting that, as in the animal models, maternal GDM is associated with offspring hypothalamic dysfunction, as evidenced by increased hypothalamic blood flow in response to a glucose challenge [16]; this may be one of the mechanisms predisposing the fetus to future risk of obesity. The combination of high maternal weight and GDM particularly contributes to the development of accelerated fetal growth and accumulation of adipose tissue, resulting in infants with higher birthweight that are classified as large for gestational age.

Increasing evidence suggests that effects of GDM on offspring adiposity persist into adolescence and beyond; offspring follow up at ages 10 and 17 years in the Colorado longitudinal Exploring Perinatal Outcomes among Children (EPOCH) study showed that, compared with unexposed participants, those exposed to maternal GDM had higher a BMI and greater visceral and subcutaneous adipose tissue measured by magnetic resonance imaging [17]. The magnitude of these differences was similar at both ages and the effect of prenatal GDM exposure was not explained by postnatal behaviours. Prenatal GDM exposure was also associated with higher total and LDL cholesterol in girls and with higher systolic blood pressure in boys [18*]. There is some evidence that maternal GDM may be associated with offspring overweight risk only in female infants [19].

In the Maternal Obesity Childhood Outcomes study follow-up of 160,757 mother-offspring pairs from 34 European or North American cohorts, gestational diabetes was associated with increased odds of overweight or obesity throughout early/mid-childhood and into adolescence; these associations were, however, attenuated after adjustment for maternal BMI, particularly for offspring overweight or obesity in adolescence [20]. A detailed study of a small South African cohort reported similar attenuation of GDM effects on offspring adiposity after adjusting for maternal BMI [21], but contrasting observations were made in a follow-up of 4,832 offspring aged 10-14 years of women who took part in the international study Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study; this found that maternal BMI and gestational glycemia were independently and additively associated with adiposity in early adolescence [22*]. In HAPO, combination of maternal obesity and GDM was associated with the highest odds of adiposity in adolescence as assessed by BMI, percent body fat, sum of skinfolds and waist circumference, with an odds ratio of adolescent overweight or obese of 3.55 [95% CI 2.49-5.05].

A nationwide Swedish case-control study of young people aged ≤25 years with biopsy-proven fatty liver found a strong association between maternal overweight and obesity and the risk of future non-alcoholic fatty liver disease in the offspring [23**]. The findings support those from experimental studies in rodents, with developmental effects on epigenetic processes proposed as a key underlying mechanism [24]. DNA methylation has also been proposed as a mechanism mediating lasting effects of higher maternal plasma glucose concentrations on adverse outcomes in the offspring. A recent study has provided clear evidence of GDM and dysglycemia associated methylation signatures in the cord blood of the infant, supporting involvement of epigenetic processes in holding the “memory” of an adverse intrauterine environment; interestingly, the dysglycemia associated methylation signatures appeared to be attenuated by a dietary and physical activity intervention during pregnancy [25**].

Cardiovascular outcomes

A study examining effects of maternal obesity on cardiovascular development in utero used magnetocardiography to non-invasively assess fetal heart activity, finding an increased fetal heart rate in those whose mothers had pre-pregnancy obesity or overweight, and reduced fetal heart rate variability in mothers with high maternal weight gain [26]. Systematic review of maternal obesity and metabolic disorders in relation to congenital heart defects in the offspring found that maternal obesity and GDM marginally increased the risk of congenital heart defects, with much weaker effects than pre-gestational diabetes and early-onset preeclampsia, with one study suggesting a possible additive effect of maternal obesity and gestational diabetes [27*].

In a population-based cohort study of the Swedish Medical Birth Register, the risk of offspring cardiovascular disease between ages 1 and 25 years was found to be higher with greater maternal obesity severity, with a hazard ration of 2·51 [95%CI 1·60–3·92] for those whose mothers had grade III obesity (≥40·0 kg/m²) in pregnancy [28*]. The majority of cardiovascular disease cases were due to cerebrovascular diseases, and rates of cerebrovascular diseases increased with maternal obesity severity.

