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Three Existential Challenges in Optimizing the Lifelong Health of Infants Born Preterm

2022; Elsevier BV; Volume: 252; Linguagem: Inglês

10.1016/j.jpeds.2022.09.002

1097-6833

Alan H. Jobe,

Neonatal Respiratory Health Research

Large databases provide new information regarding the outcomes of infants born prematurity that raise concerns regarding the roles that science and clinical neonatology need to optimize long-term outcomes of extreme prematurity. In this commentary, I will use information based on 2 primary publications: Life in the Womb: The Origins of Health and Disease by Peter W. Nathanielsz, published by Promethean Press in Utica, New York, in 19991Nathanielsz P.W. Life in the womb: the origin of health and disease. Promethean Press, Utica (NY)1999Google Scholar and Where is the Evidence: Debates and Modern Medicine by William A. Silverman, published by Oxford University Press in Oxford, United Kingdom, in 1998.2Silverman W.A. Where's the evidence? Debates in modern medicine. Oxford University Press, Oxford (UK)1998Google Scholar Together, these publications provide a framework to consider our goals in optimizing the outcomes of infants born prematurity. I will consider 3 existential challenges faced by present caregivers to optimize the outcomes of infants born prematurity:1.Interruption of sequencing constrains normal development.2.There are limits of viability of infants born preterm.3.Options for safe and effective therapies to improve the health and outcomes of prematurity births—for example, antenatal steroids. With the advances in technology and medical care over the last 50 years, we are able to support ever more immature infants born preterm. At present, there will be clear limits to viability related to fundamental developmental processes. For infants who survive prematurity, how do we address the issues related to Developmental Origins of Health and Disease (DOHaD) and the limits to cell biology and achieving healthy outcomes (Table)? Organogenesis and organ functions result from carefully sequenced transformations as organs grow and differentiate. Can the fetus recoup lost developmental steps with resilience after birth? How can we protect the fetus from these developmental disruptions and seek new ways of fully restoring the organ to more normal health trajectories over the life of the person? As we support smaller and more immature infants, research and clinical efforts should address the diversity of challenges to all organ systems in survivors. It is highly likely that as infants born preterm age, their long-term health will face expected and unexpected problems in organ function (lung, heart, kidney, brain) and disease susceptibility that are presently unrecognized.3Martinez F.D. Early-life origins of chronic obstructive pulmonary disease.N Engl J Med. 2016; 375: 871-878Crossref PubMed Scopus (334) Google Scholar, 4Jordan B.K. McEvoy C.T. Trajectories of lung function in infants and children: setting a course for lifelong lung health.Pediatrics. 2020; 146: e20200417Crossref PubMed Scopus (8) Google Scholar, 5Markopoulou P. Papanikolaou E. Analytis A. Zoumakis E. Siahanidou T. Preterm birth as a risk factor for metabolic syndrome and cardiovascular disease in adult life: a systematic review and meta-analysis.J Pediatr. 2019; 210: 69-80.e65Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 6Rodriguez A. Wang Y. Ali Khan A. Cartwright R. Gissler M. Jarvelin M.R. Antenatal corticosteroid therapy (ACT) and size at birth: a population-based analysis using the Finnish Medical Birth Register.PLoS Med. 2019; 16: e1002746Crossref PubMed Scopus (38) Google Scholar, 7Raikkonen K. Gissler M. Kajantie E. Associations between maternal antenatal corticosteroid treatment and mental and behavioral disorders in children.JAMA. 2020; 323: 1924-1933Crossref PubMed Scopus (164) Google Scholar, 8Backes C.H. Rivera B.K. Pavlek L. Beer L.J. Ball M.K. Zettler E.T. et al.Proactive neonatal treatment at 22 weeks of gestation: a systematic review and meta-analysis.Am J Obstet Gynecol. 2021; 224: 158-174Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar We need to carefully evaluate and study these infants as they age, carefully phenotyping and genotyping them throughout their life.TableThe 10 principles of DOHaD1Nathanielsz P.W. Life in the womb: the origin of health and disease. Promethean Press, Utica (NY)1999Google Scholar1.There are critical periods of vulnerability during development. Rapidly dividing cell populations are at the greatest risk.2.Programming has permanent effects that alter responses that influence disease susceptibility as the child age.3.Fetal development is a sequential process. Each phase establishes conditions for the subsequent phase.4.Programming results in structural changes in organs (cell numbers/receptors, etc)5.The placental function can program the fetus.6.Compensation for an adverse event carries a price as stages of development are missed.7.Attempts after birth to reverse the consequences of programming may have unwanted consequences.8.Fetal cellular responses may differ from adult responses.9.The effects of programming may pass across generations.10.Programming often has different effects on male and female fetuses. Open table in a new tab There seems to be new enthusiasm for supporting smaller and smaller and more immature infants born preterm.8Backes C.H. Rivera B.K. Pavlek L. Beer L.J. Ball M.K. Zettler E.T. et al.Proactive neonatal treatment at 22 weeks of gestation: a systematic review and meta-analysis.Am J Obstet Gynecol. 