Long-Term Healthcare Outcomes of Preterm Birth: An Executive Summary of a Conference Sponsored by the National Institutes of Health.

In 1998, Dr David Barker pioneered the novel idea that common chronic diseases result not only from bad genes and an unhealthy lifestyle, but also from alterations in the intrauterine and early postnatal environment.1Barker D.J. In utero programming of chronic disease.Clin Sci. 1998; 95: 115-128Crossref PubMed Google Scholar The timing of these alterations, either during a “critical” period of growth and maturation or accumulating over longer intervals, can have a permanent effect on the organism. The impact of birth weight, maternal habitus, nutrition, and smoking, and the role of the placenta on developmental programming of metabolic syndrome, obesity, hypertension, and organ development have been well-studied. More recent studies have suggested that developmental programming on the background of preterm birth may be far more important than suboptimal intrauterine growth. In the US, about 10%-12% of births occur before 37 completed weeks of postmenstrual age.2Centers for Disease Control and Prevention National Centers for Chronic Disease Prevention and Health Promotion Preterm birth.http://www.cdc.gov/reproductivehealth/MaternalInfantHealth/PretermBirth.htmDate: 2015Google Scholar Worldwide rates vary. Today, more than 95% of these “preterm infants” survive to adulthood in most industrialized nations owing to remarkable advances in perinatal, neonatal, and pediatric care.3Stoll B.J. Hansen N.I. Bell E.F. Walsh M.C. Carlo W.A. Shankaran S. et al.Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012.JAMA. 2015; 314: 1039-1051Crossref PubMed Scopus (200) Google Scholar, 4Raju T.N. Growth of neonatal perinatal medicine—a historical perspectives.in: Martin R.J. Fanaroff A.A. Walsh M.C. Fanaroff & Martin's neonatal-perinatal medicine: diseases of the fetus and infant. 10th ed. 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Cohen H.J. et al.Perinatal complications and aging indicators by midlife.Pediatrics. 2014; 134: e1315-23Crossref PubMed Scopus (0) Google Scholar Individuals born preterm are at an increased risk for type 2 diabetes, cardiovascular and cerebrovascular diseases, hypertension, chronic kidney disease, asthma and pulmonary function abnormalities, and neurocognitive and psychosocial disorders and poorer social adaptation.8Bolton C.E. Bush A. Hurst J.R. Kotecha S. McGarvey L. Lung consequences in adults born prematurely.Thorax. 2015; 70: 574-580Crossref PubMed Scopus (19) Google Scholar, 9de Jong F. Monuteaux M.C. van Elburg R.M. Gillman M.W. Belfort M.B. Systematic review and meta-analysis of preterm birth and later systolic blood pressure.Hypertension. 2012; 59: 226-234Crossref PubMed Scopus (174) Google Scholar, 10de Jong M. Verhoeven M. van Baar A.L. School outcome, cognitive functioning, and behaviour problems in moderate and late preterm children and adults: a review.Semin Fetal Neonatal Med. 2012; 17: 163-169Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 11Kajantie E. Strang-Karlsson S. Hovi P. Wehkalampi K. Lahti J. Kaseva N. et al.Insulin sensitivity and secretory response in adults born preterm: the Helsinki Study of Very Low Birth Weight Adults.J Clin Endocrinol Metab. 2015; 100: 244-250Crossref PubMed Scopus (39) Google Scholar, 12Lawlor D.A. Ronalds G. Clark H. Smith G.D. Leon D.A. Birth weight is inversely associated with incident coronary heart disease and stroke among individuals born in the 1950s: findings from the Aberdeen children of the 1950s prospective cohort study.Circulation. 