The relation between GDM and offspring cardiovascular disease is less well studied. In a case control study from Tianjin, China, adjusting for maternal and children’s characteristics, children born to mothers with GDM during pregnancy had higher mean systolic blood pressure and higher prevalence of hypertension (6.4% vs. 3.5%) compared to children born to mothers without GDM during pregnancy [29]. A population based 40 year follow up study using the Danish national health registries found increased rates of cardiovascular disease in offspring following both pre-pregnancy type-1 and type-2 diabetes (1.34 [95%CI 1.25 to 1.43]) and GDM (1.19 [95%CI 1.07 to 1.32]). Cardiovascular diseases associated with maternal GDM included heart failure, hypertensive disease, deep vein thrombosis and pulmonary embolism [30*].

Infections and allergy

Maternal pre-pregnancy obesity has been identified as an independent risk factor for the development of lower respiratory tract infections during infancy in a low-income urban minority birth cohort [31]. A variety of mechanisms could underlie the association, including effects on immune and lung development and alterations in offspring microbiome acquisition [32].

Maternal obesity has also been associated with an increased risk of wheezing and asthma in children, alongside increasing data suggesting that in utero factors influence the development of allergic disease [33]. A meta-analysis of 22 observational studies involving 145,574 mother-child pairs has reported that both pre-pregnancy maternal obesity or overweight, and very to moderate high or low gestational weight gain are associated with increased risks of childhood asthma and wheeze in the children [34**]. A dose-dependent relation was noted between higher pre-pregnancy maternal weight and childhood asthma and wheeze, with nutritional and inflammatory/immunomodulatory effects proposed as potential mechanisms underlying the associations [34**]. Additionally, a cross-sectional study of 8,877 children in the Shanghai Children Allergy Study found increased risks of asthma and/or wheezing, allergic rhinitis, eczema, and food and/or drug allergy following excessive gestational weight gain, notably when this occurred in the context of maternal pre-pregnancy overweight or obesity [35*].

Among 19,933 Canadian children followed up around age 4 years in the National Longitudinal Survey of Children and Youth (NLSCY), 5.9% had mothers with GDM. Adjusting for potential confounders, the adjusted hazard ratio for incident asthma in offspring whose mothers had had GDM was 1.25 [95% CI 1.03, 1.51][36]. An association between GDM an increased risk of asthma and wheeze outcomes at age 4 years was also found in a racially diverse US cohort, with increased adjusted risk ratios of physician-diagnosed asthma (2.13 [1.35, 3.38]), current wheeze (1.85 [1.23, 2.78]) and current asthma (2.01 (1.30, 3.10)) [37*]. A retrospective cohort study followed up at age 6 - 9 years 97,554 singletons born in Kaiser Permanente Southern California (KPSC) hospitals; an increased risk of childhood asthma was predominately observed after prenatal exposure to maternal pre-existing T2D, with a small risk for those mothers had GDM requiring medication, and no increased risk for GDM not requiring medication during pregnancy, compared with no diabetes during pregnancy [38]. A meta-analysis of eight published studies examining the association between any type of diabetes in pregnancy and allergic outcomes suggested increased odds ratios for childhood asthma (1.13 [1.01-1.27]), wheezing (1.13 [1.07-1.21]), and atopic dermatitis (1.43 [1.22-1.57]); subgroup analysis suggested similar findings for GDM and pre-gestational diabetes. Maternal diabetes was not, however, found to be associated with the risk of allergic sensitization [39*].

Neuro-behavioural disorders

In an analysis of 2 European cohorts, greater gestational weight gain was associated with higher problem behaviours in school age children assessed using the Child Behaviour Checklist, with this association seen only mother-offspring dyads where the mother had been overweight or obese pre-pregnancy. Children born to women with pre-pregnancy overweight/obesity who gained 0.5 kg or more weekly during pregnancy showed higher scores in total problems, internalizing behaviours and externalizing behaviours [40*]. This provides further evidence that particular attention should be directed at avoiding excessive weight gain in women with pre-pregnancy overweight or obesity.

