Over the past quarter century, the scientific community has gained a new perspective on the origins of chronic disease, which now includes a central role for the placenta. It began when the team of Barker et al1Barker D.J. Osmond C. Golding J. Kuh D. Wadsworth M.E. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease.BMJ. 1989; 298: 564-567Crossref PubMed Scopus (1856) Google Scholar reported an inverse relationship between death risk from cardiovascular disease and birthweight among English men and women. They found that term babies born at the 5 pound end of the birthweight scale had a 3–5 times greater risk for cardiovascular disease compared with babies born at the 9 pound end. Later it was discovered that there is an increasing risk for disease in term babies as their weights exceed the 9 pound birthweight at the high end of the birthweight scale.2Plagemann A. Harder T. Dudenhausen J.W. The diabetic pregnancy, macrosomia, and perinatal nutritional programming.Nestle Nutr Workshop Ser Pediatr Program. 2008; 61: 91-102Crossref PubMed Scopus (28) Google Scholar, 3Oken E. Gillman M.W. Fetal origins of obesity.Obes Res. 2003; 11: 496-506Crossref PubMed Scopus (687) Google Scholar, 4Wei J.N. Sung F.C. Li C.Y. et al.Low birth weight and high birth weight infants are both at an increased risk to have type 2 diabetes among schoolchildren in taiwan.Diabetes Care. 2003; 26: 343-348Crossref PubMed Scopus (217) Google Scholar The discovery of the relationship between birthweight and later chronic disease stimulated extensive research among scientists worldwide and brought to light a new level of understanding regarding life-long health in offspring.5Gluckman P.D. Hanson M.A. Cooper C. Thornburg K.L. Effect of in utero and early-life conditions on adult health and disease.N Engl J Med. 2008; 359: 61-73Crossref PubMed Scopus (2690) Google Scholar, 6Seckl J.R. Holmes M.C. Mechanisms of disease: glucocorticoids, their placental metabolism and fetal 'programming' of adult pathophysiology.Nat Clin Pract Endocrinol Metab. 2007; 3: 479-488Crossref PubMed Scopus (548) Google Scholar, 7Myatt L. Placental adaptive responses and fetal programming.J Physiol. 2006; 572: 25-30Crossref PubMed Scopus (402) Google Scholar, 8Godfrey K.M. The role of the placenta in fetal programming-a review.Placenta. 2002; 23: S20-S27Abstract Full Text PDF PubMed Scopus (236) Google Scholar, 9McMillen I.C. Robinson J.S. Developmental origins of the metabolic syndrome: prediction, plasticity, and programming.Physiol Rev. 2005; 85: 571-633Crossref PubMed Scopus (1513) Google Scholar, 10de Rooij SR, van Pelt AM, Ozanne SE, et al. Prenatal undernutrition and leukocyte telomere length in late adulthood: the Dutch famine birth cohort study. Am J Clin Nutr, in press.Google Scholar The mechanism by which compromised development leads to adult onset disease is called programming. It was the unexpected trends in public health that brought a new urgency to the concept of programming in the United States. Beginning in the mid-1990s, the prevalence of obesity and type 2 diabetes began to rise in the Western world in a dramatic way (http://www.cdc.gov/diabetes/statistics/prev/national/figpersons.htm). The upsurge in these 2 interrelated conditions, plus the ever-increasing numbers of people who have uncontrolled blood pressure,11Chobanian A.V. Shattuck Lecture. The hypertension paradox—more uncontrolled disease despite improved therapy.N Engl J Med. 2009; 361: 878-887Crossref PubMed Scopus (310) Google Scholar led medical scientists to predict that the current generation of young people in the United States are likely to live shorter lives than will their parents.12Olshansky S.J. Passaro D.J. Hershow R.C. et al.A potential decline in life expectancy in the United States in the 21st century.N Engl J Med. 2005; 352: 1138-1145Crossref PubMed Scopus (2027) Google Scholar The links between increasing prevalence of diseases like diabetes and heart disease and early life development are powerful and exist across mammalian species. Figure 1 shows the relationship between type 2 diabetes or insulin resistance and birthweight in which there is an 8-fold risk for diabetes across the birthweight scale. The relationship between birthweight and disease risk was so clear cut that Barker et al13Barker D.J.P. Eriksson J.G. Forsen T. Osmond C. Fetal origins of adult disease: strength of effects and biological basis.Int J Epidemiol. 