2005; 112: 1414-1418Crossref PubMed Scopus (154) Google Scholar Even a modest increase (eg, 10%-20%) in risk for these chronic conditions can translate into a substantial population burden. Because of this, the US National Institutes of Health convened a conference of multidisciplinary experts to elucidate the evidence for the epidemiologic, public health, and societal burden of diseases among those born preterm, to review potential mechanisms and to consider future research priorities. An understanding of these areas is crucial for developing prevention and treatment strategies. This report summarizes the key concepts discussed at the conference, and poses many unanswered questions that may serve to guide future research endeavors in each domain (Table).TableUnanswered questions to guide future research in individuals born pretermGeneral Which types of study designs and innovative tools are needed to accumulate evidence to guide the care of preterm born individuals into adulthood? What contributes to more favorable outcomes or resiliency in some preterm born individuals? How can existing preterm-born cohorts, trials, databases and samples be leveraged for the study of future health risks?Pulmonary Is the clinical syndrome labeled “asthma” the same for those born prematurely versus at term? What characterizes the syndrome of obstructive lung disease in individuals born preterm? What are the best strategies for maximizing lung health and disease prevention? Have changes in NICU management altered/improved long-term respiratory outcomes? Does lower lung function contribute to adult respiratory morbidity and if so, what type? What are the mechanisms behind the reported lung function abnormalities? What are the mechanisms of increased risk of OSAS? What are the differences in responses to interventions for OSAS? Do preterm infants start out with low lung function, followed by normal or accelerated growth later? What is the relationship between preterm birth and age at peak lung function? How does preterm lung pulmonary vascular growth change over time? Is there a relationship between preterm birth and exercise-induced pulmonary hypertension?Cardiovascular, peripheral vascular and metabolic Does the etiology of the preterm birth and degree of prematurity influence outcomes? How do we balance immediate benefits versus long-term harm (eg, corticosteroids and optimal nutrition and growth)? How can we decrease exogenous cortisol exposure during the postnatal period? How can we assess the impact of postnatal complications versus lifestyle on cardiometabolic disease later in life? What are the pathways that lead to reduced physical activity and fitness? How can we address the many challenges faced in epigenetic studies such as differences in tissue and cell type differences, changes over time, external influences and the need for multiple comparisons? What are the best study designs to address the limitations of long-term cohort follow-up studies and obtain outcomes in a reasonable period of time? Which interventions should be tested to improve cardiometabolic health later in life? How do we optimize the recognition, treatment, and prevention of thromboembolism in adults born at preterm gestations? What are the best approaches to prevent obesity among those born preterm?Renal What are the best methods to assess kidney function in infants, children, and teens? What biomarkers can accurately assess kidney health? What are the long-term follow-up guidelines to assess kidney functions prospectively for high-risk infants after hospital discharge? How can one assess kidney size relative to body mass in infants, children, and adults? How can nutritional support be optimized to mitigate adverse renal health? What are the independent effects of intrauterine growth restriction and prematurity on ultimate kidney health? What are the effects of maternal hypertension, neonatal acute kidney injury, childhood hypertension, and chronic kidney disease among those born preterm? How do we evaluate the impact of neonatal acute kidney injury on long-term renal function? What are the effects of poor kidney function among preterm infants (eg, loss of growth factors or hormones in the urine) on general and organ-specific health during the life course of the individual?Neurologic and neuropsychiatric What are the clinical consequences of increased periodic limb movement syndrome? What are the causes and consequences of preterm white matter injury? Can early interventions mitigate adverse outcomes secondary to preterm brain injury from periventricular leukomalacia and intraventricular hemorrhage? What specific interventions will improve learning of math and language skills? What childhood and adolescent