Long-term outcomes and rehabilitation perspectives in children after neonatal sepsis: a systematic review

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Abstract

Neonatal sepsis remains a significant cause of mortality and long-term complications in newborns. However, evidence-based approaches to the rehabilitation of children surviving sepsis remain insufficiently developed, highlighting the need to synthesize available data. This review summarizes current evidence on the long-term outcomes and rehabilitation opportunities in children who experienced sepsis during the neonatal period. A scientific data search covering 2019–2024 was conducted in PubMed and eLibrary.ru databases using keywords related to rehabilitation, sepsis, and neonates. After removing duplicates and applying multi-stage screening for relevance to the review topic, 55 publications were included for analysis. The review revealed a high risk of long-term multi-organ sequelae after neonatal sepsis, including neurological impairments (cognitive deficits, cerebral palsy), sensory deficits, bronchopulmonary dysplasia, and cardiovascular dysfunction. It also highlights the lack of unified criteria and methodology for diagnosing neonatal sepsis, as well as protocols for assessing immediate and long-term outcomes in newborns who survived sepsis, and convincing evidence regarding the effectiveness of specific rehabilitation methods. The challenge of implementing modern rehabilitation in neonates is emphasized, since most existing scientific and practical approaches are based on extrapolation of data obtained from the rehabilitation of preterm infants or patients with other conditions, and are not supported by high-quality randomized controlled trials specifically in the population of children after sepsis. The review outlines the current three-stage rehabilitation model (in the intensive care unit, during inpatient care, and in outpatient settings) and discusses several key directions: neurorehabilitation (neuroprotective agents, kinesiotherapy, sensory integration), nutritional support (enriched feeding, optimization of protein–energy balance, prebiotics and probiotics), and psychological support (family-centered early intervention model). Promising approaches that require further investigation include novel neuroprotective agents (xenon, darbepoetin, topiramate, melatonin, caffeine, metformin, hydrocortisone, RLS-0071, stem cells, and sovateltide) and mesenchymal stromal cell secretome therapies. Despite the importance of this issue, the rehabilitation of children after neonatal sepsis remains a field with a low level of evidence. This review systematizes the available evidence, highlights the need for further research to develop evidence-based rehabilitation programs, and to establish individualized rehabilitation trajectories aimed at improving long-term outcomes and quality of life in neonates.

About the authors

Alexandr V. Golomidov

S.V. Belyaev Kuzbass Regional Clinical Hospital

Author for correspondence.
Email: golomidov.oritn@yandex.ru
ORCID iD: 0000-0001-7522-9094
SPIN-code: 4406-2065

MD, Cand. Sci. (Medicine)

Russian Federation, Kemerovo

Evgeny V. Grigoriev

Research Institute for Complex Issues of Cardiovascular Diseases

Email: grigorievev@hotmail.com
ORCID iD: 0000-0001-8370-3083
SPIN-code: 2316-2287

MD, Dr. Sci. (Medicine), Professor, Corresponding Member of the RAS

Russian Federation, Kemerovo

Vadim G. Mozes

Kemerovo State University

Email: vadimmoses@mail.ru
ORCID iD: 0000-0002-3269-9018
SPIN-code: 5854-6890

MD, Dr. Sci. (Medicine), Professor

Russian Federation, Kemerovo

Kira B. Mozes

S.V. Belyaev Kuzbass Regional Clinical Hospital

Email: kbsolo@mail.ru
ORCID iD: 0000-0003-2906-6217
SPIN-code: 7479-6695
Russian Federation, Kemerovo

