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Z Geburtshilfe Neonatol 2021; 225(03): 203-215
DOI: 10.1055/a-1019-6007
Übersicht

Den Mangel überleben: Natürliche Anpassungen bei Neugeborenen

Surviving the Lack: Natural Adaptations in Newborns
Dominique Singer
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Zusammenfassung

Neugeborene sind mit einer Reihe natürlicher Anpassungsmechanismen ausgestattet, die sie trotz ihres (körpergrößenabhängig) hohen Energiebedarfs vor Mangelversorgung schützen. Hierzu gehört der aus einer bradykarden Kreislaufzentralisation mit begleitender Apnoe bestehende, von wasserlebenden Säugetieren bekannte Tauchreflex, der einen sparsamen Umgang mit den O2-Reserven gewährleistet und sich in einer nachlaufenden Laktateinschwemmung aus der Körperperipherie äußert. Metabolisch verhalten sich Säugetierfeten „wie ein Organ der Mutter“ und zeigen damit eine Winterschlaf-artige Abweichung von der üblichen Körpergröße-Energieumsatz-Beziehung, durch die sie an das limitierte intrauterine O2-/Substratangebot angepasst sind. Im Falle einer Mangelversorgung können sie ihren Energiebedarf weiter drosseln, indem sie auf Wachstum verzichten, wobei der Plazenta eine Gatekeeper-Funktion zukommt. Ein postnataler O2-Mangel hat nicht nur eine Suppression der zitterfreien Thermogenese, sondern auch einen hypoxischen Hypometabolismus zur Folge, wie er sonst nur von poikilothermen Tierarten bekannt ist. Nach prolongierter Apnoe setzen Schnappatemzüge ein, die durch kurze pO2-Anstiege eine rudimentäre Herzaktion aufrechterhalten (Selbstwiederbelebung). Insgesamt verzögern diese Mechanismen ein kritisches O2-Defizit und bedingen so eher eine „Resistenz“ als eine „Toleranz“ gegenüber einer Hypoxie. Da sie auf einer (aktiven) Drosselung des Energiebedarfs beruhen, sind sie nicht leicht von dem (passiven) Zusammenbruch des Stoffwechsels aufgrund einer Hypoxie zu unterscheiden.

Abstract

Newborns are equipped with a number of natural adaptation mechanisms preventing them from impaired energy supply, despite their elevated (size-related) metabolic rate. These include the diving response known from aquatic mammals, which – being composed of apnea, bradycardia, and vasoconstriction – ensures an economical use of O2 reserves and results in a subsequent influx of lactate out of peripheral tissues. From a metabolic point of view, mammalian fetuses behave “like an organ of the mother” and thus exhibit a hibernation-like deviation from the overall metabolic size relationship that adapts them to the limited intrauterine O2/substrate availability. In case of lacking supply, they can reduce their energy demands even further by foregoing growth, with the placenta acting as a gatekeeper. Postnatal hypoxia does not only result in the suppression of non-shivering thermogenesis, but also in a hypoxic hypometabolism that otherwise has only been known from poikilothermic animals. After prolonged apnea, gasps do occur that maintain a rudimentary heart action through short elevations in pO2 (autoresuscitation). Overall, these mechanisms postpone a critical O2 deficit and thereby provide a “resistance” rather than a “tolerance” to hypoxia. As they are based on an (active) reduction in energy demand, they are not easy to distinguish from the (passive) breakdown of metabolism resulting from hypoxia.

Schlüsselwörter

Neugeborene - Hypoxie - Anpassung - Tauchreflex - Winterschlaf - Hypometabolismus

Key words

newborns - hypoxia - adaptation - diving response - hibernation - hypometabolism


Publication History

Received: 29 May 2020

Accepted after revision: 21 August 2020

Article published online:
07 December 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • Literatur

