Perinatal Neuroprotection in Preterm Birth

Abstract

Preterm birth is one of the main causes of perinatal morbidity and mortality. The rate of grade III and IV cerebral hemorrhages in infants with a birth weight of less than 1500 g in Germany in 2022 was 2.97% and the periventricular leukomalacia rate was 1.07%. In addition to these severe forms of brain damage which are visible on sonography, recent MRI studies carried out at the calculated due date of affected children also showed diffuse white and grey matter injuries, especially of the basal ganglia and the cerebellum, indicating impaired brain development and function. To offer these children the best possible start in life it is essential that they are cared for in a level I perinatal center right from the start. In addition, a number of perinatal measures are available which may significantly improve the neuronal development in preterm infants. They include the use of antenatal corticosteroids and magnesium as well as deferred cutting of the umbilical cord. Recent studies have shown that in contrast to term-born infants, hypothermia treatment is unsuitable for neuroprotection in premature babies. As secondary and tertiary cell damage may occur days or even weeks after the primary insult due to persistent inflammation and the lack of trophic stimulation, in addition to providing premature infants with the best possible initial care, it is also necessary to optimize subsequent care in the intensive care unit in terms of providing a neuronal-positive stimulating environment. Breastfeeding and supply of breast milk are particularly important in this context.

Keywords: neuroprotection; periventricular leukomalacia; periventricular-intraventricular hemorrhage; preterm birth.

Fig. 1

Perinatal brain damage in preterm infants is caused by a number of factors. They include hypoxia/ischemia, ascending infection as well as cardiovascular changes resulting from invasive ventilation or other invasive interventions required because of the immaturity of the infant. This leads to cell loss from astrogliosis, changes in oligodendrocyte development and consequently impaired myelination. Interventions to reduce brain damage in affected infants are possible in every phase, i.e., the primary, secondary, or tertiary phase, after the original insult . Source: Molloy EJ, El-Dib M, Soul J et al. Neuroprotective therapies in the NICU in preterm infants: present and future (Neonatal Neurocritical Care Series). Pediatr Res 2024; 95: 1224–1236. DOI: 10.1038/s41390-023-02895-6 . © The Author(s) 2023. Licensed under a Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ ). Adapted.).

Fig. 2

Cross-sectional diagram of the blood-brain barrier: endothelium with tight junctions, basement membrane, pericytes, astrocyte end-feet . GFAP = glial fibrillary acidic protein. Reprinted from Clinics in Perinatology, Volume 41, Issue 1, Praveen Ballabh, Pathogenesis and Prevention of Intraventricular Hemorrhage, 47–67, 2014, with permission from Elsevier. The Creative Commons license does not apply to this content. Any further use is subject to permission from Elsevier. [rerif]

Fig. 3

Compared to white matter vasculature, germinal matrix vessels are characterized by fibronectin deficiency and lower astrocyte end-feet coverage . a Representative frozen section through the germinal matrix and white matter in a preterm infant aged 24 GW. Fibronectin, visualized here in red with immunofluorescence, is strongly expressed in the white matter vasculature but not in germinal matrix vessels (arrows). Scale: 20 µm. b Representative frozen section through the germinal matrix and white matter in a preterm infant aged 24 GW. The endothelium is visualized in red with immunofluorescence and glial fibrillary acidic protein (GFAP) in the astrocytes is green. GFAP-positive astrocyte end-feet are wrapped closely around the external endothelium in white matter vasculature but are barely present in the germinal matrix (arrows). Scale: 20 µm. Reprinted from Clinics in Perinatology, Volume 41, Issue 1, Praveen Ballabh, Pathogenesis and Prevention of Intraventricular Hemorrhage, 47–67, 2014, with permission from Elsevier. The Creative Commons license does not apply to this content. Any further use is subject to permission from Elsevier. [rerif]

Fig. 4

Glucocorticoids suppress endothelial proliferation . a Pregnant rabbits were administered 0.2 mg/kg betamethasone on days 27 and 28 of gestation. Rabbit fetuses were delivered by caesarean section on day 29 of gestation (due date: 32nd day of gestation) and their brains were examined. The upper two images show representative frozen sections of the germinal matrix. The endothelium was visualized immunohistochemically with CD 31 antibodies (red), Ki67 (green) was used as the proliferation marker. Double staining (endothelial proliferation; arrows) was not observed after betamethasone administration. Scale 20 µm. b Representative cross-section through the germinal matrix and white brain matter of two infants aged 23 GW with and without the administration of betamethasone. The endothelium was visualized immunohistochemically with CD 34 antibodies (red); Ki67 (green) was used as the proliferation marker. Double staining (endothelial proliferation; arrows) was seen much less after betamethasone administration. Scale: 50 µm. Source: Govindaiah Vinukonda, Krishna Dummula, Sabrina Malik, Furong Hu, Carl I. Thompson, Anna Csiszar, Zoltan Ungvari, and Praveen Ballabh, Effect of Prenatal Glucocorticoids on Cerebral Vasculature of the Developing Brain, Stroke, 2010, Volume 41, Number 8, 1766–1773, DOI: 10.1161/strokeaha.110.588400 , The American Heart Association, with permission from Wolters Kluwer Health Inc. The Creative Commons license does not apply to this content. Use of this material in any format is prohibited without written permission from the publisher, Wolters Kluwer Health, Inc. Please contact permissions@lww.com for further information. [rerif]

