Evidence-based Neonatology in the Age of Information and Big Data

Balaji  Govindaswami

SECTION 1

1Introduction to Newborn Medicine

Evidence-based Neonatology in the Age of Information and Big Data

Balaji Govindaswami
Historical Understanding and Current Approaches in Neonatology

Sharyn Frentner, Robin Daughters Wu, Balaji Govindaswami
Educational Interventions to Improve Newborn Care

Emily Altick Hartford
Managing Your Patients’ Data with an Electronic Database

Joseph Schulman
Quality and Safety

Aarti Raghavan2

Evidence-based Neonatology in the Age of Information and Big DataCHAPTER 1

Balaji Govindaswami

“I honestly beleave it iz better tew know nothing than two know what ain't so.” 1874

(Everybody's Friend, or Josh Billing's Encyclopedia and Proverbial Philosophy of Wit and Humor)

ABSTRACT

Globally, disease burden is borne disproportionately by the poor. Those working in newborn medicine have the opportunity and responsibility to optimize the health of mothers and infants, moving towards health equity even in resource-poor populations. Worldwide implementation of simple public health measures and lifesaving practices at birth can improve newborn outcomes regardless of where they are born.

Information and big data assist in incorporating evidence-based medicine into practice, providing both best practices and best value for the community, families, and infants at birth and beyond. Education of both providers and society at large will ensure that advancements in knowledge and technology are employed to improve empathy and healthcare delivery for families and their newborn infants.

INTRODUCTION

As we begin the year 2020, much global news is devoted to dramatic climactic shifts, species extinctions, raging fires, and renewed projections of midcentury demographic changes, with rising waters and migratory populations ravaged no longer solely by Malthusian fears of war, famine, and disease. Still, many billion humans are successfully reproducing, with over 120 million live-born babies each year, while enjoying a century of dramatic increase in life expectancy and general quality of life. The probability of death remains greatest most proximate to the moment of birth. How many neonatal deaths are preventable? Equally importantly, how much early morbidity is preventable, avoiding a lifetime of crippling disability due to moderate and severe birth defects, many of which are amenable to repair and/or significant remediation? Inequities in distribution of wealth and resources combined with geopolitical instability have resulted in varied healthcare delivery models with much disparity in healthcare structures, processes, and outcomes. Great global institutions including the United Nations’ World Health Organization, myriad nongovernmental institutions (e.g., March of Dimes, Red Cross, and Red Crescent), and numerous academic and professional societies are devoted to the health of women and children, and health of the family and human population at large. How shall we use these resources to our collective human advantage?

For those of us privileged to witness the moment of birth, we have the opportunity not only to ameliorate the burden of death, disease, and disability, but also to promote individual well-being and joy in society. Neonatology, perceived as a pediatric subspecialty in recent decades, has existed through millennia as a tribal role borne largely by peer women birth attendants present in pregnancy and the puerperium. Disease burden in newborns has shifted to various providers in all manner of healthcare systems due to a wide spectrum of heterogeneity in 4newborn disease, complicated by resurgence of infectious disease (e.g., congenital syphilis in high-risk populations), novel viral diseases (H1N1, ZIKV, and hepatitis C), improved knowledge of rare disease (metabolic, genetic, environmental, or other largely unknown etiology), and novel application of surgical and nonsurgical [e.g., total body cooling (TBC)] technologies. Much disease burden accrues to infants born into disadvantaged populations with substance use and/or mental health and hygiene disorders.

Newborn medicine provides much opportunity for improved global health in this age of information and big data. We “labor” in a time and place, fraught with tedium, inequity, ethical dilemma, uncertainty, and exhaustion, and yet that joyous moment of birth is a daily reminder that every great journey, in personhood, deserves a healthy beginning.

ART, SCIENCE, AND HUMANITIES

Nowhere in human medicine is the complex interplay between art, science, and humanity more evident than in our nascent field of newborn medicine. Birthing is a normal physiological process, accompanied by the evolution of care to help both mother and child achieve a peaceful and healthy transition and to promote bonding of the mother-child couplet, eventually leading to a more united family and society. A significant proportion of these births are complicated by maternal, fetal, neonatal, or other disease. The increasingly stratified societies of today, with our microclimates of abundance and despair, make it difficult to generate solutions across socioeconomic boundaries and geopolitical axes. The age of information is transformative in that we can learn from experience in different parts of the world and bring it to bear relevance to our local environment and prioritize development of local programs and solutions.

Traditional models have explained natural disease progression^1,2 as it relates to infectious particle burden (Fig. 1). Newer paradigms seek to illuminate risk-factor-based contribution to prevalence of other disease, e.g., congenital disorders (Fig. 2).³ Every day new information emerges, providing novel insights into windows of opportunity for intervention,⁴ rare/orphan diseases,^5,6 or into fetal and neonatal developmental biology. Encoding of light in the developing retina drives several early physiological processes, including photoentrainment of circadian rhythm, light aversion, and pupillary light reflexes.⁷ Dramatic changes in the remarkably stable developmental trajectory in the first week of life are illustrated using extraction of transcriptomic, proteomic, metabolomic, and chemokine signaling, validated across two independent newborn cohorts from West Africa and Australasia. Innovative data integration and systems biology approaches provide insight into a dynamic phase key for health and disease.⁸ Disruption in maternal proinflammatory cytokines may irreversibly alter infant brain connectivity and future executive function.⁹ Furthermore, changes in healthcare service delivery models, diminishing societal inequity, and long predating the moment of birth can alter infant morbidity and mortality patterns.