  • 1 Singer D. Phylogenese des Stoffwechsels der Säugetiere. Anästhesiol Intensivmed Notfallmed Schmerzther 2002; 37: 441-460
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Heldmaier G, Neuweiler G, Rössler W. Vergleichende Tierphysiologie. 2. Aufl. Berlin, Heidelberg: Springer Spektrum; 2013
    CrossrefGoogle Scholar
  • 3 Belkin DA. Anoxia: tolerance in reptiles. Science 1963; 139: 492-493
    CrossrefPubMedGoogle Scholar
  • 4 Suarez RK, Doll CJ, Buie AE. et al. Turtles and rats: a biochemical comparison of anoxia-tolerant and anoxia-sensitive brains. Am J Physiol 1989; 257: R1083-R1088
    PubMedGoogle Scholar
  • 5 Else PL, Turner N, Hulbert AJ. The evolution of endothermy: role for membranes and molecular activity. Physiol Biochem Zool 2004; 77: 950-958
    CrossrefPubMedGoogle Scholar
  • 6 Kleiber M. The fire of life: An introduction to animal energetics. New York: Wiley; 1961
    Google Scholar
  • 7 Schmidt-Nielsen K. Scaling: Why is animal size so important?. Cambridge: Cambridge University Press; 1984
    CrossrefGoogle Scholar
  • 8 Singer D. Metabolic adaptation to hypoxia: cost and benefit of being small. Respir Physiol Neurobiol 2004; 141: 215-228
    CrossrefPubMedGoogle Scholar
  • 9 Singer D. Metabolic size relationship: oxygen availability as the “missing link” between structure and function?. Thermochim Acta 2006; 446: 20-28
    CrossrefPubMedGoogle Scholar
  • 10 Singer D. Physiologie der Atmung im Kindesalter. In: Humberg A, Herting E, Göpel W. Beatmung von Kindern, Neugeborenen und Frühgeborenen: Ein Leitfaden für Pädiater, Neonatologen und Anästhesisten. Stuttgart: Thieme; 2017: 33-56
    Google Scholar
  • 11 Okken A, Koch J. eds Thermoregulation of sick and low birth weight neonates. Berlin: Springer; 1995
    CrossrefGoogle Scholar
  • 12 Agren J. The thermal environment of the intensive care nursery. In: Martin RJ, Fanaroff AA, Walsh MC. Fanaroff & Martin’s neonatal-perinatal medicine: diseases of the fetus and infant. 10th ed.. Philadelphia: Elsevier Saunders; 2015: 502-512
    Google Scholar
  • 13 Gekle M, Singer D. Wärmehaushalt und Temperaturregulation. In: Pape HC, Kurtz A, Silbernagl S. Physiologie. 9. Aufl. . Stuttgart: Thieme; 2019: 570-587
    Google Scholar
  • 14 Singer D, van der Meer F, Perez A. What is the right temperature for a neonate?. In: Herting E, Kiess W. Innovations and frontiers in neonatology (Pediatr Adolesc Med, vol. 22). Basel; Karger: 2020: 95-111
    Google Scholar
  • 15 Himwich HE, Alexander FAD, Fazekas JF. Tolerance of the newborn to hypoxia and anoxia. Am J Physiol 1941; 133: 327-339
    PubMedGoogle Scholar
  • 16 Lutz PL, Nilsson GE, Peréz-Pinzón MA. Anoxia tolerant animals from a neurobiological perspective. Comp Biochem Physiol B Biochem Mol Biol 1996; 113: 3-13
    CrossrefPubMedGoogle Scholar
  • 17 Singer D. Neonatal tolerance to hypoxia: a comparative-physiological approach. Comp Biochem Physiol A 1999; 123: 221-234
    CrossrefPubMedGoogle Scholar
  • 18 Mortola JP. How newborn mammals cope with hypoxia. Respir Physiol 1999; 116: 95-103
    CrossrefPubMedGoogle Scholar
  • 19 Larson J, Drew KL, Folkow LP. et al. No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates. J Exp Biol 2014; 217: 1024-1039
    CrossrefPubMedGoogle Scholar
  • 20 Gorr TA. Hypometabolism as the ultimate defence in stress response: how the comparative approach helps understanding of medically relevant questions. Acta Physiol 2017; 219: 409-440
    CrossrefPubMedGoogle Scholar
  • 21 Singer D. Physiologie des Feten. In: Kranke P. Anästhesie in der Geburtshilfe. Berlin: Springer; 2018: 121-135