References

  1. Hayes R, Hartnett J, Semova G, et al. Neonatal sepsis definitions from randomised clinical trials. Pediatr Res. 2023;93(5):1141–1148. doi: 10.1038/s41390-021-01749-3
  2. McGovern M, Giannoni E, Kuester H, et al. Challenges in developing a consensus definition of neonatal sepsis. Pediatr Res. 2020;88(1):14–26. doi: 10.1038/s41390-020-0785-x
  3. Molloy EJ, Bearer CF. Paediatric and neonatal sepsis and inflammation. Pediatr Res. 2022; 91(2):267–269. doi: 10.1038/s41390-021-01918-4
  4. Lekmanov AU, Mironov PI, Alexandrovich YuS, et al. Sepsis in children: federal clinical guidelines (draft). Russian Journal of Pediatric Surgery, Anesthesiology and Intensive Care. 2021;11(2):241–292. doi: 10.17816/psaic969 EDN: UDVCKO
  5. Aleksandrovich YS, Balashova EN, Boronina IV, et al. Sepsis in newborns (Draft Federal clinical guidelines). Pediatrician St. Petersburg. 2024;15(4):5–53. doi: 10.17816/PED1545-53 EDN: WZPBAT
  6. Taneri PE, Biesty L, Kirkham JJ, et al. Proposed core outcomes after neonatal sepsis: A consensus statement. JAMA Netw Open. 2025;8(2):e2461554. doi: 10.1001/jamanetworkopen.2024.61554
  7. Yao YM, Zhang H. Rehabilitation strategy for the improvement of long-term outcomes of patients after sepsis. Zhonghua Shao Shang Yu Chuang MianXiu Fu ZaZhi. 2022;20;38(3):201–206. (In Chinese). doi: 10.3760/cma.j.cn501120-20211004-00344
  8. Skei NV, Moe K, Nilsen TIL, et al. Return to work after hospitalization for sepsis: a nationwide, registry-based cohort study. Crit Care. 2023;27(1):443. doi: 10.1186/s13054-023-04737-7
  9. Cai S, Thompson DK, Anderson PJ, Yang JY-M. Short- and long-term neurodevelopmental outcomes of very preterm infants with neonatal sepsis: A systematic review and meta-analysis. Children (Basel). 2019;6(12):131. doi: 10.3390/children6120131
  10. Bedetti L, Corso L, Miselli F, et al. Neurodevelopmental outcome after culture-proven or so-called culture-negative sepsis in preterm infants. J Clin Med. 2024;13(4):1140. doi: 10.3390/jcm13041140
  11. Ong WJ, Seng JJB, Yap B, et al. Impact of neonatal sepsis on neurocognitive outcomes: a systematic review and meta-analysis. BMC Pediatr. 2024;24(1):505. doi: 10.1186/s12887-024-04977-8
  12. Bhat V, Bhandari V. Does neonatal sepsis independently increase neurodevelopmental impairment? Children (Basel). 2022;9(4):568. doi: 10.3390/children9040568
  13. Thompson DK, Cai S, Kelly CE, et al. Brain volume and neurodevelopment at 13 years following sepsis in very preterm infants. Pediatr Res. 2025;97:744–750. doi: 10.1038/s41390-024-03407-w
  14. Kartam M, Embaireeg A, Albalool S, et al. Late-onset sepsis in preterm neonates is associated with higher risks of cerebellar hemorrhage and lower motor scores at three years of age. Oman Med J. 2022;37(2):e368. doi: 10.5001/omj.2022.41
  15. Pugnaloni F, De Rose DU, Kipfmueller F, et al. Assessment of hemodynamic dysfunction in septic newborns by functional echocardiography: a systematic review. Pediatr Res. 2024;95(6):1422–1431. doi: 10.1038/s41390-024-03045-2
  16. Salimi U, Dummula K, Tucker MH, et al. Postnatal sepsis and bronchopulmonary dysplasia in premature infants: mechanistic insights into “New BPD”. Am J Respir Cell Mol Biol. 2022;66(2):137–145. doi: 10.1165/rcmb.2021-0353PS
  17. Huang J, Lin X-Z, Zheng Z, et al. Influencing factors for the development and severity of bronchopulmonary dysplasia in preterm infants with a gestational age of <32 weeks and a birth weight of <1500 g. Zhongguo Dang Dai Er Ke Za Zhi. 2022;24(12):1326–1333. (In Chinese). doi: 10.7499/j.issn.1008-8830.2207013
  18. Gabrielli M, Zaccaria R, Impagnatiello M, et al. Nutritional strategies for the treatment and prevention of sepsis outside the intensive care unit. Nutrients. 2024;16(23):3985. doi: 10.3390/nu16233985
  19. Kumar J, Anne RP, Meena J, et al. To feed or not to feed during therapeutic hypothermia in asphyxiated neonates: a systematic review and meta-analysis. Eur J Pediatr. 2023;182(6):2759–2773. doi: 10.1007/s00431-023-04950-0