Fig. 1: Stages of disease progression.

Fig. 2: Causes of congenital disorders.³Source: Adapted from Modell B, Darlison MW, Lawn JE. Historical overview of development in methods to estimate burden of disease due to congenital disorders. J Community Genet. 2018;9(4):341-5.

ROLE OF HEALTHCARE EDUCATION AND INFORMATICS IN BETTER SERVICE DELIVERY FOR NEWBORNS

We seek to provide tools and experience to educate providers, from the basics of “Helping Babies Breathe” to emphasizing the growing list of advanced practice providers and subspecialist pediatricians engaged in current healthcare delivery for newborns. The role of the general practitioner and family practice in global newborn medicine is vital and cannot be overemphasized. Our future belongs to communities of learners and learning devoted to newborn medicine. Novel definitions and nascent approaches to understanding of palliative and hospice care are requisite for optimal approaches to infants who cannot 5survive infancy. Furthermore, frameworks for electronically managing infant data have obvious implications for the growing application of informatics to healthcare service delivery improvement.

PATIENT SAFETY AND QUALITY, INFANT MENTAL HEALTH, FAMILY INTEGRATED CARE, AND HOME FOLLOW-UP

The Institute of Medicine report “To Err is Human” and subsequent iterations by the Institute for Healthcare Improvement have immortalized the principles of quality and safety in US healthcare delivery. Additional paradigms for addressing mental health and emotional well-being with family-integrated care during hospitalization followed by home follow-up for high-risk infants study other vital domains critical to establishing thoughtful systems of integrated care. The importance of charitable giving emphasizes the creative nature of addressing local gap funding vital to optimizing services for high-risk women, infants, and children. The quadruple aim of improved individual healthcare experience, value of care (i.e., better outcomes at lower per capita cost), equitable population health and bringing joy into the healthcare environment are now widely espoused and embraced principles.¹⁰

MATERNAL HEALTH AND PRECONCEPTION CARE

Maternal nutrition inclusive of adequate prenatal folate to prevent neural tube defects, prevention of maternal teratogen use (e.g., alcohol) and reducing frequency of smoking, marijuana, and medications and illicit substances known to adversely affect perinatal outcomes are critical to fetomaternal well-being. Maternal disease/disorders in pregnancy and obstetrical contributions to neonatal morbidity and mortality provide key insights into underlying risk to optimal newborn outcomes. The membranes, placenta, and umbilical cord are underappreciated and their disorders have not been optimally studied. Their contribution to perinatal sentinel events (PSE) relevant to neonatal encephalopathy is summarized in Section 3, Perinatal Medicine. Perspectives on PSE relevant to cerebral palsy by the neonatologist¹¹ and pediatric neurologist¹² are recommended reading. The global importance of preterm birth risk reduction has been reviewed elsewhere.¹³

Opportunities exist for optimizing neonatal care through understanding gaps in study areas between and within different expert clinician groups. Three recent public health examples in neonatal and infant mortality and morbidity reduction come to mind as examples of this transformative process.¹⁴

Delayed cord clamping (DCC) and its impact on preterm and term brain structure and function: Prematurity is the leading cause of death in the US, accounting for a third of infant mortality in 2002¹⁵ and globally the leading cause of death in children under age 5.¹⁶ DCC decreases mortality in preterm infants. A study of 18 randomized clinical trials (RCTs) comparing delay of ≥30 seconds (compared to early cord clamping of <30 seconds) in infants born at less than 37 weeks gestation showed reduced hospital mortality, with I² = 0 indicating no study heterogeneity.¹⁷ In three trials with 996 infants less than 29 weeks gestation, DCC reduced hospital mortality with a number needed to benefit of 20 (95% confidence interval, 11:100, I² = 0). It has thus been estimated that 300,000–700,000 lives could be saved annually worldwide with implementation of DCC for very preterm infants.¹⁷ Furthermore, in a Canadian retrospective cohort study of 4,680 infants born 2011–2015 at 22–28 weeks gestation, of whom 1,852 received DCC, compared to 2,828 receiving immediate cord clamping (ICC), DCC was associated with reduced risk of severe neurological injury or mortality.¹⁸ Cord milking in the very preterm is unsafe due to fourfold risk of major intraventricular hemorrhage (IVH).¹⁹ Long-term neurodevelopmental benefit has been shown in preterm infants randomized to DCC at ages 1.5 years²⁰ and 6.5 years.²¹ These benefits, attributed to brain structural and functional enhancement (volume and myelination), favor visual motor integration and fine language skill function.

