Maternal Lifestyle Interventions: Targeting Preconception Health

Abstract

Up to one-third of women of reproductive age are obese, predisposing their offspring to cardiometabolic diseases and initiating an intergenerational cycle of chronic metabolic disorders.Epigenetic modifications in foetal tissue play a mechanistic role in metabolic disease programming through interaction of the pregnancy environment with gene function.Primary lifestyle interventions (i.e.,diet and exercise) to improve maternal health are typically initiated in the second trimester, conferring limited benefits for mother and child.Diet–exercise interventions should commence preconception.Alternative approaches to current guidelines are urgently required to improve adherence and break the intergenerational cycle of inherited and epigenetic abnormalities of metabolism. About one-third of women of reproductive age are obese, predisposing both mother and baby to unfavourable pregnancy outcomes and initiating an intergenerational cycle of chronic metabolic disorders. Here we summarise recent research on the influence of maternal metabolic health on offspring susceptibility to future cardiometabolic diseases. Current primary lifestyle approaches (i.e., diet and exercise interventions) to halt the succession of inherited and epigenetic metabolic abnormalities have met with limited success due to late implementation, poor adherence, and/or generic guidelines. In our opinion, such interventions must commence prior to conception to improve both maternal and child health outcomes, with new approaches urgently needed to increase adherence to primary lifestyle changes among reproductive-age women. About one-third of women of reproductive age are obese, predisposing both mother and baby to unfavourable pregnancy outcomes and initiating an intergenerational cycle of chronic metabolic disorders. Here we summarise recent research on the influence of maternal metabolic health on offspring susceptibility to future cardiometabolic diseases. Current primary lifestyle approaches (i.e., diet and exercise interventions) to halt the succession of inherited and epigenetic metabolic abnormalities have met with limited success due to late implementation, poor adherence, and/or generic guidelines. In our opinion, such interventions must commence prior to conception to improve both maternal and child health outcomes, with new approaches urgently needed to increase adherence to primary lifestyle changes among reproductive-age women. Obesity and type 2 diabetes mellitus (T2D) are the biggest epidemics in human history [1.Zimmet P.Z. Diabetes and its drivers: the largest epidemic in human history?.Clin. Diabetes Endocrinol. 2017; 3: 1Crossref PubMed Scopus (121) Google Scholar] and the major challenge to health-care systems worldwide in the 21st century. Compared with 20 years ago, twice as many people are diagnosed with T2D, and the rapid increase in obesity and T2D among children, adolescents, and young adults predisposes future generations to increased risk for numerous chronic diseases [2.Zimmet P.Z. et al.Diabetes: a 21st century challenge.Lancet Diabetes Endocrinol. 2014; 2: 56-64Abstract Full Text Full Text PDF PubMed Scopus (431) Google Scholar]. Obesity is the result of complex interactions between genetic, environmental, and socioeconomic influences. While family history is a strong determinant for both obesity and T2D, genome-wide estimates suggest that only ~20% of obesity and T2D risk is attributable to fixed genomic variation [3.Locke A.E. et al.Genetic studies of body mass index yield new insights for obesity biology.Nature. 2015; 518: 197-206Crossref PubMed Scopus (2134) Google Scholar,4.Mahajan A. et al.Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps.Nat. Genet. 2018; 50: 1505-1513Crossref PubMed Scopus (405) Google Scholar], leaving a large part of heritability unexplained. Behavioural and environmental factors influence patterns of gene expression via gene–environment interactions and epigenetic modifications (see Glossary) and provide a molecular basis for the ‘missing’ heritability associated with the elevated risk for obesity and T2D [5.Barres R. Zierath J.R. The role of diet and exercise in the transgenerational epigenetic landscape of T2DM.Nat. Rev. Endocrinol. 2016; 12: 441-451Crossref PubMed Scopus (94) Google Scholar]. In support of this premise, robust associations exist between susceptibility to life-long obesity, impaired glucose tolerance (IGT), and T2D in offspring and epigenetic modifications, confirming that metabolic dysfunction is transmitted across generations [6.Jaeger K. et al.Transmission of metabolic dysfunction across generations.Physiology (Bethesda). 2017; 32: 51-59Crossref PubMed Scopus (17) Google Scholar]. The importance of early human embryonic and foetal life for later increased risk of metabolic disturbances is captured in the Developmental Origins of Health and Disease (DOHaD) hypothesis [7.Gluckman P.D. et al.A conceptual framework for the developmental origins of health and disease.J. Dev. Orig. Health Dis. 2010; 1: 6-18Crossref PubMed Scopus (188) Google Scholar]. Maternal lifestyle prior to and during pregnancy is, therefore, of paramount importance for the epigenetic mapping of the offspring [5.Barres R. Zierath J.R. The role of diet and exercise in the transgenerational epigenetic landscape of T2DM.Nat. Rev. Endocrinol. 2016; 12: 441-451Crossref PubMed Scopus (94) Google Scholar] and underpins the intergenerational cycle of obesity, insulin resistance, and associated disorders (Figure 1). Maternal overweight and obesity are associated with a substantially higher risk of gestational diabetes mellitus (GDM) [8.Chu S.Y. et al.Maternal obesity and risk of gestational diabetes mellitus.Diabetes Care. 2007; 30: 2070-2076Crossref PubMed Scopus (616) Google Scholar]. Both environmental factors and genetics contribute to the development of GDM, with up to 14% of live births negatively impacted by this condition [9.Ogurtsova K. et al.IDF Diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040.Diabetes Res. Clin. Pract. 