13th November 2022, Dr Chee L Khoo
Gestational diabetes mellitus (GDM) is one many factors that changes future generations. Maternal overnutrition, and excessive gestational weight gain with or without GDM lead to foetal overgrowth, and “programs” the offspring with an increased risk of obesity and type 2 diabetes mellitus (T2D) in childhood and adulthood. The aetiology of obesity and T2D is multifactorial and involves complex interactions between genetic, environmental and behavioural factors. Unhealthy lifestyle arising from the obesogenic environment plays a major role although there is evidence of an additional factor leading to increases in obesity and type 2 diabetes. This is the impact of the prenatal and early-life environment on long-term health via foetal programming. Managing GDM by ensuring pregnant women keep their glucose within a tight optimal range is no longer enough.
Interventions commenced during pregnancy have met with limited success in preventing adverse foetal programming effects. This could be because most interventions were instituted after the first trimester, where it may have been too late to have a positive impact on foetus programming.
Early-life environmental influences at sensitive periods of development lead to lifelong effects on health and chronic disease risk. There is evidence that exposure to an abnormal in-utero environment adversely affect the metabolic programming of the growing foetus, increasing the lifelong risk of chronic diseases including type 2 diabetes (1-5) This process is described as foetal programming. This is now recognized as a key factor contributing to the rapid rise in obesity and T2D rates worldwide. This is the only plausible reason why lifestyle changes alone may have difficulty over-riding these biological mechanisms.
Now, you can imagine that there is a complex interaction between genetic and the environmental influences in foetal programming but in animal studies, exposure to an adverse in utero environment associated with maternal overnutrition results in developmental programming of obesity and other disorders in offspring (6-9). Offsprings of over-nourished dams (mother rats) developed greater body weight and body fat compared to offspring of lean dams, even when both groups were fostered by lean dams after birth (7).
The prenatal environment in humans appears to be influenced by maternal body composition, metabolism, stress and diet from conception and throughout pregnancy. From the maturation of gametes (including sperm maturation) through to early embryonic development, parental lifestyle can adversely influence long-term risks of offspring metabolic, cardiovascular, immune, and neurological morbidities (10). Thus, prenatal paternal body composition also contributes to the prenatal environment.
The mechanistic pathways in foetal programming
We have gone beyond wondering whether the prenatal and antenatal environment affects foetal programming. While a complete understanding of the complex relationship between maternal genome, metabolome, and microbiome in foetal programming, studies in humans and animals are beginning to unravel the underlying biological mechanisms and metabolic pathways underpinning the obesogenic environment including the role of epigenetic modification. It is thought that the abnormal metabolic milieu leads to foetal DNA methylation. Indeed, neonatal methylation markers associated with birth weight have shown significant associations with the prenatal environment, as well as longitudinal associations with offspring size and/or adiposity in early childhood, providing evidence that developmental pathways to adiposity begin before birth and are influenced by environmental, genetic and epigenetic factors.
Disruption of the gut microbiome observed in maternal obesity, antibiotic use in pregnancy, delivery and early infancy, and caesarean section have also been implicated in increased childhood obesity risk.
Maternal Diabetes
Offspring of mothers with GDM have an increased risk of developing obesity, insulin resistance, T2D, hypertension and cardiovascular complications at a relatively young age (11). In the follow-up of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, 4160 children aged between 10-14 years, whose mothers had a 75-g oral glucose tolerance test at 28 wk of gestation demonstrated that exposure to higher maternal glucose spectrum levels in utero was significantly associated with childhood glucose levels and insulin resistance, independent of maternal and childhood BMI and family history of diabetes (12).
Maternal Overnutrition
It is not just maternal hyperglycaemia that affects the metabolic milieu. Lipid abnormalities (especially hypertriglyceridaemia), insulin resistance (which leads to hyperinsulinaemia), oxidative stress all contribute towards the abnormal metabolic milieu that the foetus is exposed to. Maternal obesity and/or excessive gestational weight gain causes increased adipose tissue secretion of inflammatory cytokines (including IL-6, TNF-alpha, leptin). This sets up the obesogenic and inflammatory cycle where maternal obesity leads to foetal obesity which continues into childhood and adulthood and lays the groundwork for the following generations.
The abnormal metabolic milieu leads to metabolic reprogramming of foetal biological and regulatory pathways (likely via DNA methylation) which further leads into adipo-insular axis dysregulation, impaired hypothalamic regulation of energy balance and pancreatic/skeletal muscle/liver abnormalities in nutrient sensing. Disruption of the adipo-insular axis leads to causing alterations in the central nervous system regulation of appetite, activity level, energy balance and in adipocyte metabolism. Further, maternal overnutrition leads to increase nutrient transfer to the foetus leading to foetal hyperinsulinaemia, foetal adiposity and excessive foetal growth. This is the main cause of large for gestational age which leads to the adverse foetal outcomes of increased caesarean rates and shoulder dystocia.
These children show increased weight for age and length, in comparison to offspring of normal weight women, as early as six months of age (13), and their risk of obesity is increased two-fold as preschoolers, even after controlling for birth weight and other confounding factors[36].