    Google Scholar
  • 22 Singer D. Perinatale Asphyxie – ein gleitendes Kontinuum. In: Schwarz C, Stahl K. CTG – verstehen, bewerten, dokumentieren. 5. Aufl.. Hannover: Elwin Staude Verlag; 2017: 29-36
    Google Scholar
  • 23 Elsner R, Gooden B. Diving and asphyxia. A comparative study of animals and man. Monogr Physiol Soc 1983; 40: 1-168
    PubMedGoogle Scholar
  • 24 Butler PJ, Jones DR. Physiology of diving of birds and mammals. Physiol Rev 1997; 77: 837-899
    CrossrefPubMedGoogle Scholar
  • 25 Hill RW, Wyse GA, Anderson M. Animal physiology. Sunderland (Mass). Sinauer; 2004
    Google Scholar
  • 26 Panneton WM. The mammalian diving response: an enigmatic reflex to preserve life?. Physiology 2013; 28: 284-297
    CrossrefPubMedGoogle Scholar
  • 27 Jensen A, Berger R. Fetal circulatory responses to oxygen lack. J Dev Physiol 1991; 16: 181-207
    PubMedGoogle Scholar
  • 28 Jensen A, Garnier Y, Berger R. Dynamics of fetal circulatory responses to hypoxia and asphyxia. Eur J Obstet Gynecol Reprod Biol 1999; 84: 155-172
    CrossrefPubMedGoogle Scholar
  • 29 Bennet L. Sex, drugs and rock and roll: tales from preterm fetal life. J Physiol 2017; 595: 1865-1881
    CrossrefPubMedGoogle Scholar
  • 30 Turner JM, Mitchell MD, Kumar SS. The physiology of intrapartum fetal compromise at term. Am J Obstet Gynecol 2020; 222: 17-26
    CrossrefPubMedGoogle Scholar
  • 31 Scholander PF. The master switch of life. Sci Am 1963; 209: 92-106
    CrossrefPubMedGoogle Scholar
  • 32 Casey BM, McIntire DD, Leveno KJ. The continuing value of the Apgar score for the assessment of newborn infants. N Engl J Med 2001; 344: 467-471
    CrossrefPubMedGoogle Scholar
  • 33 Wu TW, Tamrazi B, Hsu KH. et al. Cerebral lactate concentration in neonatal hypoxic-ischemic encephalopathy: in relation to time, characteristic of injury, and serum lactate concentration. Front Neurol 2018; 9: 293
    CrossrefPubMedGoogle Scholar
  • 34 Singer D, Ince A, Hallmann B. Oxygen supply, body size, and metabolic rate at the beginning of mammalian life. Thermochim Acta 2002; 394: 253-259
    CrossrefPubMedGoogle Scholar
  • 35 Singer D, Mühlfeld C. Perinatal adaptation in mammals: the impact of metabolic rate. Comp Biochem Physiol A 2007; 148: 780-784
    CrossrefPubMedGoogle Scholar
  • 36 Hasselbalch AK. Über den respiratorischen Stoffwechsel des Hühnerembryos. Skand Arch Physiol 1900; 10: 353-402
    CrossrefPubMedGoogle Scholar
  • 37 Paganelli CV, Rahn H. Adult and embryonic metabolism in birds and the role of shell conductance. In: Seymour RS. Respiration and metabolism of embryonic vertebrates. Dordrecht: Dr W Junk Publishers; 1984: 193-204
    Google Scholar
  • 38 Bohr C. Der respiratorische Stoffwechsel des Säugethierembryos. Skand Arch Physiol 1900; 10: 413-424
    CrossrefPubMedGoogle Scholar
  • 39 Rahn H. Comparison of embryonic development in birds and mammals: birth weight, time, and cost. In: Taylor CR, Johansen K, Bolis L. A companion to animal physiology. Cambridge: Cambridge University Press; 1982: 124-137
    Google Scholar
  • 40 Dawes GS, Mott JC. The increase in oxygen consumption of the lamb after birth. J Physiol 1959; 146: 295-315
    CrossrefPubMedGoogle Scholar
  • 41 Schröder HJ, Power GG. Engine and radiator: fetal and placental interactions for heat dissipation. Exp Physiol 1997; 82: 403-414
    CrossrefPubMedGoogle Scholar
  • 42 Murray AJ. Oxygen delivery and fetal-placental growth: beyond a question of supply and demand?. Placenta 2012; 33: e16-e22
    CrossrefPubMedGoogle Scholar