factors alter the trajectory of abnormal neurologic outcomes? What are the biological bases for neuropsychiatric problems? Specifically: How do various trajectories of structural and functional brain development affect or alter neuropsychiatric outcomes? What is the role of neurotransmitters and neuromodulators implicated in psychiatric disorders? What is the role of neuroimmune factors, such as maternal/fetal inflammatory responses, associated with neuropsychiatric outcomes? What genetic risks are associated with an increased vulnerability to neuropsychiatric impairment, as well as modulating pathways for risk and resilience? Which interventions can be developed to improve psychiatric outcomes and cognitive function? What are the childhood and adolescent antecedent factors for psychiatric problems and their effects on long-term outcomes? What is the value of early treatment? Specifically:How do early developmental interventions change outcomes?How do pain-related stressors and the effects of therapies for neonatal pain control alter the trajectories of personality development and long-term behavioral outcomes?Mechanisms and basic science What are the macro and molecular mechanistic pathways that might be affecting maturational processes after preterm birth?Is it due to something missing (eg, micronutrients, oxygen), something altered (eg, infection, abnormal extrauterine environment, medications), the intrauterine environment or epigenetic effects? Does the interrupted maturation and growth of various organs after preterm birth “recover”? What leads to recovery or compensation? How do organs interact with each other after preterm birth? Do individuals born prematurely develop diseases earlier because their threshold has changed and are they pathologically different from those born at term? What are the mechanisms of resiliency? Why do so many preterm infants, even those born extremely preterm, do well? How can we use the emerging fields of new imaging methods, molecular, and blood analyte studies to shed light on lifespan events that follow preterm birth?OSAS, obstructive sleep apnea syndrome. Open table in a new tab OSAS, obstructive sleep apnea syndrome. Much of our knowledge about individuals born preterm has come from prospective birth cohort studies of large populations. Although longitudinal cohort studies have many advantages, there are significant challenges, such as the long duration of follow-up (and need for long-term funding) necessary to provide meaningful associations, lack of information on confounders, changes in classification of diseases and outcomes over time, and loss to follow-up. With a few exceptions, our knowledge of the longer term outcomes of preterm birth comes from cohorts born outside of the US13Doyle L.W. Cheong J.L. Burnett A. Roberts G. Lee K.J. Anderson P.J. Biological and social influences on outcomes of extreme-preterm/low-birth weight adolescents.Pediatrics. 2015; 136: e1513-20Crossref PubMed Google Scholar, 14Hovi P. Andersson S. Eriksson J.G. Jarvenpaa A.L. Strang-Karlsson S. Makitie O. et al.Glucose regulation in young adults with very low birth weight.N Engl J Med. 2007; 356: 2053-2063Crossref PubMed Scopus (297) Google Scholar, 15Saigal S. Stoskopf B. Streiner D. Boyle M. Pinelli J. Paneth N. et al.Transition of extremely low- birth-weight infants from adolescence to young adulthood: comparison with normal birth-weight controls.JAMA. 2006; 295: 667-675Crossref PubMed Scopus (0) Google Scholar who were followed through adulthood. A Swedish study of 679 981 singleton live births between 1973 and 1979, examined the association between preterm birth and all-cause and cause-specific mortality through 2008. The adjusted HRs for death (controlling for age, sex, birth order, maternal age, marital status, and education) were higher for preterm16Crump C. Sundquist K. Sundquist J. Winkleby M.A. Gestational age at birth and mortality in young adulthood.JAMA. 2011; 306: 1233-1240Crossref PubMed Scopus (134) Google Scholar and for “early term” births (37 and 38 weeks)17Crump C. Sundquist K. Winkleby M.A. Sundquist J. Early-term birth (37-38 weeks) and mortality in young adulthood.Epidemiology. 