Download PDF
Semin Thromb Hemost 2023; 49(04): 409-415
DOI: 10.1055/s-0042-1756195
Review Article

Intracranial Hemorrhages in Neonates: Incidence, Risk Factors, and Treatment

Nadine G. Andersson
1   Center for Thrombosis and Hemostasis and Department of Pediatric Hematology and Oncology, Skåne University Hospital, Malmö/Lund, Sweden
2   Department of Clinical Sciences, Lund University, Lund, Sweden
,
Gili Kenet
3   National Hemophilia Center, Institute of Thrombosis and Hemostasis and the Amalia Biron Research Institute, Sheba Medical Center, Tel-Hashomer, Israel
4   Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

Hemostasis is a dynamic process that starts in utero. Neonates, especially those who are born preterm, are at high risk of bleeding. The coagulation system evolves with age, and the decreased levels of coagulation factors along with hypo-reactive platelets are counterbalanced with increased activity of von Willebrand factor, high hematocrit and mean corpuscular volume as well as low levels of coagulation inhibitors that promote hemostasis. Neonates with congenital bleeding disorders such as hemophilia are at even higher risk of bleeding complications. This review will focus upon one of the most devastating complications associated with neonatal bleeding: intracranial hemorrhages (ICH). While etiology may be multifactorial and impacted by maternal as well as fetal risk factors, the mode of delivery certainly plays an important role in the pathogenesis of ICH. We will address prematurity and congenital bleeding disorders such as hemophilia A and B and other rare bleeding disorders as risk factors and present an updated approach for treatment and possible prevention.