A recent review has highlighted that women with obesity are more vulnerable to develop depressive symptoms during pregnancy and/or in the postpartum period than normal weight pregnant women; maternal mood has itself been associated with neurobehavioural impacts on the child, making it challenging to disentangle specific effects of maternal obesity vs mood [41*]. Nonetheless, there is an extensive literature showing that maternal obesity during pregnancy is associated with the offspring’s risk of developing attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, and schizophrenia [41*]. Maternal obesity now recognised as an inflammatory disorder, and maternal immune activation associated with maternal obesity is now being implicated in long-term offspring neurobehavioural outcomes [42]. Additionally, the young adult offspring of mothers with a high body mass index have been found to have lower cortisol levels, especially in the morning, suggesting a possible lasting effect of maternal obesity on offspring hypothalamic pituitary adrenal axis activity [43].

In a community cross-sectional study based on 66 Spanish schools, children whose mothers had had GDM had an increased risk childhood ADHD independent of other risk factors, while high maternal weight gain was associated with sub-clinical ADHD [44]. These findings are in line with previous studies but the mechanisms remain to be defined. In a population-based cohort study of 2.4 million births in Denmark 1978 to 2016, offspring born to mothers with pre-gestational diabetes or GDM during pregnancy were more likely to receive a diagnosis of a psychiatric disorder during the first 40 years of life [45*]. Maternal GDM was associated with elevated rates of specific psychiatric disorders, namely schizophrenia, anxiety disorders, intellectual disabilities, developmental disorders and behavioural disorders, but not with mood, substance use or eating disorders. The higher rates of anxiety disorders, intellectual disabilities, developmental disorders and behavioural disorders in GDM exposed offspring were seen from childhood onwards [45*].

Examination of the combined effects of maternal obesity and different types of diabetes has been undertaken in population-based cohort analyses from nationwide registries in Finland encompassing all 649 043 live births from 2004-2014. Severe obesity in mothers with diabetes was associated with an increased overall risk for psychiatric disorders in their offspring up to age 11 years. The risk was highest for those exposed to insulin-treated pre-gestational diabetes, followed by non-insulin-treated type 2 diabetes and gestational diabetes [46*].

Other health impacts

During up to 25 years of follow up using the Danish national health registries, maternal diabetes during pregnancy was found to be associated with an increased risk of high refractive error, with elevated risks observed for hypermetropia, myopia and astigmatism [47*]. Estimated risks for high refractive error in the offspring were similar for exposure to pre-gestational diabetes and GDM, and across under 3, 4–15 and 16–25 year age bands. The underlying mechanisms are not known, but might include maternal diabetes-induced intrauterine ocular impairment or subnormal development of refractive accommodation.

Population-based cohort studies with data linkage are now enabling examination of potential wider effects of maternal obesity into adulthood. In a study of more than 18,000 mother–child dyads, maternal obesity increased the risk of colorectal cancer in offspring in later adulthood [48**]. Mechanisms that have been proposed to underlie this association include the establishment during development of obesogenic growth patterns that lead to adult obesity, and prenatal epigenetic programming of the sensitivity of fetal gastrointestinal tissue to later life impacts.

Conclusion

Obesity is pregnancy is arguably one of the biggest challenges for global public health and for future generations. For mothers, it acutely has significant impacts on their reproductive health, including complications in pregnancy and labour, alongside playing an increasingly recognised role in cardiometabolic, respiratory, allergic and neurodevelopmental outcomes in the child. Likewise, maternal GDM is increasingly prevalent and has long-term consequences for the offspring in childhood and later adult life. Tackling these challenges requires a systems-based approach to support achieving a healthy weight in young people prior to conception, alongside new insights into population based preventive measures against GDM.

Key points:

• The high and rising prevalences of maternal obesity and gestational diabetes are contributing substantially to the worsening burden of childhood obesity and associated disorders.

• Maternal obesity is also linked with increased offspring risks of cardiovascular disease, non-alcoholic fatty liver disease, lower respiratory tract infections during infancy, wheezing illnesses, asthma and attention deficit hyperactivity disorder during childhood, and with psychiatric disorders and colorectal cancer in adulthood.

• Gestational diabetes is associated with increased offspring risks of cardiovascular disease, childhood wheeze/asthma, and with high refractive error, attention deficit hyperactivity and psychiatric disorders from childhood onwards.

• The long-term consequences of maternal obesity and gestational diabetes for the offspring present major challenges for public health across the life course and for future generations.

• Tackling these challenges requires a systems-based approach to support achieving a healthy weight prior to conception, alongside new insights into measures to prevent gestational diabetes.