2013; 24: 270-276Crossref PubMed Scopus (31) Google Scholar than for births at 39-42 weeks, illustrating that the lower the gestational age at birth, the higher the risk of death in the neonatal, postnatal, early childhood, and young adult age ranges. Data from US cohorts permit comparisons of socioeconomic, ethnic, and cultural factors, important for generalizability to the broader US population. But US cohorts of individuals born preterm are few, owing in part to the difficulties of maintaining longitudinal cohorts into adulthood.18Hack M. Adult outcomes of preterm children.J Dev Behav Pediatr. 2009; 30: 460-470Crossref PubMed Scopus (74) Google Scholar, 19Hack M. Flannery D.J. Schluchter M. Cartar L. Borawski E. Klein N. Outcomes in young adulthood for very-low-birth-weight infants.N Engl J Med. 2002; 346: 149-157Crossref PubMed Scopus (712) Google Scholar Additional research approaches should be considered to augment the paucity of data from US cohorts along with the comparison of international cohorts. Randomized controlled trials are the “gold standard” to evaluate therapies, yet they may be more challenging to execute because of limitations, such as strict eligibility criteria, short observational periods, and poor study design. Case-control studies are particularly useful when evaluating rarer and long-term outcomes, especially when data and biological specimens are available from pregnancy and early postnatal life. Using archived collections (maternal serum and newborn blood spots) to link later disorders in nested case-control studies could be a valuable approach to evaluating outcomes in individuals born preterm. However, observational studies have revealed useful insights into various early life risk factors on long-term adverse outcomes. Exposure to repeated doses of antenatal corticosteroids20Crowther C.A. Doyle L.W. Haslam R.R. Hiller J.E. Harding J.E. Robinson J.S. Outcomes at 2 years of age after repeat doses of antenatal corticosteroids.N Engl J Med. 2007; 357: 1179-1189Crossref PubMed Scopus (165) Google Scholar, 21McKinlay C.J. Cutfield W.S. Battin M.R. Dalziel S.R. Crowther C.A. Harding J.E. Cardiovascular risk factors in children after repeat doses of antenatal glucocorticoids: an RCT.Pediatrics. 2015; 135: e405-15Crossref PubMed Scopus (0) Google Scholar, 22Wapner R.J. Sorokin Y. Mele L. Johnson F. Dudley D.J. Spong C.Y. et al.Long-term outcomes after repeat doses of antenatal corticosteroids.N Engl J Med. 2007; 357: 1190-1198Crossref PubMed Scopus (177) Google Scholar and postnatal dexamethasone23Yeh T.F. Lin Y.J. Lin H.C. Huang C.C. Hsieh W.S. Lin C.H. et al.Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity.N Engl J Med. 2004; 350: 1304-1313Crossref PubMed Scopus (0) Google Scholar are examples of adverse effects of medication exposure early in life. Famine during gestation in the Netherlands resulted in lower birth weights, and increased the risk for higher blood pressure 59 years later, highlighting the importance of early nutrition on offspring health.24Stein A.D. Zybert P.A. van der Pal-de Bruin K. Lumey L.H. Exposure to famine during gestation, size at birth, and blood pressure at age 59 y: evidence from the Dutch Famine.Eur J Epidemiol. 2006; 21: 759-765Crossref PubMed Scopus (0) Google Scholar Based on the latter observation, studies were conducted to improve infant outcomes by improving maternal nutrition during pregnancy,25Kramer M.S. High protein supplementation in pregnancy.Cochrane Database Syst Rev. 2000; (CD000105)Google Scholar, 26Kramer M.S. Balanced protein/energy supplementation in pregnancy.Cochrane Database Syst Rev. 2000; (CD000032)Google Scholar encouraging regular aerobic exercise by pregnant women,27Kramer M.S. Regular aerobic exercise during pregnancy.Cochrane Database Syst Rev. 2000; (CD000180)Google Scholar and avoidance of antigens to prevent infant atopic diseases28Kramer M.S. Maternal antigen avoidance during pregnancy for preventing atopic disease in infants of women at high risk.Cochrane Database Syst Rev. 2000; (CD000133)Google Scholar; however, these interventions had mixed results. In contrast, a prospective randomized trial of postnatal dietary interventions in 2 parallel cohorts of 926 premature infants had a positive influence on reducing mean arterial blood pressure at 13-16 years of age.29Singhal A. Cole T.J. Lucas A. Early nutrition in preterm infants and later blood pressure: two cohorts after randomised trials.Lancet. 