2002; 2002: 1235-1239Crossref Scopus (1413) Google Scholar estimated that diabetes would be reduced by some 60% in one generation if babies were born at the lowest risk birthweight and did not cross body mass index (BMI) centiles in childhood. Much of what we understand about placental function has been discovered in animal models. The field of developmental origins of disease has gained enormous insight into the biological mechanisms that underlie developmental plasticity from animal studies. Langley-Evans et al14Langley-Evans S.C. Phillips G.J. Jackson A.A. In utero exposure to maternal low protein diets induces hypertension in weanling rats, independently of maternal blood pressure changes.Clin Nutr. 1994; 13: 319-324Abstract Full Text PDF PubMed Scopus (150) Google Scholar were among the first to demonstrate that rat pups born to dams eating a low-protein diet during pregnancy had high blood pressure as adults. Dozens of additional studies using different animal models have revealed the central role of the placenta.5Gluckman P.D. Hanson M.A. Cooper C. Thornburg K.L. Effect of in utero and early-life conditions on adult health and disease.N Engl J Med. 2008; 359: 61-73Crossref PubMed Scopus (2690) Google Scholar, 9McMillen I.C. Robinson J.S. Developmental origins of the metabolic syndrome: prediction, plasticity, and programming.Physiol Rev. 2005; 85: 571-633Crossref PubMed Scopus (1513) Google Scholar, 15Jansson T. Powell T.L. Role of placental nutrient sensing in developmental programming.Clin Obstet Gynecol. 2013; 56: 591-601Crossref PubMed Scopus (106) Google Scholar, 16Chen M. Zhang L. Epigenetic mechanisms in developmental programming of adult disease.Drug Discov Today. 2011; 16: 1007-1018Crossref PubMed Scopus (82) Google Scholar, 17Reynolds L.P. Borowicz P.P. Vonnahme K.A. et al.Placental angiogenesis in sheep models of compromised pregnancy.J Physiol. 2005; 565: 43-58Crossref PubMed Scopus (115) Google Scholar, 18Zhang L. Long N.M. Hein S.M. Ma Y. Nathanielsz P.W. Ford S.P. Maternal obesity in ewes results in reduced fetal pancreatic beta-cell numbers in late gestation and decreased circulating insulin concentration at term.Domest Anim Endocrinol. 2011; 40: 30-39Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Under adverse conditions, like poor maternal nutrition or periods of chronic hypoxia, or high levels of thyroid hormone or glucocorticoids, the fetus suffers alterations in fetal organ structures including reduced coronary arterial dimensions,19Jiang B. Godfrey K.M. Martyn C.N. Gale C.R. Birth weight and cardiac structure in children.Pediatrics. 2006; 117: e257-e261Crossref PubMed Scopus (55) Google Scholar low arterial elastin,20Martyn C.N. Greenwald S.E. A hypothesis about a mechanism for the programming of blood pressure and vascular disease in early life.Clin Exp Pharmacol Physiol. 2001; 28: 948-951Crossref PubMed Scopus (66) Google Scholar, 21Dodson R.B. Rozance P.J. Fleenor B.S. et al.Increased arterial stiffness and extracellular matrix reorganization in intrauterine growth-restricted fetal sheep.Pediatr Res. 2013; 73: 147-154Crossref PubMed Scopus (45) Google Scholar reduced endowment of beta cells in the pancreas,22Dumortier O. Blondeau B. Duvillie B. Reusens B. Breant B. Remacle C. Different mechanisms operating during different critical time-windows reduce rat fetal beta cell mass due to a maternal low-protein or low-energy diet.Diabetologia. 2007; 50: 2495-2503Crossref PubMed Scopus (88) Google Scholar decreased numbers of nephrons in the kidney23Woods L.L. Weeks D.A. Rasch R. Programming of adult blood pressure by maternal protein restriction: role of nephrogenesis.Kidney Int. 2004; 65: 1339-1348Crossref PubMed Scopus (303) Google Scholar, 24Luyckx V.A. Brenner B.M. Birth weight, malnutrition and kidney-associated outcomes-a global concern.Nat Rev Nephrol. 2015; 11: 135-149Crossref PubMed Scopus (185) Google Scholar and changes in brain structure and function.25Buss C. Entringer S. Wadhwa P.D. Fetal programming of brain development: intrauterine stress and susceptibility to psychopathology.Sci Signal. 2012; 5: pt7Crossref PubMed Scopus (95) Google Scholar The result is increased appetite, decreased cognitive function, endothelial dysfunction, and compromised antioxidant protection systems as well as dyslipidemias.26Thornburg KL. The programming of cardiovascular disease. J Dev Orig Health Dis, in press.Google Scholar The sum of these effects leads to increased vulnerability for heart disease, diabetes, stroke, and obesity for the remainder of an individual’s life. Thus, it is now clear that patterns of growth and accommodations to maternal stress before birth are a major driver of disease risk in offspring. The relationship between maternal dietary and tissue sources of nutrients, placental function, and eventual embryonic and fetal growth is complex but not well studied. Nevertheless, because the placenta is the source of nutrients for the fetus, the provision of nutrients by the mother gives a central place to the placenta as a driver of adult-onset disease. The role of the placenta can be either active or passive. Low rates of fetal growth are generally associated with reduced nutrient fluxes across the placenta. Furthermore, a long list of chronic diseases are associated with specific placental phenotypes.27Barker D.J. Thornburg K.L. Placental programming of chronic diseases, cancer and lifespan: a review.Placenta. 