Studies in term babies also have shown long-term neurodevelopmental benefits associated with DCC. Emerging brain imaging studies indicate that brain myelination at age 4 months is altered favorably in term infants who received ~3 minutes of DCC compared to those receiving <1 minute.²² Furthermore, long-term neurodevelopmental benefit, particularly in male infants, has been noted as late as age 4 years.²³ In spite of these emerging data, implementation of DCC in high-risk populations is limited even in centers choosing to implement DCC.²⁴ Optimal duration of “delay”²⁵ is not currently offered to the majority of the world's newborns at birth. Early implementation experience in DCC in California newborns shows disappointing results even in centers that intend to do so.²⁴
Universal saturation screening for critical congenital heart disease (CCHD): Congenital heart disease is the leading cause of death globally in the first five years of life for infants born with birth defects.²⁶ In the last two decades, advances in cardiovascular surgery have allowed for definitive care (defined as a 6restored circulation with two functioning ventricles) rather than palliative care for many infants with CCHD. In parallel, advances in prenatal diagnosis²⁷ and newborn saturation²⁸ have allowed for earlier diagnosis by prenatal detection¹⁴ or by transcutaneous saturation screening in up to 75% of asymptomatic term newborns when prenatal detection rates are <35%.²⁹ Centers for Disease Control and Prevention (CDC) data³⁰ from the first US states implementing universal CCHD screening corroborate earlier estimates of reduction in mortality from CCHD²⁹ in the US. Several nations have attempted to implement early saturation screening to prevent mortality and morbidity from CCHD, but without comprehensive screening, its usefulness is limited. In the People's Republic of China (PRC), universal saturation screening for infants with CCHD is planned for the ~15 million infants expected to be born in the year 2020. Even if and when fully implemented in the PRC, however, the majority of the world's newborns will not yet have benefit of this simple early CCHD detection/intervention. Early experience from California from universal CCHD implementation remains disappointing.³¹
Total body cooling and perinatal asphyxia: A portion of the world's annual 3 million stillbirths (sometimes miscategorized³²) may be preventable with simple public health measures such as introduction of birth attendants.³³ Perinatal asphyxia is a primary cause of early neonatal death, affecting 900,000 babies annually worldwide.³⁴

While TBC success in the adult and pediatric populations has been limited, investigations ranging from early lamb experiments³⁵ to human randomized trials^36,37 have established TBC as standard of care for newborn perinatal asphyxia in much of the industrialized world. Standardized registry protocols³⁸ and collaborative guidelines³⁹ have facilitated potentially best practice diffusion. Cooling increases survival without increasing disability.⁴⁰ While other therapies such as inhaled xenon and high dose erythropoietin (EPO) continue to be studied, it appears that additional high dose EPO benefit may be attenuated by underlying placental pathophysiology.¹² The importance of placental examination in the perinatal asphyxia population cannot be overemphasized.⁴¹ The majority of global newborn citizenry have no access to blood gas analysis at birth, thus providers are unable to ascertain asphyxial definition criteria for these infants, making interventions such as TBC inapplicable. Modified criteria may require consideration until appropriate technology transfer occurs, diminishing further perinatal inequity.

LEVELS OF EVIDENCE AND GRADING OF RECOMMENDATIONS, ASSESSMENT, DEVELOPMENT, AND EVALUATION

A thoughtful review of incorporating evidence-based medicine into practice is provided here and is recommended reading.⁴² Different medical and surgical societies have used mild variations in levels of evidence to guide best practice.^43,44 An illustration is given in Table 1.

The EQUATOR (Enhancing the QUality and Transparency Of health Research) network is developing a global initiative to achieve reporting of all health studies to increase value and minimize avoidable waste of human and financial investments in health research (equator-network.org)⁴⁶ by providing reporting guidelines for the main study types, in addition to developing other goals and resources. Examples include STROBE (Strengthening The Reporting of OBservational studies in Epidemiology),⁴⁷ SQUIRE (Standards for Quality Improvement Reporting Excellence),⁴⁸ guideline CONSORT (Consolidated Standards for Reporting Trials),⁴⁹ and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).⁵⁰

TABLE 1 Classification of category and strength of evidence.⁴⁵

	Category of evidence
1A	Meta-analysis of randomized clinical trials (RCTs)
1B	Evidence from ≥1 RCT
2A	Evidence from ≥1 controlled study without randomization
2B	Evidence from ≥1 quasi-experimental study
3	Evidence from nonexperimental, descriptive, comparative, correlation, and case-control studies
4	Expert opinions/respected authority/committees
	Strength of recommendation
A	Directly based on Category 1 evidence
B	Directly based on Category 2 or extrapolated recommendation from Category 1 evidence
C	Directly based on Category 3 or extrapolated recommendation from Category 1 or 2 evidence
D	Directly based on Category 4 or extrapolated recommendation from Category 1, 2 or 3 evidence
Source: Modified from Shekelle PG, Woolf SH, Eccles M, et al. Developing clinical guidelines. West J Med. 1999;170(6):348-51.