Abb. 1

Perinatale Hirnschäden bei frühgeborenen Kindern werden durch eine Reihe von Faktoren verursacht. Dazu zählen die Hypoxie/Ischämie, die aszendierende Infektion, aber auch Alterationen des Herz-Kreislauf-Systems infolge invasiver Beatmung oder anderer invasiver Interventionen, die aufgrund der Unreife der Kinder indiziert sind. Dies führt zum Zellverlust durch Astrogliose, Alteration der Oligodendrozyten-Entwicklung und folglich Beeinträchtigung der Markscheidenbildung. Interventionen, den Hirnschaden der betroffenen Kinder zu reduzieren, sind in jeder Phase, d. h. primär, sekundär oder tertiär, nach dem Insult denkbar . Source: Molloy EJ, El-Dib M, Soul J et al. Neuroprotective therapies in the NICU in preterm infants: present and future (Neonatal Neurocritical Care Series). Pediatr Res 2024; 95: 1224–1236. DOI: 10.1038/s41390-023-02895-6 . © The Author(s) 2023. Licensed under a Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ ). Adapted and translated.).

Abb. 2

Schematische Darstellung der Blut-Hirn-Schranke im Querschnitt: Endothel mit Tight Junctions, Basalmembran, Perizyten, astrozytäre Endplatten . GFAP = Glial Fibrillary Acidic Protein. Reprinted from Clinics in Perinatology, Volume 41, Issue 1, Praveen Ballabh, Pathogenesis and Prevention of Intraventricular Hemorrhage, 47–67, 2014, with permission from Elsevier. The Creative Commons license does not apply to this content. Any further use is subject to permission from Elsevier. [rerif]

Abb. 3

Die Gefäße der germinalen Matrix sind im Vergleich zu denen der weißen Hirnsubstanz durch einen Mangel an Fibronektin und eine geringere Ummantelung mit astrozytären Endplatten charakterisiert . a Repräsentativer Gefrierschnitt durch die germinale Matrix und weiße Hirnsubstanz bei einem 24 SSW alten Frühgeborenen. Fibronektin stellt sich mittels Immunofluoreszenz rot dar und ist stark exprimiert in Gefäßen der weißen Hirnsubstanz, aber nicht in denen der germinalen Matrix (Pfeilspitzen), Maßstab: 20 µm. b Repräsentativer Gefrierschnitt durch die germinale Matrix und weiße Hirnsubstanz bei einem 24 SSW alten Frühgeborenen. Das Endothel stellt sich mittels Immunofluoreszenz rot dar und Glial Fibrillary Acidic Protein (GFAP) in den Astrozyten grün. GFAP-positive astrozytäre Endplatten umschließen das äußere Endothel in den Gefäßen der weißen Hirnsubstanz sehr eng, jedoch kaum in der germinalen Matrix (Pfeilspitzen), Maßstab: 20 µm. Reprinted from Clinics in Perinatology, Volume 41, Issue 1, Praveen Ballabh, Pathogenesis and Prevention of Intraventricular Hemorrhage, 47–67, 2014, with permission from Elsevier. The Creative Commons license does not apply to this content. Any further use is subject to permission from Elsevier. [rerif]

Abb. 4

Glukokortikoide supprimieren die Endothelproliferation . a Trächtige Hasen erhielten 0,2 mg/kg Betamethason am 27. und 28. Gestationstag. Die Feten wurden am 29. Gestationstag (Termin: 32. Gestationstag) per Sectio entwickelt und deren Gehirne untersucht. Die oberen beiden Abbildungen zeigen repräsentative Gefrierschnitte durch die germinale Matrix. Das Endothel ist mit CD31-Antikörpern (rot) immunhistochemisch dargestellt, Ki-67 (grün) wurde als Proliferationsmarker eingesetzt. Eine Doppelfärbung (Endothelproliferation; Pfeilspitzen) ist nach Betamethason-Applikation nicht zu beobachten. Maßstab 20 µm. b Repräsentative Gefrierschnitte durch die germinale Matrix und weiße Hirnsubstanz bei 2 23 SSW alten Frühgeborenen ohne und mit Applikation von Betamethason. Das Endothel ist mit CD34-Antikörpern (rot) immunhistochemisch dargestellt, Ki-67 (grün) wurde als Proliferationsmarker eingesetzt. Eine Doppelfärbung (Endothelproliferation; Pfeilspitzen) ist nach Betamethason-Applikation sehr viel seltener zu beobachten. Maßstab 50 µm. Source: Govindaiah Vinukonda, Krishna Dummula, Sabrina Malik, Furong Hu, Carl I. Thompson, Anna Csiszar, Zoltan Ungvari, and Praveen Ballabh, Effect of Prenatal Glucocorticoids on Cerebral Vasculature of the Developing Brain, Stroke, 2010, Volume 41, Number 8, 1766–1773, DOI: 10.1161/strokeaha.110.588400 , The American Heart Association, with permission from Wolters Kluwer Health Inc. The Creative Commons license does not apply to this content. Use of this material in any format is prohibited without written permission from the publisher, Wolters Kluwer Health, Inc. Please contact permissions@lww.com for further information. Wolters Kluwer Health, Inc., und die zugehörigen Gesellschaften übernehmen keine Verantwortung für die Richtigkeit der Übersetzung aus dem veröffentlichten englischen Original und haften nicht für eventuell auftretende Fehler. [rerif]