  • 43 Postigo L, Heredia G, Illsley NP. et al. Where the O2 goes to: preservation of human fetal oxygen delivery and consumption at high altitude. J Physiol 2009; 587: 693-708
    CrossrefPubMedGoogle Scholar
  • 44 Hill JR, Rahimtulla KA. Heat balance and the metabolic rate of new-born babies in relation to environmental temperature; and the effect of age and of weight on basal metabolic rate. J Physiol 1965; 180: 239-265
    CrossrefPubMedGoogle Scholar
  • 45 Wieser W. A distinction must be made between the ontogeny and the phylogeny of metabolism in order to understand the mass exponent of energy metabolism. Respir Physiol 1984; 55: 1-9
    CrossrefPubMedGoogle Scholar
  • 46 Singer D. Thermometry and calorimetry in the neonate: recent advances in monitoring and research. Thermochim Acta 1998; 309: 39-47
    CrossrefPubMedGoogle Scholar
  • 47 Bauer K, Laurenz M, Ketteler J. et al. Longitudinal study of energy expenditure in preterm neonates <30 weeks’ gestation during the first three postnatal weeks. J Pediatr 2003; 142: 390-396
    CrossrefPubMedGoogle Scholar
  • 48 Bauer J, Maier K, Hellstern G. et al. Longitudinal evaluation of energy expenditure in preterm infants with birth weight less than 1000 g. Br J Nutr 2003; 89: 533-537
    CrossrefPubMedGoogle Scholar
  • 49 Bauer J, Werner C, Gerss J. Metabolic rate analysis of healthy preterm and full-term infants during the first weeks of life. Am J Clin Nutr 2009; 90: 1517-1524
    CrossrefPubMedGoogle Scholar
  • 50 DuBose TJ. Embryonic heart rates. Fertil Steril 2009; 92: e57-e58
    CrossrefPubMedGoogle Scholar
  • 51 Lindstedt SL, Calder WA. Body size, physiological time, and longevity of homeothermic animals. Quart Rev Biol 1981; 56: 1-16
    CrossrefPubMedGoogle Scholar
  • 52 Kaiser C. The physiology of natural hibernation. New York: Pergamon; 1961
    Google Scholar
  • 53 Geiser F. Reduction of metabolism during hibernation and daily torpor in mammals and birds: temperature effect or physiological inhibition?. J Comp Physiol 1988; 158 B: 25-37
    CrossrefPubMedGoogle Scholar
  • 54 Singer D, Bach F, Bretschneider HJ. et al. Metabolic size allometry and the limits to beneficial metabolic reduction: hypothesis of a uniform specific minimal metabolic rate. Hochachka PW, Lutz PL, Sick T. Surviving hypoxia: mechanisms of control and adaptation. Boca Raton: CRC Press; 1993: 447-458
    Google Scholar
  • 55 Heldmaier G, Ortmann S, Elvert R. Natural hypometabolism during hibernation and daily torpor in mammals. Respir Physiol Neurobiol 2004; 141: 317-329
    CrossrefPubMedGoogle Scholar
  • 56 Watts PD, Øritsland NA, Jonkel C. et al. Mammalian hibernation and the oxygen consumption of a denning black bear (Ursus americanus). Comp Biochem Physiol A 1981; 69: 121-123
    CrossrefPubMedGoogle Scholar
  • 57 Tøien Ø, Blake J, Edgar DM. et al. Hibernation in black bears: independence of metabolic suppression from body temperature. Science 2011; 331: 906-909
    CrossrefPubMedGoogle Scholar
  • 58 Ar A, Mover H. Oxygen tensions in developing embryos: system inefficiency or system requirement?. Israel J Zool 1994; 40: 307-326
    PubMedGoogle Scholar
  • 59 Reich B, Hoeber D, Bendix I. et al. Hyperoxia and the immature brain. Dev Neurosci 2016; 38: 311-330
    CrossrefPubMedGoogle Scholar
  • 60 Singer D, Engelhardt N, Ince A. et al. Body size effects on tissue metabolic rate and ischemia tolerance in neonatal rat and mouse hearts. Thermochim Acta 2004; 422: 19-23
    CrossrefPubMedGoogle Scholar