Why most published research findings are false?

While Ioannidis meant to be provocative in his sentinel paper with that title,⁵¹ he has brought attention to the fact that using p < 0.05 for statistical significance still only means that published studies likely conclude correctly two-thirds of the time and incorrectly one-third of the time if held to a higher degree of statistical certainty (e.g., p < 0.005). Uncertainties in the peer-review process^52–55 7and the movement toward democratizing knowledge (i.e., open-access publishing) are certain to aid dissemination of knowledge across socioeconomic boundaries.

PATIENT SAFETY

Shifting Landscapes: Implications for Research, Education, and Frontline Clinician Practice

A recent paper illustrates how medication side effects may be under-reported and provides a provocative new democratic paradigm for how both providers and patients can contribute in novel ways to reporting adverse effects.⁵⁶ Medication error prevention is comprehensively reviewed here and is recommended reading.⁵⁷ Providers treatment strategies may fall victim to the “twin traps of overtreatment and therapeutic nihilism”⁵⁸ often related to sociocultural bias in our (mis)interpretation of patient's background or our own inadvertent indoctrination. It is important to address these issues in ongoing medical education. Inappropriate management of “conflicts of interest” in US federally funded research is particularly alarming, as revealed recently by ProPublica.⁵⁹ This is also an opportune reminder that consumer-based investigation of current health research, conducted in this instance by using publicly available “big data”, will necessarily disrupt prior behavioral transgressions and helped clarify future regulation and research practice. Transparency and the necessary disinfectant of sunlight will eventually lead to more clarity in scientific findings, making them less likely to be manipulated by special interests in Big Pharma, establishment investigators and institutions. Ongoing ethics and leadership courses should seek to continually educate providers and institutions based on these rapidly shifting paradigms.

POTENTIAL OPPORTUNITIES IN FURTHER EXPLORATION OF KNOWLEDGE GAPS

An important part of evaluating newborn well-being at birth must include a visual examination of the placenta, cord, and membranes that have served the infant-mother couplet for months prior to delivery. Current reviews highlight the indications for submission of the placenta for a pathological examination.^60,61 While defined criteria for placental examination have existed for three decades,⁶² only a few institutions have >80–85% compliance.⁶³ Moreover, studies show that the majority of these recommendations are presumably unmeasured or disregarded in the majority of institutions.^64,65 It is concerning that nonmedically indicated examinations (e.g., from surgical deliveries) would result in more placental pathology examinations than those recommended for maternal, fetal/neonatal, or placental indications.⁶⁶ Establishing and maintaining placental registries may prove important to a better understanding of newborn health,⁶⁷ but historically have been complicated by ethical transgressions in early registry experience.⁶⁸

Since 1997, Denmark has instituted mandatory placental weight examination. An elegant observation of 924,422 live-born Danish singletons (1997–2011), including 7,569 infants with congenital heart disease, has shown that tetralogy of Fallot, double-outlet right ventricle, and major ventricular septal defects are all associated with deviations in fetal somatic and cerebral growth, possibly related to impaired placental growth.⁶⁹ This work exemplifies important contributions to understanding the relationship between congenital heart disease and placental anomalies, and possible implications for fetal growth in infants with heart disease. The association would have been missed, save for the 15 years of data yielded by the Danish approach to universal placental weight examination at birth.

In contrast, cord blood registries, with their better-understood utilitarian ethics, have gained more rapid public, consumer, and institutional support.⁷⁰ Their potential; however, has yet to be fully understood, explored, and utilized.

In an era of declining pediatric autopsy, postmortem radiograph⁷¹ and whole exome and genomic sequencing⁷² are tools worthy of further study to understand early, obscure causes of neonatal and infant mortality. Obviously, these approaches are currently limited to highly resourced settings and fundamental to exploration of these novel applications are indications;^73–76 ongoing yield, cost and value studies from Europe are forthcoming, and should enhance and refine approaches to infrequent causes of neonatal and infant death.

REDEFINING NORMAL AND ABNORMAL USING NOVEL NONINVASIVE APPROACHES

The growing role of noninvasive technology in the future of newborn medicine cannot be overemphasized. Applications range from early physiological responses predicting later illness severity in preterm infants⁷⁷ to algorithms for predictive monitoring of sepsis in neonatal intensive care unit (ICU).⁷⁸ While cerebral near-infrared spectroscopy monitoring for prevention of brain injury in very preterm infants requires further study⁷⁹ it appears application in newborns with hypoxic ischemic encephalopathy (HIE) treated with hypothermia may enhance understanding of brain perfusion, in conjunction with other technologies.^80,81 Addition of amplitude-integrated electroencephalography (aEEG) to near-infrared spectroscopy may improve short-8term prognostication.⁸² Furthermore studies of bilirubin in different race and ethnicity show sufficient variation in “nomograms”^83–85 that when placed in context of gestational age, chronological age, and underlying population genetic risk of red cell membrane or enzyme disorders⁸⁶ may lead to novel predictive management algorithms in the future. These select illustrative examples, while far from exhaustive, seek merely to illustrate the range of emerging and future possibilities in newborn care utilizing big data and noninvasive technology.