2017; 128: 40-50Abstract Full Text Full Text PDF PubMed Scopus (1645) Google Scholar]. Both maternal obesity and GDM are independently associated with adverse pregnancy outcomes and their combination has a greater impact than either one alone [10.Catalano P.M. et al.The hyperglycemia and adverse pregnancy outcome study: associations of GDM and obesity with pregnancy outcomes.Diabetes Care. 2012; 35: 780-786Crossref PubMed Scopus (549) Google Scholar]. Maternal glucose intolerance in GDM results from peripheral insulin resistance and the failure of β-cell compensation and maternal insulin production to cope with the prevailing hyperglycaemia. Maternal glucose crosses the maternoembryonic interface, but insulin does not, leading to foetal hyperglycaemia, hyperinsulinaemia, and a vicious cycle of low-grade inflammation. Offspring exposed to untreated GDMin utero are insulin resistant with limited β-cell compensation compared with offspring of mothers with normal glycaemia during pregnancy [11.Lowe Jr., W.L. et al.Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study (HAPO FUS): maternal gestational diabetes mellitus and childhood glucose metabolism.Diabetes Care. 2019; 42: 372-380Crossref PubMed Scopus (118) Google Scholar]. GDM is independently associated with childhood IGT [11.Lowe Jr., W.L. et al.Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study (HAPO FUS): maternal gestational diabetes mellitus and childhood glucose metabolism.Diabetes Care. 2019; 42: 372-380Crossref PubMed Scopus (118) Google Scholar] and exposure to hyperglycaemia in utero is strongly related to childhood adiposity, including overweight/obesity, increased skinfold thickness and body fat, and greater waist circumference [12.Lowe Jr., W.L. et al.Maternal glucose levels during pregnancy and childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study.Diabetologia. 2019; 62: 598-610Crossref PubMed Scopus (56) Google Scholar]. Even glucose concentrations lower than those diagnostic of GDM are associated with increased birth weight and elevated levels of cord-bloodC-peptide (reflective of the insulin-secretory activity of pancreatic β-cells, which modulates foetal growth), greater childhood adiposity, and elevated blood pressure, independent of maternal body mass index (BMI) [12.Lowe Jr., W.L. et al.Maternal glucose levels during pregnancy and childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study.Diabetologia. 2019; 62: 598-610Crossref PubMed Scopus (56) Google Scholar, 13.Grunnet L.G. et al.Adiposity, dysmetabolic traits, and earlier onset of female puberty in adolescent offspring of women with gestational diabetes mellitus: a clinical study within the Danish National Birth Cohort.Diabetes Care. 2017; 40: 1746-1755Crossref PubMed Scopus (44) Google Scholar, 14.Tam W.H. et al.In utero exposure to maternal hyperglycemia increases childhood cardiometabolic risk in offspring.Diabetes Care. 2017; 40: 679-686Crossref PubMed Scopus (125) Google Scholar]. Foetal exposure to maternal GDM programmes future risk of obesity, IGT, T2D, and cardiovascular disease [11.Lowe Jr., W.L. et al.Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study (HAPO FUS): maternal gestational diabetes mellitus and childhood glucose metabolism.Diabetes Care. 2019; 42: 372-380Crossref PubMed Scopus (118) Google Scholar, 12.Lowe Jr., W.L. et al.Maternal glucose levels during pregnancy and childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study.Diabetologia. 2019; 62: 598-610Crossref PubMed Scopus (56) Google Scholar, 13.Grunnet L.G. et al.Adiposity, dysmetabolic traits, and earlier onset of female puberty in adolescent offspring of women with gestational diabetes mellitus: a clinical study within the Danish National Birth Cohort.Diabetes Care. 2017; 40: 1746-1755Crossref PubMed Scopus (44) Google Scholar, 14.Tam W.H. et al.In utero exposure to maternal hyperglycemia increases childhood cardiometabolic risk in offspring.Diabetes Care. 2017; 40: 679-686Crossref PubMed Scopus (125) Google Scholar, 15.Reynolds R.M. et al.Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring: follow-up of 1 323 275 person years.BMJ. 2013; 347: f4539Crossref PubMed Scopus (290) Google Scholar, 16.Lowe Jr., W.L. et al.Association of gestational diabetes with maternal disorders of glucose metabolism and childhood adiposity.JAMA. 2018; 320: 1005-1016Crossref PubMed Scopus (159) Google Scholar]. Thus, epigenetic modifications in foetal tissue play a mechanistic role in metabolic disease programming through the interaction of the pregnancy environment with gene function. Such epigenetic modifications can occur via DNA methylation, histone modification, and/or alterations to noncoding RNAs. Evidence supporting a role for hyperglycaemia-induced changes in the pattern of DNA methylation comes from studies of maternal and offspring cord blood. Kang et al. [17.Kang J. et al.Genome-wideDNA methylation variation in maternal and cord blood of gestational diabetes population.Diabetes Res. Clin. Pract. 2017; 132: 127-136Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar] collected maternal andcord blood samples from 16 pregnant women and their newborns, including eight exposed to GDM. 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Endocrinol. 2017; PubMed Scopus Google Scholar]. we have limited the clinical of as studies have limited by and for The of histone many with of histone an in the of metabolic diseases and foetal of the impact of maternal obesity and GDM on histone are and this is a for future are of the impact of GDM on noncoding and their gene et in epigenetic modifications and gestational a of J. Endocrinol. 2017; PubMed Scopus Google Scholar]. et al. et maternal expression in early pregnancy to gestational diabetes J. 2015; PubMed Scopus Google Scholar] the expression of in mothers with GDM and and that with the of associated with insulin resistance and poor pregnancy outcomes (i.e., and study on from women with either GDM GDM by and from expression of and glucose metabolism et and glucose metabolism in the with gestational diabetes mellitus: role of 2016; PubMed Scopus Google Scholar]. 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