2021; 224: 158-174Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar,9Rysavy M.A. Mehler K. Oberthur A. Agren J. Kusuda S. McNamara P.J. et al.An immature science: intensive care for infants born at </=23 weeks of gestation.J Pediatr. 2021; 233: 16-25.e11Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar The rules of developmental biology are that at some point fetal development will be insufficient to permit survival. Based on the rules of DOHaD and cell biology, neonatology cannot support babies that are too small and too severely immature and achieve good long-term outcomes. Development occurs in a sequence of transformations. If a stage is missed, the fetus can't necessarily recoup it, so resilience in terms of buffering those effects will likely be only partial. As the field attempts to support smaller and immature infants there will be limits technologically and biologically. Relevant quote: "The concept that all 'expected losses' of human pregnancies should be prevented is a completely new idea in the long history of the human species." (Silverman W. Prescription for disaster. Ch 3, Pg. 15)2Silverman W.A. Where's the evidence? Debates in modern medicine. Oxford University Press, Oxford (UK)1998Google Scholar There are also conflicts of interest in the care of infants born preterm: (1) A recent vignette in the New England Journal of Medicine discussed whether to offer resuscitation to a 22-week pregnant mother who had multiple failed attempts of pregnancy. With the description of the case, the clinician talks to the hospital administrator about how to proceed.10Lee C.D. Nelin L. Foglia E.E. Neonatal resuscitation in 22-week pregnancies.N Engl J Med. 2022; 386: 391-393Crossref PubMed Scopus (5) Google Scholar This is a direct conflict of interest because these very tiny babies keep hospital beds occupied, and the hospital administrator has a major interest in keeping those beds occupied. The hospital administrator should have nothing to say about this clinical decision, as he or she will have no detailed knowledge of the care and survival statistics of these babies. This is a decision for clinicians and parents of an infant born premature to decide who they are going to support or who they are not going to support. Another conflict of interest is the ego of the clinicians who are trying to support smaller and smaller infants. For them, there is recognition that if they can get a 400-g infant to survive, this may be used as advertising by the hospital. Further, I do not think it is possible to adequately inform parents of what it means to do everything possible for an infant born prematurity without having a plan on how to terminate that care if it is not going in a positive direction. In the end, these infants have a very high mortality rate and poor long-term outcomes, which should be recognized.9Rysavy M.A. Mehler K. Oberthur A. Agren J. Kusuda S. McNamara P.J. et al.An immature science: intensive care for infants born at </=23 weeks of gestation.J Pediatr. 2021; 233: 16-25.e11Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar The parents need to know how difficult it will be to salvage an even more immature infant of 21 weeks' gestational age, that the child might be in the hospital for up to a year, and this will be a major stress on the parents and the rest of the family. Relevant quote: Callahan recognizes that the vulnerability to sickness and death can only be reduced, never vanquished. (Life is a universally fatal, sexually transmitted disease.) (Silverman W. Caring and curing. Ch 18, Pg. 72)2Silverman W.A. Where's the evidence? Debates in modern medicine. Oxford University Press, Oxford (UK)1998Google Scholar Although neonatologists and present newborn care systems hope that supporting the physiology of infants born preterm will enable their successful navigation to normal organ development and function, present concepts regarding developmental programming challenge the assumption that babies born prematurity will face a number of developmental problems resulting from the disruption of developmental sequencing. The Table provides a summary of 10 principles regarding the DOHaD. Infants born preterm have lung developmental abnormalities affecting the structure and function of the small airways that might be irreversible and have irreversible long-term consequences.3Martinez F.D. Early-life origins of chronic obstructive pulmonary disease.N Engl J Med. 2016; 375: 871-878Crossref PubMed Scopus (334) Google Scholar,4Jordan B.K. McEvoy C.T. Trajectories of lung function in infants and children: setting a course for lifelong lung health.Pediatrics. 2020; 146: e20200417Crossref PubMed Scopus (8) Google Scholar These infants leave the neonatal intensive care unit with low forced expiratory volume in 1 second and begin a life-long trajectory that predicts that they will develop chronic obstructive pulmonary dysplasia as young adults.3Martinez F.D. Early-life origins of chronic obstructive pulmonary disease.N Engl J Med. 2016; 375: 871-878Crossref PubMed Scopus (334) Google Scholar,4Jordan B.K. McEvoy C.T. Trajectories of lung function in infants and children: setting a course for lifelong lung health.Pediatrics. 2020; 146: e20200417Crossref PubMed Scopus (8) Google Scholar Abnormalities in heart, kidney, and brain development and metabolic disorders are associated with prematurity birth and may subsequently lead to metabolic syndrome.11Crump C. Groves A. Sundquist J. Sundquist K. Association of preterm birth with long-term risk of heart failure into adulthood.JAMA Pediatr. 