CONCLUSION

Societal sociopolitical commitment to universal healthcare coverage, particularly with attention to focused shift of public resources to populations with perinatal inequity and disparity, is fundamental to optimizing care for women and children from the moment of birth. In fact, commitment to societal health with an emphasis on population health education, mental hygiene, and well-being increases the likelihood of more planned pregnancies with greater devotion to optimal preconception care. In an era of “infinite” capital and thus much increased health resource inequity, present-day family variations include both gender binary and nonbinary adults aided by reproductive technology-assisted conception. The modern virtual village supporting this family has a different visual gestalt (genderbread.org), but not dissimilar needs for health equity and education. We need to ask the patient, who are you? and let their answer help inform the optimal treatment strategy. Advancement in technology has made it possible for conception and birthing to occur continents apart, and more recently, uterine transplants and three-parent embryos⁸⁷ to prevent lethal congenital mitochondrial disease raise further questions in future reproductive possibilities.

Similarly, awareness of healthcare options for best value in resource-constrained environments needs much critical self-examination in equitable investment of resources; each community must decide for itself what its choices are. Societal priorities may sometimes be fraught with danger prior to birth (e.g., selective prenatal female infanticide) or in childhood (e.g., ritual scarring, piercing, and genital mutilation). Societal education, including that of the growing body of stakeholders in newborn medicine, should seek to keep up with the rapid advancements in knowledge necessary to alter our attitudes and practices. An understanding of the rapidly shifting sands of mental health and substance use in populations is key to serving our newborns and families well. Awareness of preventable mortality and morbidity, investments in family planning, palliative care, and pediatric hospice while embracing missed opportunity for contribution to big data from “minority” populations give the healthcare community much to ponder, plan, and act upon as we embark on the third decade of this new millennium.

The moment of birth represents a triumphant opportunity for hope and joy for the family, community, and our species. Healthcare providers and systems need to build birthing facilities on this concept, providing optimal approaches to couplet care, early optimal bonding and nourishment with a deliberate focus on eliminating unnecessary interventions or needless mother-infant separation at birth or thereafter. High-risk pregnancies managed in regionalized perinatal systems provide opportunity for optimizing outcomes in the minority of situations that require focused devotion of resources and expertise to minimize morbidity and mortality, while providing kindness and supportive palliative care to that very small group unlikely to enjoy pleasure or endure pain, harm, and prolongation of suffering from any measure of care.

REFERENCES

Centers for Disease Control and Prevention (CDC). (2012). Lesson 1: Introduction to Epidemiology. Section 9: Natural History and Spectrum of Disease. [online] Available from: https://www.cdc.gov/csels/dsepd/ss1978/lesson1/section9.html. [Last accessed March, 2019].

Jewell NP. Natural history of diseases: Statistical designs and issues. Clin Pharmacol Ther. 2016;100(4):353–61.

Modell B, Darlison MW, Lawn JE. Historical overview of development in methods to estimate burden of disease due to congenital disorders. J Community Genet. 2018;9(4):341–5.

de Leeuw F, Barkhof F, Scheltens P. Progression of cerebral white matter lesions in Alzheimer's disease: a new window for therapy? J Neurol Neurosurg Psychiatry. 2005;76:1286–8.

McGovern MM, Aron A, Brodie SE, et al. Natural history of Type A Niemann-Pick disease. Neurology. 2006;66(2):228–32.

Pineda M, Juríčková K, Karimzadeh P, et al. Disease characteristics, prognosis and miglustat treatment effects on disease progression in patients with Niemann-Pick disease Type C: an international, multicenter, retrospective chart review. Orphanet J Rare Dis. 2019;14:32.

Caval-Holme F, Feller MB. Gap Junction Coupling Shapes the Encoding of Light in the Developing Retina. Curr Biol. 2019;29(23):4024–35.e5.

Lee AH, Shannon CP, Amenyogbe N, et al. Dynamic molecular changes during the first week of human life follow a robust developmental trajectory. Nat Commun. 2019;10(1):1092.

Rudolph MD, Graham AM, Feczko E, et al. Maternal IL-6 during pregnancy can be estimated from newborn brain connectivity and predicts future working memory in offspring. Nat Neurosci. 2018;21:765–72.

Sikka R, Morath JM, Leape L. The Quadruple Aim: care, health, cost and meaning in work. BMJ Qual Saf. 2015;24:608–10.

9 Wallenstein M, Sunshine P. Neonatal encephalopathy. In: Stevenson D, Benitz W, Sunshine P, Hintz S, Druzin M (Eds). Fetal and Neonatal Brain Injury. Cambridge: Cambridge University Press; 2017. pp. 1–20.

Wu YW, Goodman AM, Chang T, et al. Placental pathology and neonatal brain MRI in a randomized trial of erythropoietin for hypoxic-ischemic encephalopathy. Pediatr Res; 2019.