2013; 34: 841-845Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar The transport of required nutrients from mother to fetus requires optimal function of a myriad of separate transport mechanisms including the following: (1) diffusional permeability to blood gases,28Sibley C.P. Coan P.M. Ferguson-Smith A.C. et al.Placental-specific insulin-like growth factor 2 (Igf2) regulates the diffusional exchange characteristics of the mouse placenta.Proce Natl Acad Sci USA. 2004; 101: 8204-8208Crossref PubMed Scopus (247) Google Scholar, 29Jansson T. Powell T.L. Illsley N.P. Non-electrolyte solute permeabilities of human placental microvillous and basal membranes.J Physiol. 1993; 468: 261-274Crossref PubMed Scopus (37) Google Scholar, 30Willis D.M. O'Grady J.P. Faber J.J. Thornburg K.L. Diffusion permeability of cyanocobalamin in human placenta.Am J Physiol. 1986; 250: R459-R464PubMed Google Scholar, 31Bain M.D. Copas D.K. Taylor A. Landon M.J. Stacey T.E. Permeability of the human placenta in vivo to four non-metabolized hydrophilic molecules.J Physiol. 1990; 431: 505-513Crossref PubMed Scopus (36) Google Scholar (2) transporters facilitating diffusion of glucose and fatty acids,32Illsley N.P. Glucose transporters in the human placenta.Placenta. 2000; 21: 14-22Abstract Full Text PDF PubMed Scopus (237) Google Scholar, 33Hay Jr., W.W. Placental-fetal glucose exchange and fetal glucose metabolism.Trans Am Clin Climatol Assoc. 2006; 117 (discussion 339-40): 321-339PubMed Google Scholar, 34Lager S. Powell T.L. Regulation of nutrient transport across the placenta.J Pregnancy. 2012; 2012: 179827Crossref PubMed Scopus (277) Google Scholar (3) active transporters for amino acids and some ions,34Lager S. Powell T.L. Regulation of nutrient transport across the placenta.J Pregnancy. 2012; 2012: 179827Crossref PubMed Scopus (277) Google Scholar, 35Jansson T. Amino acid transporters in the human placenta.Pediatr Res. 2001; 49: 141-147Crossref PubMed Scopus (192) Google Scholar, 36Avagliano L. Garo C. Marconi A.M. Placental amino acids transport in intrauterine growth restriction.J Pregnancy. 2012; 2012: 972562Crossref PubMed Scopus (52) Google Scholar and (4) vesicular transport systems that regulate the transport of iron and immunoglobulins and many others.37Faber J. Thornburg K.L. Placental physiology. Raven Press, 1983Google Scholar, 38Dilworth M.R. Sibley C.P. Review: transport across the placenta of mice and women.Placenta. 2013; 34: S34-S39Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar Thus, each of these processes are known to be, or thought to be, associated with compromised fetal growth.39Jansson T. Powell T.L. Role of the placenta in fetal programming: underlying mechanisms and potential interventional approaches.Clin Sci. 2007; 113: 1-13Crossref PubMed Scopus (389) Google Scholar Fetal glucocorticoid levels increase toward the end of gestation in a number of mammalian species including humans.40Fowden A.L. Li J. Forhead A.J. Glucocorticoids and the preparation for life after birth: are there long-term consequences of the life insurance?.Proc Nutr Soc. 1998; 57: 113-122Crossref PubMed Scopus (384) Google Scholar Glucocorticoids are important for the maturation of several organs before birth including the lungs and heart, which underlies the rationale for administration of corticosteroids to women at risk for preterm delivery (reviewed by Challis et al, 200141Challis J.R. Sloboda D. Matthews S.G. et al.The fetal placental hypothalamic-pituitary-adrenal (HPA) axis, parturition and post natal health.Mol Cell Endocrinol. 2001; 185: 135-144Crossref PubMed Scopus (238) Google Scholar). However, when maternal levels exceed those found under normal physiological conditions, as during high levels of social stress, glucocorticoids cross the placenta and cause reduced fetal growth rates.42Fowden A.L. Szemere J. Hughes P. Gilmour R.S. Forhead A.J. The effects of cortisol on the growth rate of the sheep fetus during late gestation.J Endocrinol. 