2001; 357: 413-419Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar More studies are needed to explore how specific treatments or prevention strategies will improve long-term adverse outcomes in survivors of preterm birth. Novel study designs, use of big data, trials embedded in registries, and transnational partnerships such as the Adults Born Preterm International Collaboration30Kajantie E. Adults Born Preterm International Collaboration (APIC).http://www.apic-preterm.orgDate: 2016Google Scholar should be explored to address the methodological challenges of studying preterm born individuals across the lifespan. Several publications have drawn attention to the pulmonary function abnormalities and chronic lung diseases in individuals born prematurely.31Clemm H.H. Vollsaeter M. Roksund O.D. Eide G.E. Markestad T. Halvorsen T. Exercise capacity after extremely preterm birth. Development from adolescence to adulthood.Ann Am Thorac Soc. 2014; 11: 537-545Crossref PubMed Scopus (20) Google Scholar, 32Vollsaeter M. Clemm H.H. Satrell E. Eide G.E. Roksund O.D. Markestad T. et al.Adult respiratory outcomes of extreme preterm birth. A regional cohort study.Ann Am Thorac Soc. 2015; 12: 313-322Crossref PubMed Google Scholar, 33Vollsaeter M. Roksund O.D. Eide G.E. Markestad T. Halvorsen T. Lung function after preterm birth: development from mid-childhood to adulthood.Thorax. 2013; 68: 767-776Crossref PubMed Scopus (60) Google Scholar, 34Vollsaeter M. Skromme K. Satrell E. Clemm H. Roksund O. Oymar K. et al.Children born preterm at the turn of the millennium had better lung function than children born similarly preterm in the early 1990s.PLoS ONE. 2015; 10: e0144243Crossref Scopus (0) Google Scholar, 35Saarenpaa H.K. Tikanmaki M. Sipola-Leppanen M. Hovi P. Wehkalampi K. Siltanen M. et al.Lung function in very low birth weight adults.Pediatrics. 2015; 136: 642-650Crossref PubMed Scopus (20) Google Scholar Human lungs develop in stages during gestation with airways forming during weeks 5-26 and alveoli during weeks 24-36 with continued development during childhood. A surge in pulmonary surfactant at 34-35 weeks of gestation is mediated by cortisol. Preterm birth disrupts these processes and leads to morphologically immature lungs compared with the lungs of term infants. If the preterm birth follows a pregnancy in which there is fetal programming in response to in utero gene-environment interactions (eg, maternal smoking, inadequate maternal diet), there may already be developmental problems in the lungs that are exacerbated by preterm birth. Adverse postnatal clinical events or exposures such as the use of oxygen, assisted ventilator support, gastroesophageal reflux, and postnatal environmental toxins (eg, secondhand smoke, air pollution) during key stages of maturation can contribute to additional injury. Typically, lung function peaks by early adulthood and then begins to decline, yet the trajectory of lung function in individuals born preterm is unclear and questions remain. Arrested vascularization and augmented vasoreactivity36Kriemler S. Keller H. Saigal S. Bar-Or O. Aerobic and lung performance in premature children with and without chronic lung disease of prematurity.Clin J Sport Med. 2005; 15: 349-355Crossref PubMed Scopus (37) Google Scholar, 37Baker C.D. Abman S.H. Mourani P.M. Pulmonary hypertension in preterm infants with bronchopulmonary dysplasia.Pediatr Allergy Immunol Pulmonol. 