  • 61 Szdzuy K, Zeller U, Renfree M. et al. Postnatal lung and metabolic development in two marsupial and four eutherian species. J Anat 2008; 212: 164-179
    CrossrefPubMedGoogle Scholar
  • 62 Carter AM. Placental oxygen consumption. Part I: in vivo studies – a review. Placenta 2000; 21: S31-S37
    CrossrefPubMedGoogle Scholar
  • 63 Illsley NP. Placental metabolism. In: Kay HH, Nelson DM, Wang Y. The placenta: from development to disease. Chichester: Wiley-Blackwell; 2011: 50-56
    CrossrefGoogle Scholar
  • 64 Godfrey KM, Barker DJ. Fetal programming and adult health. Public Health Nutr 2001; 4: 611-624
    CrossrefPubMedGoogle Scholar
  • 65 Rinaudo P, Wang E. Fetal programming and metabolic syndrome. Annu Rev Physiol 2012; 74: 107-130
    CrossrefPubMedGoogle Scholar
  • 66 Roseboom TJ, Painter RC, van Abeelen AF. et al. Hungry in the womb: what are the consequences? Lessons from the Dutch famine. Maturitas 2011; 70: 141-145
    CrossrefPubMedGoogle Scholar
  • 67 Myers DA, Ducsay CA. Altitude, attitude and adaptation. Adv Exp Med Biol 2014; 814: 147-157
    CrossrefPubMedGoogle Scholar
  • 68 Hovi P, Andersson S, Eriksson JG. et al. Glucose regulation in young adults with very low birth weight. N Engl J Med 2007; 356: 2053-2063
    CrossrefPubMedGoogle Scholar
  • 69 Lacroix M, Kina E, Hivert MF. Maternal/fetal determinants of insulin resistance in women during pregnancy and in offspring over life. Curr Diab Rep 2013; 13: 238-244
    CrossrefPubMedGoogle Scholar
  • 70 Flood K, Unterscheider J, Daly S. et al. The role of brain sparing in the prediction of adverse outcomes in intrauterine growth restriction: results of the multicenter PORTO study. Am J Obstet Gynecol 2014; 211: 288.e1-5
    CrossrefPubMedGoogle Scholar
  • 71 Cohen E, Baerts W, van Bel F. Brain-sparing in intrauterine growth restriction: considerations for the neonatologist. Neonatology 2015; 108: 269-276
    CrossrefPubMedGoogle Scholar
  • 72 Mortola JP. Implications of hypoxic hypometabolism during mammalian ontogenesis. Respir Physiol Neurobiol 2004; 141: 345-356
    CrossrefPubMedGoogle Scholar
  • 73 Malan A, Mioskowski E. pH-temperature interactions on protein function and hibernation: GDP binding to brown adipose tissue mitochondria. J Comp Physiol B 1988; 158: 487-493
    CrossrefPubMedGoogle Scholar
  • 74 Jayasinghe D. Innate hypothermia after hypoxic ischaemic delivery. Neonatology 2015; 107: 220-223
    CrossrefPubMedGoogle Scholar
  • 75 Gautier H. Invited editorial on “Oxygen transport in conscious newborn dogs during hypoxic hypometabolism”. J Appl Physiol 1998; 84: 761-762
    CrossrefPubMedGoogle Scholar
  • 76 Rohlicek CV, Saiki C, Matsuoka T. et al. Oxygen transport in conscious newborn dogs during hypoxic hypometabolism. J Appl Physiol 1998; 84: 763-768
    CrossrefPubMedGoogle Scholar
  • 77 Mortola JP, Rezzonico R. Metabolic and ventilatory rates in newborn kittens during acute hypoxia. Respir Physiol 1988; 73: 55-67
    CrossrefPubMedGoogle Scholar
  • 78 Frappell P, Saiki C, Mortola JP. Metabolism during normoxia, hypoxia and recovery in the newborn kitten. Respir Physiol 1991; 86: 115-124
    CrossrefPubMedGoogle Scholar
  • 79 Sidi D, Kuipers JR, Teitel D. et al. Developmental changes in oxygenation and circulatory responses to hypoxemia in lambs. Am J Physiol 1983; 245: H674-H682
    PubMedGoogle Scholar
  • 80 Fahey JT, Lister G. Response to low cardiac output: developmental differences in metabolism during oxygen deficit and recovery in lambs. Pediatr Res 1989; 26: 180-187
    CrossrefPubMedGoogle Scholar
