{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:40:24Z","timestamp":1792172424989,"version":"4.4.0"},"reference-count":30,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","license":[{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>The PASSIoN study (Perinatal Arterial Stroke Treated With Stromal Cells Intranasally) demonstrated the feasibility and short-term safety of single-dose allogeneic mesenchymal stromal cells (MSCs) administered intranasally to neonates with perinatal arterial ischemic stroke between February 2020 and April 2021. In this study, we assessed long-term safety and neurodevelopmental outcomes and explored outcome differences with a non\u2013MSC-treated cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      In this post hoc analysis, we evaluated the safety of MSC administration by assessing brain tissue loss, adverse events, and neurodevelopmental outcomes of PASSIoN participants (N=10). The tissue loss ratio was calculated using semi-automatic segmentation based on neonatal and 3-month magnetic resonance imaging. At the age of 2 years, we assessed the occurrence of cerebral palsy, motor and cognitive delays (\n                      <jats:italic toggle=\"yes\">Z<\/jats:italic>\n                      score &lt;\u22121 SD), behavioral and language problems, visual field defects, and epilepsy. We selected a non\u2013MSC-treated registry cohort (N=39) born between 1994 and 2022, who would have met PASSIoN trial inclusion criteria to compare magnetic resonance imaging and outcome characteristics.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      At 3 months, the mean\u00b1SD tissue loss ratio of PASSIoN participants was 89\u00b121%, indicating more preserved tissue than expected based on initial stroke volume. By the age of 2 years, no related adverse events were reported. Two children (20%) developed cerebral palsy (Gross Motor Function Classification System I) without motor developmental delays. Cognitive, behavioral, and language problems affected 10% to 20%, and none had developed epilepsy. Compared with the registry cohort, and PASSIoN participants showed less often asymmetry of the posterior limb of the internal capsule (40% versus 81%;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.02) and the cerebral peduncle (10% versus 61%;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.01) on 3-month magnetic resonance imaging and had a better motor performance at the age of 2 years (median [interquartile range]\n                      <jats:italic toggle=\"yes\">Z<\/jats:italic>\n                      score, 0.3 [0.8] versus \u22120.4 [1.5];\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.003).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>This study demonstrates the long-term safety of intranasal MSC therapy in 10 infants with perinatal arterial ischemic stroke and may suggest better motor outcomes compared with the literature and a non\u2013MSC-treated cohort. Randomized controlled trials are required to confirm MSC efficacy for children with perinatal arterial ischemic stroke.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>REGISTRATION:<\/jats:title>\n                    <jats:p>\n                      URL:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n                      ; Unique identifier: NCT03356821.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/strokeaha.125.050786","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T09:00:10Z","timestamp":1752483610000},"page":"2410-2418","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["Perinatal Arterial Stroke Treated With Stromal Cells Intranasally: 2-Year Safety and Neurodevelopment"],"prefix":"10.1161","volume":"56","clinical-trial-number":[{"clinical-trial-number":"nct03356821","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2759-094X","authenticated-orcid":true,"given":"Nienke","family":"Wagenaar","sequence":"first","affiliation":[{"name":"Department of Neonatology (N.W., L.M.B., N.E.v.d.A., F.G., J.D., M.L.T., C.K., L.S.d.V., F.v.B., M.J.N.L.B.), University Medical Center Utrecht Brain Center and Wilhelmina Children\u2019s Hospital, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5857-0351","authenticated-orcid":true,"given":"Lisanne M.","family":"Baak","sequence":"additional","affiliation":[{"name":"Department of Neonatology (N.W., L.M.B., N.E.v.d.A., F.G., J.D., M.L.T., C.K., L.S.d.V., F.v.B., M.J.N.L.B.), University Medical Center Utrecht Brain Center and Wilhelmina Children\u2019s Hospital, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niek E.","family":"van der Aa","sequence":"additional","affiliation":[{"name":"Department of Neonatology (N.W., L.M.B., N.E.v.d.A., F.G., J.D., M.L.T., C.K., L.S.d.V., F.v.B., M.J.N.L.B.), University Medical Center Utrecht Brain Center and Wilhelmina Children\u2019s Hospital, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9284-1637","authenticated-orcid":true,"given":"Floris","family":"Groenendaal","sequence":"additional","affiliation":[{"name":"Department of Neonatology (N.W., L.M.B., N.E.v.d.A., F.G., J.D., M.L.T., C.K., L.S.d.V., F.v.B., M.J.N.L.B.), University Medical Center Utrecht Brain Center and Wilhelmina Children\u2019s Hospital, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0446-3646","authenticated-orcid":true,"given":"Jeroen","family":"Dudink","sequence":"additional","affiliation":[{"name":"Department