Keywords

intracranial hemorrhage - neonates - bleeding disorders


Publication History

Article published online:
15 September 2022

© 2022. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Reverdiau-Moalic P, Delahousse B, Body G, Bardos P, Leroy J, Gruel Y. Evolution of blood coagulation activators and inhibitors in the healthy human fetus. Blood 1996; 88 (03) 900-906
    CrossrefPubMedSearch in Google Scholar
  • 2 Andrew M, Paes B, Milner R. et al. Development of the human coagulation system in the healthy premature infant. Blood 1988; 72 (05) 1651-1657
    CrossrefPubMedSearch in Google Scholar
  • 3 Monagle P, Ignjatovic V, Savoia H. Hemostasis in neonates and children: pitfalls and dilemmas. Blood Rev 2010; 24 (02) 63-68
    CrossrefPubMedSearch in Google Scholar
  • 4 Ignjatovic V, Pelkmans L, Kelchtermans H. et al. Differences in the mechanism of blood clot formation and nanostructure in infants and children compared with adults. Thromb Res 2015; 136 (06) 1303-1309
    CrossrefPubMedSearch in Google Scholar
  • 5 Toulon P, Berruyer M, Brionne-François M. et al. Age dependency for coagulation parameters in paediatric populations. Results of a multicentre study aimed at defining the age-specific reference ranges. Thromb Haemost 2016; 116 (01) 9-16
    PubMedSearch in Google Scholar
  • 6 Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood. Blood 1992; 80 (08) 1998-2005
    CrossrefPubMedSearch in Google Scholar
  • 7 Summaria L. Comparison of human normal, full-term, fetal and adult plasminogen by physical and chemical analyses. Haemostasis 1989; 19 (05) 266-273
    PubMedSearch in Google Scholar
  • 8 Davenport P, Sola-Visner M. Hemostatic challenges in neonates. Front Pediatr 2021; 9: 627715
    CrossrefPubMedSearch in Google Scholar
  • 9 Nowak-Göttl U, Limperger V, Kenet G. et al. Developmental hemostasis: a lifespan from neonates and pregnancy to the young and elderly adult in a European white population. Blood Cells Mol Dis 2017; 67: 2-13
    CrossrefPubMedSearch in Google Scholar
  • 10 Strauss T, Levy-Shraga Y, Ravid B. et al. Clot formation of neonates tested by thromboelastography correlates with gestational age. Thromb Haemost 2010; 103 (02) 344-350
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 Strauss T, Elisha N, Ravid B. et al. Activity of Von Willebrand factor and levels of VWF-cleaving protease (ADAMTS-13) in preterm and full term neonates. Blood Cells Mol Dis 2017; 67: 14-17
    CrossrefPubMedSearch in Google Scholar
  • 12 Nagel K, Pai MK, Paes BA, Chan AK. Diagnosis and treatment of intracranial hemorrhage in children with hemophilia. Blood Coagul Fibrinolysis 2013; 24 (01) 23-27
    CrossrefPubMedSearch in Google Scholar
  • 13 Linder N, Haskin O, Levit O. et al. Risk factors for intraventricular hemorrhage in very low birth weight premature infants: a retrospective case-control study. Pediatrics 2003; 111 (5 Pt 1): e590-e595
    CrossrefPubMedSearch in Google Scholar
  • 14 Al-Abdi SY, Al-Aamri MA. A systematic review and meta-analysis of the timing of early intraventricular hemorrhage in preterm neonates: clinical and research implications. J Clin Neonatol 2014; 3 (02) 76-88
    CrossrefPubMedSearch in Google Scholar
  • 15 Bolisetty S, Dhawan A, Abdel-Latif M, Bajuk B, Stack J, Lui K. New South Wales and Australian Capital Territory Neonatal Intensive Care Units' Data Collection. Intraventricular hemorrhage and neurodevelopmental outcomes in extreme preterm infants. Pediatrics 2014; 133 (01) 55-62
    CrossrefPubMedSearch in Google Scholar
  • 16 McCauley KE, Carey EC, Weaver AL. et al. Survival of ventilated extremely premature neonates with severe intraventricular hemorrhage. Pediatrics 2021; 147 (04) e20201584
    CrossrefPubMedSearch in Google Scholar
  • 17 Brandt JS, Hill J, Reddy A. et al. Epidemiology of coronavirus disease 2019 in pregnancy: risk factors and associations with adverse maternal and neonatal outcomes. Am J Obstet Gynecol 2021; 224 (04) 389.e1-389.e9
    CrossrefPubMedSearch in Google Scholar
  • 18 Cole L, Dewey D, Letourneau N. et al. clinical characteristics, risk factors, and outcomes associated with neonatal hemorrhagic stroke: a population-based case-control study. JAMA Pediatr 2017; 171 (03) 230-238
    CrossrefPubMedSearch in Google Scholar
  • 19 Towner D, Castro MA, Eby-Wilkens E, Gilbert WM. Effect of mode of delivery in nulliparous women on neonatal intracranial injury. N Engl J Med 1999; 341 (23) 1709-1714
    CrossrefPubMedSearch in Google Scholar
  • 20 Lane PA, Hathaway WE. Vitamin K in infancy. J Pediatr 1985; 106 (03) 351-359
    CrossrefPubMedSearch in Google Scholar
  • 21 Sutor AH. Vitamin K deficiency bleeding in infants and children. Semin Thromb Hemost 1995; 21 (03) 317-329