2014; 27: 8-16Crossref PubMed Scopus (37) Google Scholar, 38Thebaud B. Abman S.H. Bronchopulmonary dysplasia: where have all the vessels gone? Roles of angiogenic growth factors in chronic lung disease.Am J Respir Crit Care Med. 2007; 175: 978-985Crossref PubMed Scopus (264) Google Scholar may lead to the development of pulmonary hypertension in the weeks and months after preterm birth, contributing to increased mortality in infants with bronchopulmonary dysplasia. Whether these individuals are more susceptible to developing baseline or exercise-induced pulmonary hypertension associated with right heart failure, compared with their term-born counterparts, is unknown. Young adults with a history of bronchopulmonary dysplasia have worse lung function compared with healthy controls, and even those with no history of bronchopulmonary dysplasia manifested poorer lung function than those born at term.35Saarenpaa H.K. Tikanmaki M. Sipola-Leppanen M. Hovi P. Wehkalampi K. Siltanen M. et al.Lung function in very low birth weight adults.Pediatrics. 2015; 136: 642-650Crossref PubMed Scopus (20) Google Scholar, 39Gough A. Linden M. Spence D. Patterson C.C. Halliday H.L. McGarvey L.P. Impaired lung function and health status in adult survivors of bronchopulmonary dysplasia.Eur Respir J. 2014; 43: 808-816Crossref PubMed Scopus (37) Google Scholar, 40Gough A. Spence D. Linden M. Halliday H.L. McGarvey L.P. General and respiratory health outcomes in adult survivors of bronchopulmonary dysplasia: a systematic review.Chest. 2012; 141: 1554-1567Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar These reductions in lung function are not trivial; they have been shown to be associated with reductions in aerobic exercise capacity,41Lovering A.T. Elliott J.E. Laurie S.S. Beasley K.M. Gust C.E. Mangum T.S. et al.Ventilatory and sensory responses in adult survivors of preterm birth and bronchopulmonary dysplasia with reduced exercise capacity.Ann Am Thorac Soc. 2014; 11: 1528-1537Crossref PubMed Scopus (15) Google Scholar with the potential to adversely affect long-term pulmonary and/or cardiovascular health. Individuals born preterm also have increased respiratory symptoms (cough, wheezing, exertional dyspnea) and nearly one-third are diagnosed with asthma during childhood. However, the “asthma” seen in these individuals may have phenotypes and treatment responses that are different from those seen in children and adults born at term, making testing and treatment more challenging. Infants born preterm who have experienced fetal programming that altered the development of the airways or lung parenchyma may have suboptimal lung function that tracks toward the bottom of the lung growth curves, setting them up for risk for chronic lung disease as adults. Studies in pregnant primates infused with nicotine and in women who smoked during pregnancy found that the offspring of women with specific genotypes have reduced vitamin C levels and reduced lung function soon after birth, consistent with airway narrowing. Restoring vitamin C levels results in normal lung function in the offspring.42McEvoy C.T. Schilling D. Clay N. Jackson K. Go M.D. Spitale P. et al.Vitamin C supplementation for pregnant smoking women and pulmonary function in their newborn infants: a randomized clinical trial.JAMA. 2014; 311: 2074-2082Crossref PubMed Scopus (48) Google Scholar This demonstrates an important model of an in utero gene-environment interaction, the timing of which is as critical as the type of injurious exposure for its long-term effects on the structure and function of the developing lungs. Sleep is important for health, learning, behavior, and executive functioning. Adults born preterm have a 3- to 5-fold higher risk of obstructive sleep apnea syndrome43Greenfeld M. Tauman R. DeRowe A. Sivan Y. Obstructive sleep apnea syndrome due to adenotonsillar hypertrophy in infants.Int J Pediatr Otorhinolaryngol. 2003; 67: 1055-1060Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 44Marcus C.L. Meltzer L.J. Roberts R.S. Traylor J. Dix J. D'Ilario J. et al.Long-term effects of caffeine therapy for apnea of prematurity on sleep at school age.Am J Respir Crit Care Med. 2014; 190: 791-799Crossref PubMed Google Scholar and a 2-fold increased risk of snoring compared with those born at term.45Paavonen E.J. Strang-Karlsson S. Raikkonen K. Heinonen K. Pesonen A.K. Hovi P. et al.Very low birth weight increases risk for sleep-disordered breathing in young adulthood: the Helsinki Study of Very Low Birth Weight Adults.Pediatrics. 