  • 81 Buchner T, Abele D, Pörtner HO. Oxyconformity in the intertidal worm Sipunculus nudus: the mitochondrial background and energetic consequences. Comp Biochem Physiol B 2001; 129: 109-120
    CrossrefPubMedGoogle Scholar
  • 82 Boutilier RG, Donohoe PH, Tattersall GJ. et al. Hypometabolic homeostasis in overwintering aquatic amphibians. J Exp Biol 1997; 200: 387-400
    CrossrefPubMedGoogle Scholar
  • 83 Fewell JE. Protective responses of the newborn to hypoxia. Respir Physiol Neurobiol 2005; 149: 243-255
    CrossrefPubMedGoogle Scholar
  • 84 Fewell JE, Smith FG, Ng VK. et al. Postnatal age influences the ability of rats to autoresuscitate from hypoxic-induced apnea. Am J Physiol Regul Integr Comp Physiol 2000; 279: R39-R46
    CrossrefPubMedGoogle Scholar
  • 85 Serdarevich C, Fewell JE. Influence of core temperature on autoresuscitation during repeated exposure to hypoxia in normal rat pups. J Appl Physiol 1999; 87: 1346-1353
    CrossrefPubMedGoogle Scholar
  • 86 Chen J, Magnusson J, Karsenty G. et al. Time- and age-dependent effects of serotonin on gasping and autoresuscitation in neonatal mice. J Appl Physiol 2013; 114: 1668-1676
    CrossrefPubMedGoogle Scholar
  • 87 Erickson JT. Central serotonin and autoresuscitation capability in mammalian neonates. Exp Neurol 2020; 326: 113162
    CrossrefPubMedGoogle Scholar
  • 88 Sanocka UM, Donnelly DF, Haddad GG. Autoresuscitation: a survival mechanism in piglets. J Appl Physiol 1992; 73: 749-753
    CrossrefPubMedGoogle Scholar
  • 89 Manole MD, Hickey RW, Momoi N. et al. Preterminal gasping during hypoxic cardiac arrest increases cardiac function in immature rats. Pediatr Res 2006; 60: 174-179
    CrossrefPubMedGoogle Scholar
  • 90 Samuels M, Wieteska S. eds Advanced paediatric life support: the practical approach. 5th . Oxford: Wiley-Blackwell; 2011
    CrossrefGoogle Scholar
  • 91 Walsh CK, Krongrad E. Terminal cardiac electrical activity in pediatric patients. Am J Cardiol 1983; 51: 557-561
    CrossrefPubMedGoogle Scholar
  • 92 Vannucci RC, Duffy TE. Cerebral metabolism in newborn dogs during reversible asphyxia. Ann Neurol 1977; 1: 528-534
    CrossrefPubMedGoogle Scholar
  • 93 Jones CT, Rolph TP. Metabolism during fetal life: a functional assessment of metabolic development. Physiol Rev 1985; 65: 357-430
    CrossrefPubMedGoogle Scholar
  • 94 Gunn AJ, Thoresen M. Neonatal encephalopathy and hypoxic-ischemic encephalopathy. Handb Clin Neurol 2019; 162: 217-237
    CrossrefPubMedGoogle Scholar
  • 95 Jacobs SE, Berg M, Hunt R. et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013; 2013: CD003311
    Google Scholar
  • 96 Wassink G, Davidson JO, Dhillon SK. et al. Therapeutic hypothermia in neonatal hypoxic-ischemic encephalopathy. Curr Neurol Neurosci Rep 2019; 19: 2
    CrossrefPubMedGoogle Scholar
  • 97 Titomanlio L, Kavelaars A, Dalous J. et al. Stem cell therapy for neonatal brain injury: perspectives and challenges. Ann Neurol 2011; 70: 698-712
    CrossrefPubMedGoogle Scholar
  • 98 Archambault J, Moreira A, McDaniel D. et al. Therapeutic potential of mesenchymal stromal cells for hypoxic ischemic encephalopathy: a systematic review and meta-analysis of preclinical studies. PLoS One 2017; 12: e0189895
    Google Scholar
  • 99 Hassell KJ, Ezzati M, Alonso-Alconada D. et al. New horizons for newborn brain protection: enhancing endogenous neuroprotection. Arch Dis Child Fetal Neonatal Ed 2015; 100: F541-F552
    CrossrefPubMedGoogle Scholar
  • 100 Davidson JO, Dean JM, Fraser M. et al. Perinatal brain injury: mechanisms and therapeutic approaches. Front Biosci 2018; 23: 2204-2226
    CrossrefPubMedGoogle Scholar