Govindaswami B, Jegatheesan P, Nudelman MJR, et al. Prevention of Prematurity: Advances and Opportunities. Clin Perinatol. 2018;45(3):579–95.

Levy DJ, Pretorius DH, Rothman A, et al. Improved prenatal detection of congenital heart disease in an integrated health care system. Pediatr Cardiol. 2013;34(3):670–9.

Callaghan WM, MacDorman MF, Rasmussen SA, et al. The contribution of preterm birth to infant mortality rates in the United States. Pediatrics. 2006;118(4):1566–73.

Chawanpaiboon S, Vogel JP, Moller A, et al. Global, regional, and national estimates of levels of preterm birth in 2014: a systematic review and modelling analysis. Lancet Glob Health. 2019;7(1):e37–e46.

Fogarty M, Osborn DA, Askie L, et al. Delayed Versus Early Umbilical Cord Clamping for Preterm Infants: A Systematic Review and Meta-Analysis. Am J Obstet Gynecol. 2017; 300(3):531–43.

Lodha A, Shah PS, Soraisham AS, et al. Association of Deferred vs Immediate Cord Clamping With Severe Neurological Injury and Survival in Extremely Low-Gestational-Age Neonates. JAMA Netw Open. 2019;2(3):e191286.

Katheria AC, Reister F, Hummler H, et al. LB 1: Premature Infants Receiving Cord Milking or Delayed Cord Clamping: A Randomized Controlled Non-inferiority Trial. Am J Obstet Gynecol. 2019;220:S682.

Mercer JS, Erickson-Owens DA, Vohr BR, et al. Effects of Placental Transfusion on Neonatal and 18 Month Outcomes in Preterm Infants: A Randomized Controlled Trial. J Pediatr. 2016;168:50-5.e1.

Bolk J, Padilla N, Forsman L, et al. Visual–motor integration and fine motor skills at 6½ years of age and associations with neonatal brain volumes in children born extremely preterm in Sweden: a population-based cohort study. BMJ Open. 2018;8:e020478.

Mercer JS, Erickson-Owens DA, Deoni SCL, et al. Effects of delayed cord clamping on 4-month ferritin levels, brain myelin content, and neurodevelopment: a randomized controlled trial. J Pediatr. 2018;203:266-72.e2.

Andersson O, Lindquist B, Lindgren M, et al. Effect of Delayed Cord Clamping on Neurodevelopment at 4 Years of Age: A Randomized Clinical Trial. JAMA Pediatr. 2015;169(7):631–8.

Tran CL, Parucha JM, Jegatheesan P, et al. Delayed Cord Clamping and Umbilical Cord Milking among Infants in California Neonatal Intensive Care Units. Am J Perinatol. 2020;37(2):151–7.

Nudelman MJR, Belogolovsky E, Jegatheesan P, et al. Effect of Delayed Cord Clamping on Umbilical Blood Gas Values in Term Newborns: A Systematic Review. Obstet Gynecol. 2020;135:576–82.

March of Dimes. (2006). Global Report on Birth Defects: The Hidden Toll of Dying and Disabled children. [online] Available from https://www.marchofdimes.org/materials/global-report-on-birth-defects-the-hidden-toll-of-dying-and-disabled-children-executive-summary.pdf. [Last accessed March, 2020].

Sklansky MS, Berman DP, Pruetz JD, et al. Prenatal Screening for Major Congenital Heart Disease. J Ultrasound Med. 2009;28:889–99.

de-Wahl Granelli A, Wennergren M, Sandberg K, et al. Impact of pulse oximetry screening on the detection of duct dependent congenital heart disease: A Swedish prospective screening study in 39, 821 newborns. BMJ. 2009;338:a3037.

Govindaswami B, Jegatheesan P, Song D. Oxygen saturation screening for critical congenital heart disease. Neoreviews. 2012;13(12):e724–31.

Abouk R, Grosse SD, Ailes EC, et al. Association of US State Implementation of Newborn Screening Policies for Critical Congenital Heart Disease With Early Infant Cardiac Deaths. JAMA. 2017;318(21):2111–8.

Siefkes H, Jocson M, Lakshminrusimha S, et al. Hospital reporting of critical congenital heart disease screening. J Investig Med. 2020;68:7.

Spector JM, Daga S. Preventing those so-called stillbirths. Bull World Health Organ. 2008;86(4):241–320.

Daga SR, Daga AS, Dighole RV, et al. Rural neonatal care: Dahanu experience. Indian Pediatr. 1992;29:189–93.

Lawn JE, Manandhar A, Haws RA, et al. Reducing one million child deaths from birth asphyxia: a survey of health systems gaps and priorities. Health Res Policy Syst. 2007;5:4.

Gluckman PD, Gunn TR, Johnston BM. The Effect of Cooling on Breathing and Shivering in Unanesthetized Fetal Lambs in Utero. J Physiol. 1983;343:495–506.

Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-Body Hypothermia for Neonates with Hypoxic–Ischemic Encephalopathy. N Engl J Med. 2005;353:1574–84.

Shankaran S, Pappas A, McDonald SA, et al. Childhood Outcomes after Hypothermia for Neonatal Encephalopathy. N Engl J Med. 2012;366:2085–92.

Olsen SL, Dejonge M, Kline A, et al. Optimizing therapeutic hypothermia for neonatal encephalopathy. Pediatrics. 2013;131(2):e591–603.

Jegatheesan P, Morgan A, Shimotake T, et al. (2015). Early Screening and Identification of Candidates for Neonatal Therapeutic Hypothermia Toolkit. [online] Available from: https://www.cpqcc.org/sites/default/files/FINAL%20HIE%20Toolkit_2-15-15%20California%20Perinatal%20Quality%20Care%20Collaborative.pdf. [Last accessed March, 2020].

Jacobs SE, Berg M, Hunt R, et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2013;(1):CD003311.

Harteman JC, Nikkels PG, Benders MJ, et al. Placental pathology in full-term infants with hypoxic-ischemic neonatal encephalopathy and association with magnetic resonance imaging pattern of brain injury. J Pediatr. 2013;163(4):968–95.e2.

Burns PB, Rohrich RJ, Chung KC. The levels of evidence and their role in evidence-based medicine. Plast Reconstr Surg. 2011;128(1):305–10.

Siemieniuk R, Guyatt GH. (2019). What is GRADE? [online] Available from: https://bestpractice.bmj.com/info/toolkit/learn-ebm/what-is-grade/. [Last accessed March, 2020].

10 CEBM. (2016). OECBM Levels of Evidence. [online] Available from: https://www.cebm.net/2016/05/ocebm-levels-of-evidence/. [Last accessed March, 2020].

Shekelle PG, Woolf SH, Eccles M, et al. Developing clinical guidelines. West J Med. 1999;170(6):348–51.

EQUATOR Network. EQUATOR Network: what we do and how we are organised. [online] Available from: https://www.equator-network.org/about-us/equator-network-what-we-do-and-how-we-are-organised/. [Last accessed March, 2020].

von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. PLoS Med. 2007;4(10):e296.

Ogrinc G, Davies L, Goodman D, et al. SQUIRE 2.0(Standards for QUality Improvement Reporting Excellence): revised publication guidelines from a detailed consensus process. BMJ Qual Saf. 2016;25:986–92.

Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. PLoS Med. 2010;7(3):e1000251.

Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.

Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124.

Tancock C. (2018). When reviewing goes wrong: the ugly side of peer review. [online] Available from: https://www.elsevier.com/connect/editors-update/when-reviewing-goes-wrong-the-ugly-side-of-peer-review. [Last accessed March, 2020].

Smith R. Peer review: a flawed process at the heart of science and journals. J R Soc Med. 2006;99(4):178–82.

Pollett M. (2020). The Evolution and Critical Role of Peer Review in Academic Publishing. [online] Available from: https://www.wiley.com/network/researchers/being-a-peer-reviewer/the-evolution-and-critical-role-of-peer-review-in-academic-publishing-2. [Last accessed March, 2020].

Balietti S. (2016). Science is suffering because of peer review's big problems. [online] Available from: https://newrepublic.com/article/135921/science-suffering-peer-reviews-big-problems. [Last accessed March, 2020].

Healy D, Mangin D. Clinical judgments, not algorithms, are key to patient safety—an essay by David Healy and Dee Mangin. BMJ. 2019;367:l5777.

Antonucci R, Porcella A. Preventing medication errors in neonatology: Is it a dream? World J Clin Pediatr. 2014;3(3):37–44.

Mamede S, Schmidt HG. The twin traps of overtreatment and therapeutic nihilism in clinical practice. Med Educ. 2014;48(1):34–43.

Armstrong D, Waldman A. (2019). Federally Funded Health Researchers Disclose at Least $188 Million in Conflicts of Interest. Can You Trust Their Findings? [online] Available from: https://www.propublica.org/article/federally-funded-health-researchers-disclose-at-least-188-million-in-conflicts-of-interest-can-you-trust-their-findings?utm_source=pardot&utm_medium=email&utm_campaign=majorinvestigations. [Last accessed March, 2020].

Baergen RN. Indications for submission and macroscopic examination of the placenta. APMIS. 2018;126:544–50.

Roberts DJ, McKenny A, Barss VA. (2019). The placental pathology report. [online] Available from: https://www.uptodate.com/contents/the-placental-pathology-report. [Last accessed March, 2020].

Yetter JF 3rd. Examination of the placenta. Am Fam Physician. 1998;57(5):1045–54.

Sills A, Steigman C, Ounpraseuth ST, et al. Pathologic examination of the placenta: recommended versus observed practice in a university hospital. Int J Womens Health. 2013;5:309–12.

Curtin WM, Krauss S, Metlay LA, et al. Pathologic examination of the placenta and observed practice. Obstet Gynecol. 2007;109(1):35–41.