1996; 151: 97-105Crossref PubMed Scopus (99) Google Scholar An exception to the suppression of growth is found in the heart in which cell proliferation and growth is stimulated by the actions of glucocorticoids.43Giraud G.D. Louey S. Jonker S. Schultz J. Thornburg K.L. Cortisol stimulates cell cycle activity in the cardiomyocyte of the sheep fetus.Endocrinology. 2006; 147: 3643-3649Crossref PubMed Scopus (91) Google Scholar In most cases of human intrauterine growth retardation, both maternal and fetal concentrations of circulating cortisol are elevated.44Goland R.S. Tropper P.J. Warren W.B. Stark R.I. Jozak S.M. Conwell I.M. Concentrations of corticotrophin-releasing hormone in the umbilical-cord blood of pregnancies complicated by pre-eclampsia.Reprod Fertil Dev. 1995; 7: 1227-1230Crossref PubMed Scopus (104) Google Scholar, 45McTernan C.L. Draper N. Nicholson H. et al.Reduced placental 11beta-hydroxysteroid dehydrogenase type 2 mRNA levels in human pregnancies complicated by intrauterine growth restriction: an analysis of possible mechanisms.J Clin Endocrinol Metab. 2001; 86: 4979-4983Crossref PubMed Scopus (253) Google Scholar Ordinarily active cortisol in the human (and corticosterone in small mammals) is inactivated in the placenta by 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), which catalyzes the rapid metabolism of active cortisol and corticosterone to inert, inactive, 11-keto forms. Unfortunately, when maternal levels exceed the rate of inactivation in the placenta, active cortisol will cross the placenta and exert programming effects on the fetus. Thus, either elevated levels of maternal cortisol or reduced levels of placental 11β-HSD2 will lead to programming in offspring. Expression levels of 11β-HSD2 are down-regulated by a number of factors including sex steroids and hypoxia and up-regulated by glucocorticoids themselves and cyclic adenosine monophosphate (reviewed by Seckl and Holmes, 20076Seckl J.R. Holmes M.C. Mechanisms of disease: glucocorticoids, their placental metabolism and fetal 'programming' of adult pathophysiology.Nat Clin Pract Endocrinol Metab. 2007; 3: 479-488Crossref PubMed Scopus (548) Google Scholar). Such offspring will have higher resting levels of cortisol as adults46Phillips D.I. Jones A. Fetal programming of autonomic and HPA function: do people who were small babies have enhanced stress responses?.J Physiol. 2006; 572: 45-50Crossref PubMed Scopus (104) Google Scholar and will have higher cortisol peaks during periods of stress.47Kapoor A. Dunn E. Kostaki A. Andrews M.H. Matthews S.G. Fetal programming of hypothalamo-pituitary-adrenal function: prenatal stress and glucocorticoids.J Physiol. 2006; 572: 31-44Crossref PubMed Google Scholar, 48Mikaelsson M.A. Constancia M. Dent C.L. Wilkinson L.S. Humby T. Placental programming of anxiety in adulthood revealed by Igf2-null models.Nat Commun. 2013; 4: 2311Crossref PubMed Scopus (46) Google Scholar Babies who were born small and had high glucocorticoid levels have elevated risks for chronic diseases later in life including hypertension, hyperinsulinemia, hyperglycemia, and hyperactivity of the hypothalamic-pituitary-adrenal axis.6Seckl J.R. Holmes M.C. Mechanisms of disease: glucocorticoids, their placental metabolism and fetal 'programming' of adult pathophysiology.Nat Clin Pract Endocrinol Metab. 2007; 3: 479-488Crossref PubMed Scopus (548) Google Scholar There is increasing evidence that in addition to characteristic inflammatory responses to infectious agents, placental inflammation that derives from maternal conditions such as diabetes and obesity leads to fetal programming. Acute and chronic inflammation conditions in the placenta are associated with fetal morbidity and mortality including preterm birth.49Romero R. Espinoza J. Goncalves L.F. Kusanovic J.P. Friel L.A. Nien J.K. Inflammation in preterm and term labour and delivery.Semin Fetal Neonat Med. 2006; 11: 317-326Abstract Full Text Full Text PDF PubMed Scopus (528) Google Scholar, 50Salafia C, Popek E, Glob. libr. women's med., (ISSN: 1756-2228) 2008; doi 10.3843/GLOWM.10152. Available at: http://www.glowm.com/section_view/heading/Inflammatory%2520and%2520Vascular%2520Placental%2520Pathology/item/152. Accessed September 11, 2015.Google Scholar In addition to these nicely described categories, there may be milder forms of inflammation that do not fit easily under current definitions. O’Tierney et al51O'Tierney P.F. Lewis R.M. McWeeney S.K. et al.Immune response gene profiles in the term placenta depend upon maternal muscle mass.Reprod Sci. 2012; 19: 1041-1056Crossref PubMed Scopus (16) Google Scholar showed that women who lack muscle have placentas characterized by elevated expression of proinflammatory genes. In this study, expression of interferon-gamma in the placentas of women who had low muscle mass was elevated, as were a host of placental target genes. However, there was no sign of classical inflammation in the tissue. For example, neither T cells bearing CD3 markers nor B cells (CD20), nor macrophages (CD68) nor neutrophils (CD64) were elevated in these placentas. The lack of cellular response contrasts the placentas from obese mothers in whom CD68- and CD14-positive cells more than doubled.52Challier J.C. Basu S. Bintein T. et al.Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta.Placenta. 2008; 29: 274-281Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar However, the placental response to the low muscle mass condition and the augmentation of inflammatory signals associated with obesity53Aye I.L. Lager S. Ramirez V.I. et al.Increasing maternal body mass index is associated with systemic inflammation in the mother and the activation of distinct placental inflammatory pathways.Biol Reprod. 2014; 90: 129Crossref PubMed Scopus (177) Google Scholar suggest the need for more precise definitions of placental inflammation that are not characterized by a full-blown immune response. This need has been suggested in cases of systemic inflammatory changes in cancer that stimulate known signaling cascades but lack the full response seen in local hot inflammation in which granulocytes accumulate.54Calay E.S. Hotamisligil G.S. Turning off the inflammatory, but not the metabolic, flames.Nat Med. 2013; 19: 265-267Crossref PubMed Scopus (55) Google Scholar We hypothesize that the known stressors that lead to fetal programming, including poor nutrition, toxic social stress, and hypoxia, can alter immune function, reduce the actions of protectants of oxidative stress, and lead to a cold form of inflammation.54Calay E.S. Hotamisligil G.S. Turning off the inflammatory, but not the metabolic, flames.Nat Med. 2013; 19: 265-267Crossref PubMed Scopus (55) Google Scholar Many of the same signaling pathways, including activation of activator protein-1, nuclear factor-kappa B, and interferon regulatory factors, mediate tissue responses in both hot and cold conditions. We speculate that the cold type of inflammation is often present in the human placenta and that it mediates a persisting smoldering inflammation in the fetus that makes it vulnerable for chronic disease over years in the future. The team of Barker et al55Barker D.J. Larsen G. Osmond C. Thornburg K.L. Kajantie E. Eriksson J.G. The placental origins of sudden cardiac death.Int J Epidemiol. 2012; 41: 1394-1399Crossref PubMed Scopus (61) Google Scholar showed a U-shaped relationship between cardiovascular death risk and the ratio of placental weight to birthweight (Figure 2). Small placentas bearing large babies are defined as highly efficient and large placentas bearing small babies are deemed inefficient. Figure 3 shows the birthweight of some 17,000 placentas from babies born in Saudi Arabia according to their placental weight. In the upper left-hand quadrant are large babies born with small efficient placentas; the lower right-hand quadrant shows small babies born with large inefficient placentas.Figure 3High- and low-efficiency placentasModified from Alwasel et al.81Alwasel S.H. Abotalib Z. Aljarallah J.S. et al.Secular increase in placental weight in Saudi Arabia.Placenta. 2011; 32: 391-394Abstract Full Text Full Text PDF PubMed Scopus (30) Google ScholarShow full captionThis figure shows 17,000 live births in Unizah, Saudi Arabia. Boxes show quadrants of high- and low-efficiency placentas. Efficiency is the weight of the placenta as a fraction of birthweight. This suggests that efficiencies at the extremes are associated with chronic disease.Thornburg. The placental roots of chronic disease. Am J Obstet Gynecol 2015.View Large Image Figure ViewerDownload Hi-res image Download (PPT) This figure shows 17,000 live births in Unizah, Saudi Arabia. Boxes show quadrants of high- and low-efficiency placentas. Efficiency is the weight of the placenta as a fraction of birthweight. This suggests that efficiencies at the extremes are associated with chronic disease. Thornburg. The placental roots of chronic disease. Am J Obstet Gynecol 2015. Based on the placental ratios in the UK study,8Godfrey K.M. The role of the placenta in fetal programming-a review.Placenta. 