of Neonatology (N.W., L.M.B., N.E.v.d.A., F.G., J.D., M.L.T., C.K., L.S.d.V., F.v.B., M.J.N.L.B.), University Medical Center Utrecht Brain Center and Wilhelmina Children\u2019s Hospital, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Luisa","family":"Tataranno","sequence":"additional","affiliation":[{"name":"Department of Neonatology (N.W., L.M.B., N.E.v.d.A., F.G., J.D., M.L.T., C.K., L.S.d.V., F.v.B., M.J.N.L.B.), University Medical Center Utrecht Brain Center and Wilhelmina Children\u2019s Hospital, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6011-2854","authenticated-orcid":true,"given":"Corine","family":"Koopman","sequence":"additional","affiliation":[{"name":"Department of Neonatology (N.W., L.M.B., N.E.v.d.A., F.G., J.D., M.L.T., C.K., L.S.d.V., F.v.B., M.J.N.L.B.), University Medical Center Utrecht Brain Center and Wilhelmina Children\u2019s Hospital, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6266-5724","authenticated-orcid":true,"given":"Cornelia H.","family":"Verhage","sequence":"additional","affiliation":[{"name":"Child Development and Exercise Center (C.H.V., R.M.J.C.E.), University Medical Center Utrecht, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rian M.J.C.","family":"Eijsermans","sequence":"additional","affiliation":[{"name":"Child Development and Exercise Center (C.H.V., R.M.J.C.E.), University Medical Center Utrecht, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heleen C.","family":"van Teeseling","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neuropsychology (H.C.v.T.), University Medical Center Utrecht, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liesbeth S.","family":"Smit","sequence":"additional","affiliation":[{"name":"Department of Neonatology (N.W., L.M.B., N.E.v.d.A., F.G., J.D., M.L.T., C.K., L.S.d.V., F.v.B., M.J.N.L.B.), University Medical Center Utrecht Brain Center and Wilhelmina Children\u2019s Hospital, Utrecht University, the Netherlands."},{"name":"Department of Pediatric Neurology, Erasmus MC-Sophia Children\u2019s Hospital, Rotterdam, the Netherlands (L.S.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6918-0930","authenticated-orcid":true,"given":"Reint K.","family":"Jellema","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Maastricht University Medical Center, the Netherlands (R.K.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo R.","family":"de Haan","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Emma Children\u2019s Hospital, Academic Medical Center, Amsterdam University Medical Center, the Netherlands (T.R.d.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrik J.","family":"ter Horst","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Beatrix Children\u2019s Hospital, University Medical Center Groningen, University of Groningen, the Netherlands (H.J.t.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3194-7005","authenticated-orcid":true,"given":"Willem P.","family":"de Boode","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Radboud University Medical Center, Radboud Institute for Health Sciences, Amalia Children\u2019s Hospital, Nijmegen, the Netherlands (W.P.d.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5603-5697","authenticated-orcid":true,"given":"Sylke J.","family":"Steggerda","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Willem-Alexander Children\u2019s Hospital, Leiden University Medical Center, the Netherlands (S.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5847-6886","authenticated-orcid":true,"given":"Susanne M.","family":"Mulder-de Tollenaer","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Isala Clinics, Zwolle, the Netherlands (S.M.M.-d.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0765-929X","authenticated-orcid":true,"given":"Koen P.","family":"Dijkman","sequence":"additional","affiliation":[{"name":"Department of Neonatology, Maxima Medical Center Veldhoven, the Netherlands (K.P.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin G.","family":"de Haar","sequence":"additional","affiliation":[{"name":"Cell Therapy Facility, Pharmacy Department, University Medical Center Utrecht, the Netherlands (C.G.d.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7282-8304","authenticated-orcid":true,"given":"Linda S.","family":"de Vries","sequence":"additional","affiliation":[{"name":"Department of Neonatology (N.W., L.M.B., N.E.v.d.A., F.G., J.D., M.L.T., C.K., L.S.d.V., F.v.B., M.J.N.L.B.), University Medical Center Utrecht Brain Center and Wilhelmina Children\u2019s Hospital, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"van Bel","sequence":"additional","affiliation":[{"name":"Department of Neonatology (N.W., L.M.B., N.E.v.d.A., F.G., J.D., M.L.T., C.K., L.S.d.V., F.v.B., M.J.N.L.B.), University Medical Center Utrecht Brain Center and Wilhelmina Children\u2019s Hospital, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1928-3050","authenticated-orcid":true,"given":"Cobi J.","family":"Heijnen","sequence":"additional","affiliation":[{"name":"Department of Psychological Sciences, Rice University, Houston, TX (C.J.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1223-1861","authenticated-orcid":true,"given":"Cora 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