Al Harazi AH, Frass KA. Low rate of placental pathological examination in a tertiary care hospital in Sana'a, Yemen. East Mediterr Health J. 2011;17(4):277–80.

Booth VJ, Nelson KB, Dambrosia JM, et al. What factors influence whether placentas are submitted for pathologic examination? Am J Obstet Gynecol. 1997;176(3):567–71.

Terry M. (2018). Modern Tech Teases out Important Role of the Placenta. [online] Available from: https://www.biospace.com/article/modern-tech-teases-out-important-role-of-the-placenta/. [Last accessed March, 2020].

Neumeister L. (2006). Up to 700 Women in West Not Told about Placenta Registry. [online] Available from: https://www.insurancejournal.com/news/west/2006/02/13/65318.htm. [Last accessed March, 2020].

Matthiesen NB, Henriksen TB, Agergaard P, et al. Congenital Heart Defects and Indices of Placental and Fetal Growth in a Nationwide Study of 924422 Liveborn Infants. Circulation. 2016;134:1546–56.

American College of Obstetricians and Gynecologists. (2016). Cord Blood Banking. [online] Available from: https://www.acog.org/Patients/FAQs/Cord-Blood-Banking?IsMobileSet=false. [Last accessed March, 2020].

Arthurs OJ, Hutchinson JC, Sebire NJ. Current issues in postmortem imaging of perinatal and forensic childhood deaths. Forensic Sci Med Pathol. 2017;13(1):58–66.

European Society of Human Genetics. (2018). Genomic testing for the causes of stillbirth should be considered for routine use. [online] Available from: www.sciencedaily.com/releases/2018/06/180617204419.htm. [Last accessed March, 2020].

Bouchireb K, Teychene AM, Rigal O, et al. Post-mortem MRI reveals CP2 deficiency after sudden infant death. Eur J Pediatr. 2010;169(12):1561–3.

Methner D, Scherer S, Welch K, et al. Postmortem genetic screening for the identification, verification, and reporting of genetic variants contributing to the sudden death of the young. Genome Res. 2016;26:1170–7.

Armes JE, Williams M, Price G, et al. Application of Whole Genome Sequencing Technology in the Investigation of Genetic Causes of Fetal, Perinatal, and Early Infant Death. Pediatr Dev Pathol. 2018;21(1):54–67.

Oshima Y, Yamamoto T, Ishikawa T, et al. Postmortem genetic analysis of sudden unexpected death in infancy: neonatal genetic screening may enable the prevention of sudden infant death. J Hum Genet. 2017;62:989–95.

Saria S, Rajani AK, Gould J, et al. Integration of early physiological responses predicts later illness severity in preterm infants. Sci Transl Med. 2010;2(48):48–65.

11 Fairchild KD. Predictive monitoring for early detection of sepsis in neonatal ICU patients. Curr Opin Pediatr. 2013;25(2):172–9.

Hyttel-Sorensen S, Greisen G, Als-Nielsen B, et al. Cerebral near-infrared spectroscopy monitoring for prevention of brain injury in very preterm infants. Cochrane Database Syst Rev. 2017;(9):CD011506.

Dix LML, van Bel F, Lemmers PMA. Monitoring Cerebral Oxygenation in Neonates: An Update. Front Pediatr. 2017;5:46.

Wintermark P, Hansen A, Warfield SK, et al. Near-infrared spectroscopy versus magnetic resonance imaging to study brain perfusion in newborns with hypoxic-ischemic encephalopathy treated with hypothermia. Neuroimage. 2014;85:287–93.

Goeral K, Urlesberger B, Giordano V, et al. Prediction of Outcome in Neonates with Hypoxic-Ischemic Encephalopathy II: Role of Amplitude-Integrated Electroencephalography and Cerebral Oxygen Saturation Measured by Near-Infrared Spectroscopy. Neonatology. 2017;112:193–202.

Olusanya BO, Mabogunje CA, Imosemi DO, et al. Transcutaneous bilirubin nomograms in African neonates. PLoS One. 2017;12(2):e0172058.

De Luca D, Jackson GL, Tridente A, et al. Transcutaneous Bilirubin Nomograms: A Systematic Review of Population Differences and Analysis of Bilirubin Kinetics. Arch Pediatr Adolesc Med. 2009;163(11):1054–9.

Varughese PM, Rajan N, Mani M, et al. Race specific nomograms: time for change? Int J Contemp Pediatr. 2018;5(2):420–6.

Hansen TWR. (2017). Neonatal Jaundice. [online] Available from: https://emedicine.medscape.com/article/974786-overview. [Last accessed March, 2020].

Hamzelou J. (2016). Exclusive: World's First Baby Born with new “3 parent” technique. [online] Available from: https://www.newscientist.com/article/2107219-exclusive-worlds-first-baby-born-with-new-3-parent-technique/. [Last accessed March, 2020].

Chapter Notes

Evidence-based Neonatology in the Age of Information and Big DataCHAPTER 1