2002; 23: S20-S27Abstract Full Text PDF PubMed Scopus (236) Google Scholar we can predict that the efficiency extremes of this population will carry elevated risks for chronic disease. We also know that boys tend to make placentas that are more efficient than do girls.56Eriksson J.G. Kajantie E. Osmond C. Thornburg K. Barker D.J. Boys live dangerously in the womb.Am J Hum Biolo. 2010; 22: 330-335Crossref PubMed Scopus (348) Google Scholar, 57Roseboom T.J. Painter R.C. de Rooij S.R. et al.Effects of famine on placental size and efficiency.Placenta. 2011; 32: 395-399Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar This may explain some of the differences in disease patterns between the sexes during adulthood. The regulation of growth of the placenta is not well understood. It is well known that to grow heavier lambs, farmers placed previously well-fed pregnant ewes on poor pasture early in pregnancy to stimulate the growth of the placenta and later returned the ewes to good pasture.58McCrabb G.J. EA Hasking B.J. Maternal undernutrition during med-pregnancy in sheep; variable effects on placental growth.J Agricult Sci. 1992; 118: 127-132Crossref Scopus (94) Google Scholar Human placentas may also respond to inadequate nutrient delivery by expanding their tissue mass. Data from nonhuman primates illustrate the loss of plasticity of the placenta as a function of gestational age. When the bridge vessels between the 2 lobes of the rhesus placenta are ligated, the nonligated primary lobe is able to compensate by enlargement.59Roberts V.H. Rasanen J.P. Novy M.J. et al.Restriction of placental vasculature in a non-human primate: a unique model to study placental plasticity.Placenta. 2012; 33: 73-76Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar But this is true only at midgestation and not if the vessels are ligated at or after 67% of the gestational period. Thus, there seems to be a period of time when the growth of the placenta responds to the demands placed on it. When that period has passed, it can no longer accommodate the increasing demands for nutrients. This change in placental plasticity will influence the fetal response to maternal insults. Epidemiological studies demonstrate that a woman’s body composition, including her relative fat, muscle, and pelvic bone masses, are important regulators of placental function and fetal outcomes.27Barker D.J. Thornburg K.L. Placental programming of chronic diseases, cancer and lifespan: a review.Placenta. 2013; 34: 841-845Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 60Barker D.J. Thornburg K.L. The obstetric origins of health for a lifetime.Clin Obstet Gynecol. 2013; 56: 511-519Crossref PubMed Scopus (186) Google Scholar These epidemiological associations and others suggest that maternal body composition affects placentation.61Roland M.C. Friis C.M. Godang K. Bollerslev J. Haugen G. Henriksen T. Maternal factors associated with fetal growth and birthweight are independent determinants of placental weight and exhibit differential effects by fetal sex.PloS One. 2014; 9: e87303Crossref PubMed Scopus (53) Google Scholar High BMI is associated with adverse pregnancy outcomes including preeclampsia, thromboembolism, and gestational diabetes mellitus62Sebire N.J. Jolly M. Harris J.P. et al.Maternal obesity and pregnancy outcome: a study of 287,213 pregnancies in London.Int J Obes Relat Metab Disord. 2001; 25: 1175-1182Crossref PubMed Scopus (1275) Google Scholar, 63Baeten J.M. Bukusi E.A. Lambe M. Pregnancy complications and outcomes among overweight and obese nulliparous women.Am J Public Health. 2001; 91: 436-440Crossref PubMed Scopus (603) Google Scholar and has detrimental effects on the fetus including macrosomia and preeclampsia.64Catalano P.M. Ehrenberg H.M. The short- and long-term implications of maternal obesity on the mother and her offspring.BJOG. 2006; 113: 1126-1133Crossref PubMed Scopus (635) Google Scholar, 65Marshall N.E. Guild C. Cheng Y.W. Caughey A.B. Halloran D.R. Maternal superobesity and perinatal outcomes.Am J Obstet Gynecol. 2012; 206: 417.e1-417.e6Abstract Full Text Full Text PDF Scopus (93) Google Scholar Furthermore, babies born to obese mothers have a compromised immune system.66Wilson R.M. Marshall N.E. Jeske D.R. Purnell J.Q. Thornburg K. Messaoudi I. Maternal obesity alters immune cell frequencies and responses in umbilical cord blood samples.Pediatr Allergy Immunol. 2015; 26: 344-351Crossref PubMed Scopus (52) Google Scholar The Helsinki birth cohort comprises 13,345 men and women born during 1934-194467Sandboge S. Fellman J. Nilsson P.M. Eriksson A.W. Osmond C. Eriksson J.G. Regional differences in birth size: a comparison between the Helsinki Birth Cohort Study and contemporaneous births on the Aland Islands.J Dev Orig Health Dis. 2015; 6: 263-267Crossref PubMed Scopus (3) Google Scholar, 68Osmond C. Kajantie E. Forsen T.J. Eriksson J.G. Barker D.J. Infant growth and stroke in adult life: the Helsinki Birth Cohort Study.Stroke. 