  20. Boyd RN, Greaves S, Ziviani J, et al. Randomized comparison trial of rehabilitation very early for infants with congenital hemiplegia. J Pediatr. 2025;277:114381. doi: 10.1016/j.jpeds.2024.114381
  21. Deng W, Anastasopoulos S, deRegnier R-A, et al. Protocol for a randomized controlled trial to evaluate a year-long (NICU-to-home) evidence-based, high dose physical therapy intervention in infants at risk of neuromotor delay. PLoS One. 2023;18(9):e0291408. doi: 10.1371/journal.pone.0291408
  22. Dall’Orso S, Fifer WP, Balsam PD, et al. Cortical processing of multimodal sensory learning in human neonates. Cereb Cortex. 2021;31(3):1827–1836. doi: 10.1093/cercor/bhaa340
  23. Beltrán MI, Dudink J, de Jong TM, et al. Sensory-based interventions in the NICU: systematic review of effects on preterm brain development. Pediatr Res. 2022;92(1):47–60. doi: 10.1038/s41390-021-01718-w
  24. McAdams RM, Berube MW. Emerging therapies and management for neonatal encephalopathy-controversies and current approaches. J Perinatol. 2021;41(4):661–674. doi: 10.1038/s41372-021-01022-9
  25. Ma X, Shi Y. Whether erythropoietin can be a neuroprotective agent against premature brain injury: Cellular mechanisms and clinical efficacy. Curr Neuropharmacol. 2022;20(3):611–629. doi: 10.2174/1570159X19666210524154519
  26. Salamah A, El Amrousy D, Elsheikh M, Mehrez M. Citicoline in hypoxic ischemic encephalopathy in neonates: a randomized controlled trial. Ital J Pediatr. 2023;49(1):55. doi: 10.1186/s13052-023-01452-5
  27. Ranjan AK, Gulati A. Advances in therapies to treat neonatal hypoxic-ischemic encephalopathy. J Clin Med. 2023;12(20):6653. doi: 10.3390/jcm12206653
  28. Sharkey KA, Mawe GM. The enteric nervous system. Physiol Rev. 2023;103(2):1487–1564. doi: 10.1152/physrev.00018.2022
  29. Bell KA, Cherkerzian S, Drouin K, et al. Associations of macronutrient intake determined by point-of-care human milk analysis with brain development among very preterm infants. Children (Basel). 2022;9(7):969. doi: 10.3390/children9070969
  30. Fabrizio V, Trzaski JM, Brownell EA, et al. Individualized versus standard diet fortification for growth and development in preterm infants receiving human milk. Cochrane Database Syst Rev. 2020;11(11):CD013465. doi: 10.1002/14651858
  31. Cuna A, Morowitz MJ, Ahmed I, et al. Dynamics of the preterm gut microbiome in health and disease. Am J Physiol Gastrointest Liver Physiol. 2021;320(4):G411–G419. doi: 10.1152/ajpgi.00399.2020
  32. Morgan RL, Preidis GA, Kashyap PC, et al. Probiotic, prebiotic, and synbiotic work group. probiotics reduce mortality and morbidity in preterm, low-birth-weight infants: A systematic review and network meta-analysis of randomized trials. Gastroenterology. 2020;159(2):467–480. doi: 10.1053/j.gastro.2020.05.096
  33. Sharif S, Meader N, Oddie SJ, et al. Probiotics to prevent necrotisingenterocolitis in very preterm or very low birth weight infants. Cochrane Database Syst Rev. 2023;7(7):CD005496. doi: 10.1002/14651858.CD005496.pub6
  34. Wang Y, Florez ID, Morgan RL, et al. Probiotics, prebiotics, lactoferrin, and combination products for prevention of mortality and morbidity in preterm infants: A systematic review and network meta-analysis. JAMA Pediatr. 2023;177(11):1158–1167. doi: 10.1001/jamapediatrics.2023.3849
  35. Chi C, Buys N, Li C, et al. Effects of prebiotics on sepsis, necrotizing enterocolitis, mortality, feeding intolerance, time to full enteral feeding, length of hospital stay, and stool frequency in preterm infants: a meta-analysis. Eur J Clin Nutr. 2019;73(5):657–670. doi: 10.1038/s41430-018-0377-6
  36. Liu J, Zhu H, Li B, et al. Beneficial effect of butyrate on intestinal damage. J Pediatr Surg. 2020;55(6):1088–1093. doi: 10.1016/j.jpedsurg.2020.02.036
  37. Mueller NT, Dominguez-Bello MG, Appel LJ, Hourigan SK. ‘Vaginal seeding’ after a caesarean section provides benefits to newborn children: FOR: Does exposing caesarean-delivered newborns to the vaginal microbiome affect their chronic disease risk? The critical need for trials of ‘vaginal seeding’ during caesarean section. BJOG. 2020;127(2):301. doi: 10.1111/1471-0528.15979