Maternal Undernutrition
You really can’t win. The relationship between maternal nutrition and foetal programming is in the shape of a J-curve. Too much is no good but there is now evidence that maternal undernutrition during critical periods of foetal development has been linked with foetal programming of central obesity, insulin resistance, metabolic syndrome and T2D in later life, especially when exposed to an energy-rich diet postnatally (see below later). According to the thrifty phenotype hypothesis, maternal undernutrition during critical periods leads to compensatory changes in the foetus, including tendency to store fat. The offspring is prepared for starvation but if there is a mismatch of postnatal nutrition (i.e. overfeeding), there is central obesity in later life.
Epigenetic influence during the prenatal and antenatal period from undernutrition lead to histone modifications in skeletal muscle that directly decrease GLUT-4 gene expression. GLUT-4 is the insulin regulated glucose transporter on the surface of adipose and skeletal tissues and beta cells which facilitate the diffusion of glucose into those cells. Reduction of GLUT-4 gene expression is a critical mechanism which leads to metabolic dysregulation of peripheral glucose transport and insulin resistance.
Foetal nutritional deficiency combined with the effects of maternal obesity, ageing and physical inactivity, are the most important factors in determining type 2 diabetes in those born with low birthweight. Further, specific maternal nutrient deficiencies during pregnancy, including low maternal protein consumption, and poor vitamin B and methionine status are also associated with an increased risk of metabolic derangements and T2D in later life in the offsprings. Prenatal stress, smoking, exposure to endocrine disruptors and maternal infection add insult to injury.
Paternal Influence
What about the health of the fathers? Epidemiological data suggest that father’s health conditions such as diabetes, and even grandfather’s nutritional status can program diseases in the offspring via germ cell-mediated transmission (14). Not unexpectedly, there must be epigenetic influences on spermatozoa development and maturation from the paternal metabolic milieu. High paternal BMI, smoking, over and under-nutrition induces foetal programming in offspring. In a recent presentation at the EASD, evidence was presented on the effect of paternal metformin use on the gender of the offspring. There is more work to be done in that sphere but suddenly, we have to think about other drugs the father might be on leading up to conception.
Post-natal influence – the first 1000 days
Postnatal factors from the time of birth to the second birthday of a child, could also contribute towards adverse programming increasing the risk of obesity and T2D in later life. There is emerging evidence that it is associated with altered neuro-endocrine programming and modified by breastfeeding duration and maternal pre-pregnancy overweight (15,16). Breastfeeding for greater than 40 wk has been associated with lower weight gain by 1 year, and longer duration of breastfeeding with lower odds of developing hypercholesterolemia, hypertension, obesity and type 2 diabetes in later life.
Naturally, social and environmental factors including poor nurturing practices and role modelling by parents, early introduction of highly processed high fat, high sugar snacks/meals and exposure to unhealthy food advertising, are early life factors associated with increased offspring obesity.
Solutions – are there any?
Obviously, a focus on primary prevention of obesity/type 2 diabetes targeting the first 1000-d of life[5] will be more beneficial and cost effective than treating the mother and offspring later in life. . The first 1000 days of life offers a unique and critical window of opportunity to shape long-term health at the population level, which can have a lasting effect on a country’s health and prosperity. So far, much of the evidence of the success in intervention to improve the prenatal and in utero environment of the foetus are from animal studies and their applicability to humans are not yet established.
Targeting the mother
Tight glycaemic control, appropriate weight gain and will help minimise adverse foetal programming of obesity and diabetes in the offspring. For women with both pre-existing and gestational diabetes, offspring outcomes can be optimized by ensuring appropriate gestational weight gain, and optimal glycaemic control via close monitoring of blood glucose levels, and appropriate medical and nutritional therapy and exercise, throughout the pregnancy (16).
In overweight/obese women, multicomponent interventions consisting of both diet and physical activity components have shown reduction in gestational weight gain, pregnancy-induced hypertension, macrosomia and neonatal respiratory distress syndrome. The LIMIT study in Australia reported that providing pregnant women who were overweight or obese with an antenatal dietary and lifestyle intervention also improved maternal diet and physical activity during pregnancy but did not alter 6-mo infant growth and adiposity, or childhood dietary intake, growth and adiposity at 3-5 years of age.
All is not lost. Studies comparing offspring pairs born to morbidly obese women conceived before and after substantial weight loss following bariatric surgery found that children conceived after surgery had a lower risk of macrosomia (birth weight > 4 kg) at birth, and continued to have better health outcomes in childhood and adolescence including a 50% lower risk of obesity, three-fold lower risk of severe obesity, and better insulin sensitivity and lipid profile, compared to their older siblings.
Antenatal exercise during pregnancy on offspring health appear to vary depending on exercise intensity and frequency, as well as its timing in relation to the period of gestation. Commencing exercise in early pregnancy appeared to stimulate feto-placental growth, and increase birth weight, while exercising in the second half of pregnancy appeared to reduce birth weight.
Preconception interventions?
Healthy lifestyle behaviours during the preconception period must be important to optimie maternal and child outcomes. However, there is a lack of international consensus guidelines on weight management preconception, and its impact on fertility, pregnancy and subsequent maternal and infant outcomes. Programmed changes to offspring health may be partially restored via diet/exercise interventions in obese fathers, prior to conception although most of the data comes from animal studies.