2007; 38: 264-270Crossref PubMed Scopus (158) Google Scholar and an older cohort comprising 7086 people born during 1924-1933.69Forsen T. Eriksson J.G. Tuomilehto J. Teramo K. Osmond C. Barker D.J. Mother's weight in pregnancy and coronary heart disease in a cohort of Finnish men: follow up study.BMJ. 1997; 315: 837-840Crossref PubMed Scopus (336) Google Scholar The Helsinki birth cohort is a gold mine for placentologists because at the time of birth, midwives and nurses measured the weights, widths, and lengths of all births in Helsinki hospitals during those periods of time. Among ∼6000 placentas, the lengths exceeded their widths by an average of 2.6 cm with the difference ranging from 0 to 21 cm. From these data and others, it is now possible to link poor fetal growth and/or placental phenotype with70Barker D.J. Thornburg K.L. Osmond C. Kajantie E. Eriksson J.G. The surface area of the placenta and hypertension in the offspring in later life.Int J Dev Biol. 2010; 54: 525-530Crossref PubMed Scopus (149) Google Scholar metabolic disease and obesity,71Vickers M.H. Breier B.H. Cutfield W.S. Hofman P.L. Gluckman P.D. Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition.Am J Physiol Endocrinol Metab. 2000; 279: E83-E87PubMed Google Scholar coronary heart disease,72Eriksson J.G. Kajantie E. Thornburg K.L. Osmond C. Barker D.J. Mother's body size and placental size predict coronary heart disease in men.Eur Heart J. 2011; 32: 2297-2303Crossref PubMed Scopus (86) Google Scholar heart failure,73Barker D.J. Gelow J. Thornburg K. Osmond C. Kajantie E. Eriksson J.G. The early origins of chronic heart failure: impaired placental growth and initiation of insulin resistance in childhood.Eur J Heart Fail. 2010; 12: 819-825Crossref PubMed Scopus (129) Google Scholar sudden cardiac death,55Barker D.J. Larsen G. Osmond C. Thornburg K.L. Kajantie E. Eriksson J.G. The placental origins of sudden cardiac death.Int J Epidemiol. 2012; 41: 1394-1399Crossref PubMed Scopus (61) Google Scholar asthma,74Barker D.J. Osmond C. Forsen T.J. Thornburg K.L. Kajantie E. Eriksson J.G. Foetal and childhood growth and asthma in adult life.Acta Paediatr. 2013; 102: 732-738Crossref PubMed Scopus (33) Google Scholar and osteoporosis75Goodfellow L.R. Cooper C. Harvey N.C. Regulation of placental calcium transport and offspring bone health.Front Endocrinol. 2011; 2: 3Crossref PubMed Scopus (10) Google Scholar as well as cancers including Hodgkin’s lymphoma,76Barker D.J. Osmond C. Thornburg K.L. Kajantie E. Eriksson J.G. The intrauterine origins of Hodgkin's lymphoma.Cancer Epidemiol. 2013; 37: 321-323Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar lung cancer,77Barker D.J. Thornburg K.L. Osmond C. Kajantie E. Eriksson J.G. The prenatal origins of lung cancer. II. The placenta.Am J Hum Biol. 2010; 22: 512-516Crossref PubMed Scopus (45) Google Scholar and colorectal cancer.78Barker D.J. Osmond C. Thornburg K.L. Kajantie E. Eriksson J.G. The shape of the placental surface at birth and colorectal cancer in later life.Am J Hum Biol. 2013; 25: 566-568Crossref PubMed Scopus (31) Google Scholar Among 187 men and 47 women, sudden cardiac death outside the hospital55Barker D.J. Larsen G. Osmond C. Thornburg K.L. Kajantie E. Eriksson J.G. The placental origins of sudden cardiac death.Int J Epidemiol. 2012; 41: 1394-1399Crossref PubMed Scopus (61) Google Scholar was associated with a thin placenta and had a hazard ratio of 1.47 (95% confidence interval, 1.11–1.93) for every gram per square centimeter decrease in placental thickness. Sudden cardiac death is thought to be associated with excess sympathetic tone and subsequent ventricular fibrillation. Thus, one can speculate that an inadequate placenta, perhaps caused by inadequate trophoblast invasion, compromised nutrient exchange and the development of the autonomic nervous system. Among 187 people in the Helsinki birth cohort of 1934–1944, chronic heart failure was associated with a small surface area of the delivered placenta.73Barker D.J. Gelow J. Thornburg K. Osmond C. Kajantie E. Eriksson J.G. The early origins of chronic heart failure: impaired placental growth and initiation of insulin resistance in childhood.Eur J Heart Fail. 2010; 12: 819-825Crossref PubMed Scopus (129) Google Scholar In people who were born with a placenta of <225 cm2, the odds ratio was 1.7 (95% confidence