  38. Orton J, Doyle LW, Tripathi T, et al. Early developmental intervention programmes provided post hospital discharge to prevent motor and cognitive impairment in preterm infants. Cochrane Database Syst Rev. 2024;2(2):CD005495. doi: 10.1002/14651858.CD005495.pub5
  39. Toma AI, Dima V, Alexe A, et al. Early intervention guided by the general movements examination at term corrected age-short term outcomes. Life (Basel). 2024;14(4):480. doi: 10.3390/life14040480
  40. Clarke-Sather AR, Compton C, Roberts K, et al. Systematic review of kangaroo care duration’s impact in neonatal intensive care units on infant-maternal health. Am J Perinatol. 2024;41(8):975–987. doi: 10.1055/a-2003-3935
  41. Lyamina SV, Baranovskiy DS, Kozhevnikova EO, et al. Mesenchymal stromal cells secretome: research methods and diagnostic significance in age-dependent changes and inflammaging-associated conditions (review of literature). Clinical Laboratory Diagnostics. 2024;69(3):140–147. doi: 10.51620.0869-2084-2024-69-3-134-140 EDN: LJMNFO
  42. Tung S, Delavogia E, Fernandez-Gonzalez A, et al. Harnessing the therapeutic potential of the stem cell secretome in neonatal diseases. Semin Perinatol. 2023;47(3):151730. doi: 10.1016/j.semperi.2023.151730
  43. Riley LE, Stark AR, Kilpatrick SJ, et al editors. Guidelines for perinatal care. American Academy of Pediatrics; 2012. 576 p.
  44. Ross K, Heiny E, Conner S, et al. Occupational therapy, physical therapy and speech-language pathology in the neonatal intensive care unit: Patterns of therapy usage in a level IV NICU. Res Dev Disabil. 2017;64:108–117. doi: 10.1016/j.ridd.2017.03.009
  45. Taito S, Taito M, Banno M, et al. Rehabilitation for patients with sepsis: A systematic review and meta-analysis. PLoS One. 2018;13(7):e0201292. doi: 10.1371/journal.pone.0201292
  46. Jouffroy R, Djossou F, Neviere R, et al. The chain of survival and rehabilitation for sepsis: concepts and proposals for healthcare trajectory optimization. Ann Intensive Care. 2024;14(1):58. doi: 10.1186/s13613-024-01282-6
  47. Sakai Y, Yamamoto S, Karasawa T, et al. Effects of early rehabilitation in sepsis patients by a specialized physical therapist in an emergency center on the return to activities of daily living independence: A retrospective cohort study. PLoS One. 2022;17(3):e0266348. doi: 10.1371/journal.pone.0266348
  48. Perepelitsa SА. Early rehabilitation of newborns moved by perinatal hypoxia. Physical and rehabilitation medicine, medical rehabilitation. 2020;2(1):71–78. doi: 10.36425/rehab19287 EDN: IEWIBI
  49. Fitzgerald JC, Kelly N-A, Hickey C, et al. Implementation of a follow-up system for pediatric sepsis survivors in a large academic pediatric intensive care unit. Front Pediatr. 2021;9:691692. doi: 10.3389/fped.2021.691692
  50. Shamsiev AM, Rabbimova DT, Shamsiev ZA. Differentiated approach to the problem of rehabilitation of babies with sepsis. Russian Journal of Pediatric Surgery. 2018;22(5):269–271. doi: 10.18821/1560-9510-2018-22-5269-271 EDN: VLCOMY
  51. Reddy AR, Stinson HR, Alcamo AM, et al. Pediatric sepsis requiring intensive care admission: potential structured follow-up protocols to identify and manage new or exacerbated medical conditions. Risk Manag Healthc Policy. 2023;16:1881–1891. doi: 10.2147/RMHP.S394458
  52. Zimmerman JJ, Banks R, Berg RA, et al. Trajectory of mortality and health-related quality of life morbidity following community-acquired pediatric septic shock. Crit Care Med. 2020;48(3):329–337. doi: 10.1097/ccm.0000000000004123
  53. Sankar J, Moodu S, Kumar K, et al. Functional outcomes at 1 year after PICU discharge in critically ill children with severe sepsis. Pediatr Crit Care Med. 2021;22(1):40–49. doi: 10.1097/pcc.0000000000002592
  54. Fan J, Wang J, Zhang X, et al. A home-based, post-discharge early intervention program promotes motor development and physical growth in the early preterm infants: a prospective, randomized controlled trial. BMC Pediatr. 2021;21:162. doi: 10.1186/s12887-021-02627-x

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