2007; 120: 778-784Crossref PubMed Scopus (54) Google Scholar Perinatal exposure to maternal chorioamnionitis increases the risk for obstructive sleep apnea,46Tapia I.E. Shults J. Doyle L.W. Nixon G.M. Cielo C.M. Traylor J. et al.Perinatal risk factors associated with the obstructive sleep apnea syndrome in school-aged children born preterm.Sleep. 2016; 39: 737-742Crossref PubMed Scopus (6) Google Scholar whereas caffeine administration during the neonatal period is not a risk factor.44Marcus C.L. Meltzer L.J. Roberts R.S. Traylor J. Dix J. D'Ilario J. et al.Long-term effects of caffeine therapy for apnea of prematurity on sleep at school age.Am J Respir Crit Care Med. 2014; 190: 791-799Crossref PubMed Google Scholar Children born preterm also have a higher prevalence of periodic limb movements, which may disrupt their sleep.47Cielo C.M. DelRosso L.M. Tapia I.E. Biggs S.N. Nixon G.M. Meltzer L.J. et al.Periodic limb movements and restless legs syndrome in children with a history of prematurity.Sleep Med. 2016; (in press)Google Scholar However, there is no clear understanding of the mechanistic roles of ventilatory-control abnormalities, upper airway muscle hypotonia, palatal deformation (owing to prolonged neonatal endotracheal intubation), adenotonsillar hypertrophy, and obesity in causing sleep-related disturbances. The causes and mechanisms for these conditions during childhood and adolescence remain to be addressed.48Biggs S.N. Meltzer L.J. Tapia I.E. Traylor J. Nixon G.M. Horne R.S. et al.Sleep/wake patterns and parental perceptions of sleep in children born preterm.J Clin Sleep Med. 2016; 12: 711-717Crossref PubMed Google Scholar Interest in the cardiovascular consequences of preterm birth dates to the seminal observations of David Barker, who reported that birth weight was inversely related to adult blood pressure and later showed that lower birth weight was a risk factor for adult cardiovascular diseases, hypertension, and type 2 diabetes.49Barker D.J. Winter P.D. Osmond C. Margetts B. Simmonds S.J. Weight in infancy and death from ischaemic heart disease.Lancet. 1989; 2: 577-580Abstract PubMed Scopus (1843) Google Scholar Even though initial research focused on low birth weight owing to intrauterine growth restriction and maternal nutrition, evolving data suggest that lower gestational age portends worse adult outcomes. However, the mechanism may differ from Barker's initial hypothesis: it is quite likely that low birth weight and later cardiovascular disorders may reflect shared genetic and environmental risk factors in the families of affected infants. One of the most consistent findings in individuals born preterm is higher blood pressure. In 2 meta-analyses of adults born preterm versus term, systolic and diastolic blood pressures were higher in the preterm groups.9de Jong F. Monuteaux M.C. van Elburg R.M. Gillman M.W. Belfort M.B. Systematic review and meta-analysis of preterm birth and later systolic blood pressure.Hypertension. 2012; 59: 226-234Crossref PubMed Scopus (174) Google Scholar, 50Parkinson J.R. Hyde M.J. Gale C. Santhakumaran S. Modi N. Preterm birth and the metabolic syndrome in adult life: a systematic review and meta-analysis.Pediatrics. 2013; 131: e1240-63Crossref PubMed Scopus (107) Google Scholar Among those born to mothers with preeclampsia, a slightly greater increase was seen. Females had higher ambulatory blood pressures than males.51Hovi P. Kajantie E. Soininen P. Kangas A.J. Jarvenpaa A.L. Andersson S. et al.Lipoprotein subclass profiles in young adults born preterm at very low birth weight.Lipids Health Dis. 2013; 12: 57Crossref PubMed Google Scholar, 52Sipola-Leppanen M. Vaarasmaki M. Tikanmaki M. Matinolli H.M. Miettola S. Hovi P. et al.Cardiometabolic risk factors in young adults who were born preterm.Am J Epidemiol. 2015; 181: 861-873Crossref PubMed Scopus (42) Google Scholar Whether preterm infants were small for gestational age or appropriate for gestational age made little difference. Prematurity increases the risk of type 2 diabetes and insulin resistance during childhood into adulthood.11Kajantie E. Strang-Karlsson S. Hovi P. Wehkalampi K. Lahti J. Kaseva N. et al.Insulin sensitivity and secretory response in adults born pr