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Andersson NG, Chalmers EA, Kenet G, Ljung R, Mäkipernaa A, Chambost H. PedNet Haemophilia Research Foundation. Mode of delivery in hemophilia: vaginal delivery and Cesarean section carry similar risks for intracranial hemorrhages and other major bleeds. Haematologica 2019; 104 (10) 2100-2106
    CrossrefPubMedSearch in Google Scholar
  • 23 Ljung RC. Intracranial haemorrhage in haemophilia A and B. Br J Haematol 2008; 140 (04) 378-384
    CrossrefPubMedSearch in Google Scholar
  • 24 Davies J, Kadir RA. Mode of delivery and cranial bleeding in newborns with haemophilia: a systematic review and meta-analysis of the literature. Haemophilia 2016; 22 (01) 32-38
    CrossrefPubMedSearch in Google Scholar
  • 25 Witmer C, Presley R, Kulkarni R, Soucie JM, Manno CS, Raffini L. Associations between intracranial haemorrhage and prescribed prophylaxis in a large cohort of haemophilia patients in the United States. Br J Haematol 2011; 152 (02) 211-216
    CrossrefPubMedSearch in Google Scholar
  • 26 Andersson NG, Auerswald G, Barnes C. et al. Intracranial haemorrhage in children and adolescents with severe haemophilia A or B - the impact of prophylactic treatment. Br J Haematol 2017; 179 (02) 298-307
    CrossrefPubMedSearch in Google Scholar
  • 27 Kulkarni R, Presley RJ, Lusher JM. et al. Complications of haemophilia in babies (first two years of life): a report from the Centers for Disease Control and Prevention Universal Data Collection System. Haemophilia 2017; 23 (02) 207-214
    CrossrefPubMedSearch in Google Scholar
  • 28 Chalmers EA, Alamelu J, Collins PW. et al; Paediatric & Rare Disorders Working Parties of the UK Haemophilia Doctors Organization. Intracranial haemorrhage in children with inherited bleeding disorders in the UK 2003-2015: a national cohort study. Haemophilia 2018; 24 (04) 641-647
    CrossrefPubMedSearch in Google Scholar
  • 29 Kasper CK, Lin JC. Prevalence of sporadic and familial haemophilia. Haemophilia 2007; 13 (01) 90-92
    CrossrefPubMedSearch in Google Scholar
  • 30 Balak DM, Gouw SC, Plug I. et al. Prenatal diagnosis for haemophilia: a nationwide survey among female carriers in the Netherlands. Haemophilia 2012; 18 (04) 584-592
    CrossrefPubMedSearch in Google Scholar
  • 31 Chalmers E, Williams M, Brennand J, Liesner R, Collins P, Richards M. Paediatric Working Party of United Kingdom Haemophilia Doctors' Organization. Guideline on the management of haemophilia in the fetus and neonate. Br J Haematol 2011; 154 (02) 208-215
    CrossrefPubMedSearch in Google Scholar
  • 32 Streif W, Knöfler R. Perinatal management of haemophilia. Hamostaseologie 2020; 40 (02) 226-232
    Search in Google Scholar
  • 33 Chalmers EA, Williams MD, Richards M. et al; Paediatric Working Party of Ukhcdo. Management of neonates with inherited bleeding disorders—survey of current UK practice. Haemophilia 2005; 11 (02) 186-187
    CrossrefPubMedSearch in Google Scholar
  • 34 Bidlingmaier C, Bergmann F, Kurnik K. Haemophilia A in two premature infants. Eur J Pediatr 2005; 164 (02) 70-72
    CrossrefPubMedSearch in Google Scholar
  • 35 Fink S, Kunzmann S, Andres O, Eyrich M, Wiegering V. Haemophilia in extreme immature preterm infants: increased risk for intracranial haemorrhage?. J Matern Fetal Neonatal Med 2014; 27 (06) 621-624
    CrossrefPubMedSearch in Google Scholar
  • 36 Moorehead PC, Chan AKC, Lemyre B. et al. A Practical Guide to the Management of the Fetus and Newborn With Hemophilia. Clin Appl Thromb Hemost 2018; 24 (Suppl. 09) 29S-41S
    CrossrefPubMedSearch in Google Scholar
  • 37 Kulkarni R, Lusher JM. Intracranial and extracranial hemorrhages in newborns with hemophilia: a review of the literature. J Pediatr Hematol Oncol 1999; 21 (04) 289-295
    CrossrefPubMedSearch in Google Scholar
  • 38 Andersson NG, Wu R, Carcao M. et al; ICH study group. Long-term follow-up of neonatal intracranial haemorrhage in children with severe haemophilia. Br J Haematol 2020; 190 (02) e101-e104
    CrossrefPubMedSearch in Google Scholar
  • 39 Smith AR, Leonard N, Kurth MH. Intracranial hemorrhage in newborns with hemophilia: the role of screening radiologic studies in the first 7 days of life. J Pediatr Hematol Oncol 2008; 30 (01) 81-84
    CrossrefPubMedSearch in Google Scholar
  • 40 Ballardini E, Tarocco A, Rosignoli C, Baldan A, Borgna-Pignatti C, Garani G. Universal head ultrasound screening in full-term neonates: a retrospective analysis of 6771 infants. Pediatr Neurol 2017; 71: 14-17
    CrossrefPubMedSearch in Google Scholar