interval, 1.1–2.5) compared with people with larger placentas having a surface area of >295 cm2. Short placental width but not length also predicted the disease but only in short mothers. Other factors were also associated with heart failure. A rapid gain in BMI between 2 and 11 years of age was also associated with chronic heart failure, a path of growth that has been associated with insulin resistance. It appears that the combination of a small placenta and rapid childhood weight gain leads to poor glucose control, which predisposes to heart failure later in life. Among 7000 men born in the Helsinki birth cohort during 1934–1944,72Eriksson J.G. Kajantie E. Thornburg K.L. Osmond C. Barker D.J. Mother's body size and placental size predict coronary heart disease in men.Eur Heart J. 2011; 32: 2297-2303Crossref PubMed Scopus (86) Google Scholar those who developed coronary heart disease were thin at birth and their disease was associated with the following 3 different placental/maternal phenotypes: (1) in short primiparous mothers, the hazard ratio for coronary disease was related to the difference between the length and width of the placental surface; (2) in tall mothers whose BMI was above the median, a small placental surface predicted the disease (see Table); and (3) in tall mothers who were thin, coronary heart disease was related to placental efficiency. The hazard ratio was elevated with an increase in the placental weight/birthweight ratio. Thus, there was a profound interaction between maternal phenotype, placental deviation from roundness, placental surface area at delivery, and placental efficiency. These complex relationships suggest a profound interaction between maternal body composition and placental form and function as suggested by others.61Roland M.C. Friis C.M. Godang K. Bollerslev J. Haugen G. Henriksen T. Maternal factors associated with fetal growth and birthweight are independent determinants of placental weight and exhibit differential effects by fetal sex.PloS One. 2014; 9: e87303Crossref PubMed Scopus (53) Google ScholarTableCoronary heart disease in men born to tall mothers (>160 cm) according to her body mass indexVariableMother’s BMI ≤26 kg/m2Mother’s BMI >26 kg/m2HR (95% CI)HR (95% CI)Placental weight, g ≤5500.8 (0.4–1.3)2.2 (1.3–4.0) –6500.9 (0.6–1.5)1.9 (1.2–3.2) –7500.8 (0.5–1.4)1.0 (baseline) P value for trend.5.002Placental area, cm2 ≤2251.0 (0.6–1.7)2.2 (1.4–3.7) –2551.0 (0.6–1.6)1.3 (0.8–2.2) –2951.1 (0.7–1.9)1.7 (1.0–.7) >2951.0 (baseline)1.0 (baseline) P value for trend.5< .001The table shows that risks for acquiring coronary heart disease in men depends on maternal stature and body mass index. Among men born in Helsinki to taller mothers with a high body mass index, low placental weight and surface area were associated with coronary heart disease.72Eriksson J.G. Kajantie E. Thornburg K.L. Osmond C. Barker D.J. Mother's body size and placental size predict coronary heart disease in men.Eur Heart J. 2011; 32: 2297-2303Crossref PubMed Scopus (86) Google ScholarBMI, body mass index. CI, confidence interval; HR, hazard ratio.Thornburg. The placental roots of chronic disease. Am J Obstet Gynecol 2015. Open table in a new tab The table shows that risks for acquiring coronary heart disease in men depends on maternal stature and body mass index. Among men born in Helsinki to taller mothers with a high body mass index, low placental weight and surface area were associated with coronary heart disease.72Eriksson J.G. Kajantie E. Thornburg K.L. Osmond C. Barker D.J. Mother's body size and placental size predict coronary heart disease in men.Eur Heart J. 2011; 32: 2297-2303Crossref PubMed Scopus (86) Google Scholar BMI, body mass index. CI, confidence interval; HR, hazard ratio. Thornburg. The placental roots of chronic disease. Am J Obstet Gynecol 2015. The placenta is at the center of the programming universe because fetal growth determines the degree of vulnerability that a neonate carries for adult onset disease. Stress, poor diet, and hypoxia are major stressors that are mediated by the placenta. When it comes to understanding the mechanisms that regulate the growth and function of the placenta, we are stifled by ignorance. We can say with confidence, however, that unless we ensure that women and their offspring are able to eat healthy diets and generate healthy placentas, we cannot expect much improvement in the health of the US population. Thus, to optimize fetal growth and improve life-long health, it now falls on scientists to study placental nutrient transport to provide nutritional guidance for future generations.