Interventions in offspring in infancy and childhood
Breastfeeding appears to protect against obesity in childhood. Longer duration of full breastfeeding and partial breastfeeding and delaying the introduction of complementary feeding could protect the offspring from obesity. Exclusive breastfeeding for 6 months or longer, and delaying the introduction of complementary feeding until 5th month of age, has been associated with a lower risk of overweight at 5-6 years of age.
Early antibiotic use before 2 years of age has been associated with disruption of the gut microbiota, and a higher risk of childhood overweight and obesity [98]. Recent evidence on the associations with gut microbiota and infant weight gain or child weight status, suggest that dietary manipulation with human milk and pre/probiotic formulations holds promise for preventing obesity.
Rapid weight gain in infancy also increases the long-term risk of obesity and type 2 diabetes in infants from both low-and high-income countries, among infants born preterm or at term, with normal or low birth weight for gestation.
In summary, maternal pre-pregnancy and early pregnancy metabolic milieu often set the scene for the future health of the offspring via foetal programming. Intervention trials where interventions are commenced during pregnancy have improved adverse maternal and foetal outcomes but have met with limited success in preventing adverse foetal programming effects. This could be because (1) most interventions were instituted after the first trimester, where it may have been too late to have a positive impact on foetus programming and (2) the preconception environment may be as important in foetal programming.
The GP has a very important role in encouraging a multi-pronged life-course approach to both maternal preconception and peripartum health as well as healthy lifestyle for the offspring.
References:
- Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med 2008; 359: 61-73
- Barker DJ. In utero programming of chronic disease. Clin Sci (Lond) 1998; 95: 115-128
- Barker DJ. The fetal and infant origins of adult disease. BMJ 1990; 301: 1111
- Oken E, Gillman MW. Fetal origins of obesity. Obes Res 2003; 11: 496-506
- Gluckman PD, Hanson M, Zimmet P, Forrester T. Losing the war against obesity: the need for a developmental perspective. Sci Transl Med 2011; 3: 93cm19
- Levin BE, Govek E. Gestational obesity accentuates obesity in obesity-prone progeny. Am J Physiol 1998; 275: R1374-R1379
- Shankar K, Harrell A, Liu X, Gilchrist JM, Ronis MJ, Badger TM. Maternal obesity at conception programs obesity in the offspring. Am J Physiol Regul Integr Comp Physiol 2008; 294: R528-R538
- Muhlhausler BS, Adam CL, Findlay PA, Duffield JA, McMillen IC. Increased maternal nutrition alters development of the appetite-regulating network in the brain. FASEB J 2006; 20: 1257-1259
- Friedman JE. Developmental Programming of Obesity and Diabetes in Mouse, Monkey, and Man in 2018: Where Are We Headed? Diabetes 2018; 67: 2137-2151
- Fleming TP, Watkins AJ, Velazquez MA, Mathers JC, Prentice AM, Stephenson J, Barker M, Saffery R, Yajnik CS, Eckert JJ, Hanson MA, Forrester T, Gluckman PD, Godfrey KM. Origins of lifetime health around the time of conception: causes and consequences. Lancet 2018; 391: 1842-1852
- Bianco ME, Josefson JL. Hyperglycemia During Pregnancy and Long-Term Offspring Outcomes. Curr Diab Rep 2019; 19: 143
- Scholtens DM, Kuang A, Lowe LP, Hamilton J, Lawrence JM, Lebenthal Y, Brickman WJ, Clayton P, Ma RC, McCance D, Tam WH, Catalano PM, Linder B, Dyer AR, Lowe WL Jr, Metzger BE; HAPO Follow-up Study Cooperative Research Group; HAPO Follow-Up Study Cooperative Research Group. Hyperglycemia and Adverse Pregnancy Outcome Followup Study (HAPO FUS): Maternal Glycemia and Childhood Glucose Metabolism. Diabetes Care 2019; 42: 381-392
- Deierlein AL, Siega-Riz AM, Adair LS, Herring AH. Effects of pre-pregnancy body mass index and gestational weight gain on infant anthropometric outcomes. J Pediatr 2011; 158: 221-226
- Li J, Tsuprykov O, Yang X, Hocher B. Paternal programming of offspring cardiometabolic diseases in later life. J Hypertens 2016; 34: 2111-2126
- Marseglia L, Manti S, D’Angelo G, Cuppari C, Salpietro V, Filippelli M, Trovato A, Gitto E, Salpietro C, Arrigo T. Obesity and breastfeeding: The strength of association. Women Birth 2015; 28: 81-86
- Mäkelä J, Vaarno J, Kaljonen A, Niinikoski H, Lagström H. Maternal overweight impacts infant feeding patterns—the STEPS Study. Eur J Clin Nutr 2014; 68: 43-49
- Seneviratne SN, Rajindrajith S. Fetal programming of obesity and type 2 diabetes. World J Diabetes. 2022 Jul 15;13(7):482-497. doi: 10.4239/wjd.v13.i7.482.