2021; 175: 689-697Crossref PubMed Scopus (42) Google Scholar,12Soni R. Tscherning Wel-Wel C. Robertson N.J. Neuroscience meets nurture: challenges of prematurity and the critical role of family-centred and developmental care as a key part of the neuroprotection care bundle.Arch Dis Child Fetal Neonatal Ed. 2022; 107: 242-249Crossref PubMed Scopus (11) Google Scholar Follow-up studies of infants identify potential long-term effects on the health outcome of these developmental interruptions.11Crump C. Groves A. Sundquist J. Sundquist K. Association of preterm birth with long-term risk of heart failure into adulthood.JAMA Pediatr. 2021; 175: 689-697Crossref PubMed Scopus (42) Google Scholar,12Soni R. Tscherning Wel-Wel C. Robertson N.J. Neuroscience meets nurture: challenges of prematurity and the critical role of family-centred and developmental care as a key part of the neuroprotection care bundle.Arch Dis Child Fetal Neonatal Ed. 2022; 107: 242-249Crossref PubMed Scopus (11) Google Scholar Randomized controlled trials are lacking, but large epidemiologic population-based studies regarding the long-term health consequences of extreme prematurity are compelling. Nevertheless, they identify long-term consequences of preterm birth on subsequent health and are consistent with the concepts of the Barker hypotheses. Present outcomes data and clinical experience indicate that antenatal steroids and, in some cases, postnatal glucocorticoid therapy are necessary for the survival of infants born prematurity.13Jobe A.H. Goldenberg R.L. Antenatal corticosteroids: an assessment of anticipated benefits and potential risks.Am J Obstet Gynecol. 2018; 219: 62-74Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar Few data are available to support the utility of antenatal glucocorticoids in infants born prematurity, other than epidemiologic data. Although the original data on follow-up in a randomized controlled trial from New Zealand showed no developmental delays related to steroids, synthetic steroids are incredibly and unfortunately potent drugs affecting multiple organ systems.14Chrousos G.P. Kino T. Glucocorticoid signaling in the cell. Expanding clinical implications to complex human behavioral and somatic disorders.Ann N Y Acad Sci. 2009; 1179: 153-166Crossref PubMed Scopus (164) Google Scholar Antenatal steroids are used at very high doses and different pharmacologic preparations are used internationally. A recent study suggests that dosing has not been optimized to minimize off-target effects.15Jobe A.H. Kemp M. Schmidt A. Takahashi T. Newnham J. Milad M. Antenatal corticosteroids: a reappraisal of the drug formulation and dose.Pediatr Res. 2021; 89: 318-325Crossref PubMed Scopus (31) Google Scholar Although antenatal steroids are the global standard of care, they have never been approved by the Food and Drug Administration for the safety and efficacy in the fetus or newborn. Furthermore, the agonist used for animal models of DOHaD are antenatal steroids, which are highly potent epigenetic modifiers.14Chrousos G.P. Kino T. Glucocorticoid signaling in the cell. Expanding clinical implications to complex human behavioral and somatic disorders.Ann N Y Acad Sci. 2009; 1179: 153-166Crossref PubMed Scopus (164) Google Scholar Glucocorticoids have developmental effects on virtually all organs, including brain, heart, liver, kidney, and lung function via both transcriptional, post-transcriptional, and epigenetic mechanisms. There is a paucity of data regarding gestational dependent effects of glucocorticoids on organ formation, growth, and function, both in the developing fetus and across the lifespan. There are virtually no data on the effects of glucocorticoids on human organogenesis and formation as the embryo and fetus develop. The many controlled trials supporting the use of antenatal steroids to reduce infant mortality and infants born preterm include very few infants less than 28 weeks of gestation; thus, their effects on infants extremely born preterm remain poorly understood.13Jobe A.H. Goldenberg R.L. Antenatal corticosteroids: an assessment of anticipated benefits and potential risks.Am J Obstet Gynecol. 2018; 219: 62-74Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar The toxicity of glucocorticoids is influenced by dose, duration, and repetition of exposure. We should have concerns about DOHaD in very early preterm birth because these agents are likely to disrupt developmental processes and will likely have a greater influence on early developmental stages at times when progenitor cell growth and differentiation are highly active. We need scientific data to identify toxicity as to how we use them to improve the survival of most infants born preterm.15Jobe A.H. Kemp M. Schmidt A. Takahashi T. Newnham J. Milad M. Antenatal corticosteroids: a reappraisal of the drug formulation and dose.Pediatr Res. 2021; 89: 318-325Crossref PubMed Scopus (31) Google Scholar We should hope that antenatal glucocorticoids will merit careful scientific study, rather than just hoping that they are harmless. As the survival of infants born prematurity improves, the long-term adverse effects of both antenatal and postnatal glucocorticoids as well as other therapies merit ongoing analysis opening the door for opportunities to optimize long-term health outcomes and mitigate potential disease susceptibility.16Kaiser J. A gentler way to tweak genes: epigenome editing.Science. 2022; 376: 1034-1035Crossref PubMed Scopus (3) Google Scholar Relevant quotes: "All who drink of this treatment recover in a short time. Except those whom it does not help, who all die. It is obvious, therefore, that it fails only in incurable cases."—Galen"Once the rockets are up, who cares where they come down. That's not my department."—Wernher von Braun