  • 41 Alavi SER, Jalalvand M, Assadollahi V, Tabibian S, Dorgalaleh A. Intracranial hemorrhage: a devastating outcome of congenital bleeding disorders-prevalence, diagnosis, and management, with a special focus on congenital factor XIII deficiency. Semin Thromb Hemost 2018; 44 (03) 267-275
    Thieme ConnectPubMedSearch in Google Scholar
  • 42 Mishra P, Naithani R, Dolai T. et al. Intracranial haemorrhage in patients with congenital haemostatic defects. Haemophilia 2008; 14 (05) 952-955
    CrossrefPubMedSearch in Google Scholar
  • 43 Handley SC, Passarella M, Lee HC, Lorch SA. Incidence trends and risk factor variation in severe intraventricular hemorrhage across a population based cohort. J Pediatr 2018; 200: 24-29.e3
    CrossrefPubMedSearch in Google Scholar
  • 44 Neary E, McCallion N, Kevane B. et al. Coagulation indices in very preterm infants from cord blood and postnatal samples. J Thromb Haemost 2015; 13 (11) 2021-2030
    CrossrefPubMedSearch in Google Scholar
  • 45 Keir AK, Stanworth SJ. Neonatal plasma transfusion: an evidence-based review. Transfus Med Rev 2016; 30 (04) 174-182
    CrossrefPubMedSearch in Google Scholar
  • 46 Wiedmeier SE, Henry E, Sola-Visner MC, Christensen RD. Platelet reference ranges for neonates, defined using data from over 47,000 patients in a multihospital healthcare system. J Perinatol 2009; 29 (02) 130-136
    CrossrefPubMedSearch in Google Scholar
  • 47 Israels SJ, Daniels M, McMillan EM. Deficient collagen-induced activation in the newborn platelet. Pediatr Res 1990; 27 (4 Pt 1): 337-343
    CrossrefPubMedSearch in Google Scholar
  • 48 Josephson CD, Su LL, Christensen RD. et al. Platelet transfusion practices among neonatologists in the United States and Canada: results of a survey. Pediatrics 2009; 123 (01) 278-285
    CrossrefPubMedSearch in Google Scholar
  • 49 Curley A, Stanworth SJ, Willoughby K. et al; PlaNeT2 MATISSE Collaborators. Randomized trial of platelet-transfusion thresholds in neonates. N Engl J Med 2019; 380 (03) 242-251
    CrossrefPubMedSearch in Google Scholar
  • 50 Van Winckel M, De Bruyne R, Van De Velde S, Van Biervliet S. Vitamin K, an update for the paediatrician. Eur J Pediatr 2009; 168 (02) 127-134
    CrossrefPubMedSearch in Google Scholar
  • 51 Elalfy MS, Elagouza IA, Ibrahim FA, AbdElmessieh SK, Gadallah M. Intracranial haemorrhage is linked to late onset vitamin K deficiency in infants aged 2-24 weeks. Acta Paediatr 2014; 103 (06) e273-e276
    CrossrefPubMedSearch in Google Scholar
  • 52 Sutor AH, von Kries R, Cornelissen EA, McNinch AW, Andrew M. ISTH Pediatric/Perinatal Subcommittee. International Society on Thrombosis and Haemostasis. Vitamin K deficiency bleeding (VKDB) in infancy. Thromb Haemost 1999; 81 (03) 456-461
    Thieme ConnectPubMedSearch in Google Scholar
  • 53 Batorova A, Holme P, Gringeri A. et al; European Haemophilia Treatment Standardisation Board. Continuous infusion in haemophilia: current practice in Europe. Haemophilia 2012; 18 (05) 753-759
    CrossrefPubMedSearch in Google Scholar
  • 54 Hassan E, Lancashire J, Motwani J. Emicizumab in previously untreated and minimally treated infants. Haemophilia 2022; 28 (02) e61-e63
    CrossrefPubMedSearch in Google Scholar
  • 55 Callaghan MU, Negrier C, Paz-Priel I. et al. Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. Blood 2021; 137 (16) 2231-2242
    CrossrefPubMedSearch in Google Scholar
  • 56 Gouw SC, van der Bom JG, Marijke van den Berg H. Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood 2007; 109 (11) 4648-4654
    CrossrefPubMedSearch in Google Scholar
  • 57 Gouw SC, van den Berg HM, Fischer K. et al; PedNet and Research of Determinants of INhibitor development (RODIN) Study Group. Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study. Blood 2013; 121 (20) 4046-4055
    CrossrefPubMedSearch in Google Scholar
  • 58 Teitel J, Berntorp E, Collins P. et al. A systematic approach to controlling problem bleeds in patients with severe congenital haemophilia A and high-titre inhibitors. Haemophilia 2007; 13 (03) 256-263
    CrossrefPubMedSearch in Google Scholar
  • 59 Sørensen B, Dargaud Y, Kenet G. et al. On-demand treatment of bleeds in haemophilia patients with inhibitors: strategies for securing and maintaining predictable efficacy with recombinant activated factor VII. Haemophilia 2012; 18 (02) 255-262
    CrossrefPubMedSearch in Google Scholar
  • 60 McGoldrick E, Stewart F, Parker R, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2020; 12: CD004454
    CrossrefPubMedSearch in Google Scholar
  • 61 Hemmati F, Sharma D, Namavar Jahromi B, Salarian L, Farahbakhsh N. Delayed cord clamping for prevention of intraventricular hemorrhage in preterm neonates: a randomized control trial. J Matern Fetal Neonatal Med 2022; 35 (19) 3633-3639
    CrossrefPubMedSearch in Google Scholar