Immediate, short-, and long-term impact
Umberto Simeoni and Elie Saliba
Introduction
Increasing numbers of infants are surviving after preterm birth, fetal growth restriction (FGR), perinatal infection-inflammation, and exposure to maternal hyperglycemia (HIP) or obesity-overweight in pregnancy. Outcomes of the offspring of diabetic mothers have improved thanks to the early detection of HIP allowed by widely followed guidelines, systematic screening, and better control of maternal glycemia, although major preventative and therapeutic efforts are still needed in low- and low-middle-income countries (1). Short- and medium-term outcomes after extreme preterm birth are improving, as shown by major population studies comparing time periods (2), while a proactive management of extreme preterm birth brings clearly promising results in Sweden (3). FGR is becoming less frequent at term in rich countries, thanks to screening during pregnancy by periodic ultrasounds, while it is frequently met as a complication of preterm birth, affecting approximately 30% of very preterm births (below 32 weeks of gestation). In low-income countries, low birth weight remains a major factor associated with high neonatal mortality rates. However, the steady increase in global population and number of births, and the increasing number of survivors are leading to an increasing prevalence of pregnancy complications, which in turn induce specific needs for the short- and long-term follow-up of the infants, as they may suffer altered neurocognitive, sensorial, and behavioral development, as well as an increased risk for chronic, noncommunicable diseases (NCDs), such as hypertension or type 2 diabetes as they reach adulthood. While much work still needs to be done to understand the early determinants of pregnancy complications, the limits reached by current, poorly customized approaches and the development of innovative, precision strategies based on systems biology, multiomics, and information technology, such as patient-generated data relating to their lifestyle and environment, open the way to innovative, preventative, or early interventional approaches.
Precision medicine approaches to improve health outcomes
While each of us is biologically unique, the currently prevailing paradigm in healthcare is to apply the same measures to all for disease prevention, diagnosis, and treatment. Next to our genetic makeup, our environment and lifestyle are also unique, continuously evolving while exerting a great influence on our health status. This is especially intuitive for chronic NCDs such as diabetes and cardiovascular disorders, which are major causes for premature mortality and burdens of disease, rising to epidemical proportions throughout the world. The increasing global prevalence and trends of overweight and obesity among preschool children are accordingly highly worrying. Prevention and personal health monitoring can be very effective in the battle against these insidious but debilitating diseases, since lifestyle factors such as nutrition, physical activity, as well as stress and sleep patterns can be adjusted individually to accommodate predefined genetic and acquired biological predispositions.
Investing in the health of children and their mothers, before and after birth, is key for the promotion of population health, well-being, and disease prevention lifelong. Early prevention and life course approaches show the highest health economic benefits. Compelling evidence shows that NCDs share early origins in the programming effect of developmental interactions between genes and environment. During the key window of sensitivity constituted by pregnancy, especially the period around conception, and infancy (the first 1000 days), environmental stimuli determine lifelong, lasting, transgenerationally heritable effects, due to epigenetic imprinting and other factors such as the microbiome. Clinical trials testing lifestyle interventions have shown that lifestyle, in particular, nutrition and physical activity of future parents, of pregnant women, and of infants can be modified. However, these same trials suggest that the benefits are not equally distributed between participants and that a personalization of interventions would considerably improve outcomes.
Advances in systems biology and information technology are allowing access to new emerging data such as personal “-omics” approaches and self-generated participatory patient data, of which an optimized integration through machine learning technologies could facilitate personalized monitoring and coaching of behaviors. Great obstetrical syndromes, such as gestational diabetes, preeclampsia, preterm labor, intrauterine growth restriction, and inflammation, are known not only to induce short-term morbidity and mortality, but also as extreme causes of altered developmental programming in the offspring. Moreover, gestational diabetes and preeclampsia are associated with a consistent risk for later type 2 diabetes or hypertension in the mother. A systems approach to pregnancy would allow identification of precision patterns of the effects of the environment on uncomplicated pregnancy and of the transition toward pregnancy and/or early, surrogate markers of later health or risk for chronic disease. For such personalized, systems-level approaches, large amounts of data need to be generated and also processed, integrated, and shared under precise and acceptable rules. This, in turn, poses a major, new challenge in transitioning to the era of precision medicine.
Risk for chronic diseases at adulthood as long-term complications in offspring exposed to great obstetrical syndromes
Major advances during the last decades in systems biology and information technology open an extraordinary opportunity to make the prevailing paradigm of medicine, based on a one-size-fits-all approach, evolve into precision and individualized diagnosis, treatment, and prevention. A consistent link has been identified by epidemiologic and animal studies between the risk for NCDs at adulthood, such as cardiovascular and metabolic diseases (4), and genes-environment interactions during pregnancy and infancy. In addition to the genome, nutrition, lifestyle factors, and perinatal complications play major roles in lifelong health, as well in healthy pregnancy and birth (Figure 10.1).
Figure 10.1 Concept of early predisposition to chronic disease at adulthood involves early environment, including exposure to perinatal complications and the great obstetrical syndromes.
Both NCDs and pregnancy/early infancy are major global health challenges and induce unacceptable high mortality rates and high costs, while lifestyle factors can at least be modified. Prevention and personal health monitoring can be very effective in the battle against these diseases, since lifestyle factors such as nutrition, physical activity, as well as stress and sleep patterns can be adjusted individually to accommodate predefined genetic and acquired biological predispositions.
Pregnancy is associated with normal physiological changes in order to nurture and accommodate the developing fetus, as well as to prepare for delivery. For most women experiencing an uncomplicated pregnancy, these changes resolve after pregnancy with minimal residual effects (5). It is important to understand the normal physiological changes occurring in pregnancy as this will help differentiate from adaptations that are abnormal and manage common medical problems of pregnancy, such as hypertension, gestational diabetes, anemia, and hyperthyroidism.
In addition to baseline genetic diversity, the physiologic changes of pregnancy can accentuate interindividual differences in susceptibility to medication (6). Unfortunately, many physicians stop or delay medically important agents because of the lack of information. The unique characteristics of mother and infant should be assessed for improved health outcomes through lifestyle modifications and/or adapted therapy. Physiological changes occurring during pregnancy can lead to serious medical problems described as the “great obstetrical syndromes,” including overweight, gestational diabetes/hyperglycemia in pregnancy (GDM/HIP), preeclampsia, fetal growth restriction, and threatening preterm birth and perinatal inflammation are responsible for increased maternal and perinatal mortality and morbidity. Due to their high prevalence, preeclampsia (up to 8%) and GDM/HIP (up to 18%) are major complications of gestation. GDM/HIP is widely associated with maternal overweight-obesity and in the long term induces increased risk of type 2 diabetes, hypertension, and other NCDs in both the mother and the infant (7), perpetuating a vicious circle. In addition, maternal preconceptional metabolic status and obesity increase the risk of infertility (8,9
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