Perinatology pissn eissn Original article Perinatology Vol. 27, No. 4, December, Do

pissn 2508-4887 eissn 2508-4895 Original article Vol. 27, No. 4, December, 2016 Dose Brain MRI before Discharge at NICU Predict Neurodevelopmental Out comes in Very Low Birth Weight Infants? Young Mi Yoon, MD 1,2, Young Hwa Jung, MD 2, Ji Young Kim, MD 3, Hun Min Kim, MD 2, Chang Won Choi, MD 2, Beyong Il Kim, MD 2 1 Department of Pediatrics, Seoul National University Hospital, Seoul, 2 Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, 3 Department of Radiology, Seoul National University Bundang Hospital, Seongnam, Korea Received: 10 July 2016 Revised: 18 September 2016 Accepted: 20 September 2016 Correspondence to Chang Won Choi, MD Department of Pediatrics, Seoul National University Bundang Hospital, 82 Gumi-ro 173 Beongil, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Korea Tel: +82-31-787-7286 Fax: +82-31-787-4054 E-mail: choicw1029@gmail.com Copyright 2016 by The Korean Society of This is an Open Access article distributed under the terms of the Creative Com mons Attribution Non-Commercial License (http://creativecommons.org/license/ by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided that the original work is properly cited. Purpose: To test whether brain MRI can predict neurodevelopmental outcomes of very low birth weight (VLBW) infants in a single academic center. Methods: This was a retrospective study of VLBW infants admitted to neonatal intensive care unit from January 2010 to December 2014. Infants who were taken brain MRI before discharge and followed-up at 12 or 24 months corrected age (CA) were enrolled. The neurodevelopment outcomes included cerebral palsy (CP) and cognitive or motor delay on Bayley Scale of Infant Development-II. Results: Of the 255 survivors at discharge, 182 (71.4%) had a brain MRI. Any abnormalities on brain MRI were predictive of CP (odds ratio [OR] 15.8, 95% confidence interval [CI] 1.9-128.1) and motor delay(or 4.4, 95% CI 1.0-19.3) at 12 months CA. Moderate to severe white matter abnor malities on brain MRI were significantly correlated with CP (OR 49.0, 95% CI 10.1-238.2) and moderate to severe motor delay (OR 8.3, 95% CI 1.2-56.7) at 12 months CA, and CP (OR 43.8, 95% CI 6.4-299.8) at 24 months CA. Moderate to severe white matter abnormalities on brain MRI were consistently associated with CP at 12 and 24 months CA after adjustment for demographic and clinical variables and cranial ultrasonography findings (OR 800.5, 95% CI 6.9-92,665.7 at 12 months CA, OR 52.0, 95% CI 1.3-2,168.2 at 24 months CA). Conclusion: Moderate to severe white matter abnormalities on brain MRI strongly predicted cerebral palsy at 12 months and 24 months CA in VLBW infants. Key words: Infant, Premature, Magnetic resonance imaging, Neurodevelopmental outcomes 서론 최근주산기의학및신생아집중치료술의발달로미숙아생존율은눈에띄게향상되었다. 1, 2 생존한극소저체중출생아는신경발달장애의고위험군으로, 3-10 이들의생존율이향상됨에따라 신경발달장애에대한위험인자확인및추적관리의필요성이강조되고있다. 6-9 신경학적예후를예측하는인자로짧은재태기간, 부당경량아, 기관지폐이형성증, 동맥관개 존증, 다태아, 출생후스테로이드사용, 뇌초음파상이상등이알려져있으며, 9,11-17 특히출생 전후의감염과저혈압혹은혈압상승제의사용이뇌백질이상의주된위험인자로인식되고있 다. 12,13 극소저체중출생아에서신경발달학적예후를예측하기위한도구로뇌영상이사용되고 있으며, 이를통해정밀한추적관찰이필요한환자를선별하고아기의신경발달에대한전망을 보호자에게제공하며, 필요시조기중재를통해최종적인신경발달결과를향상시키고자하는 노력이시도되고있다. 12,18,19 전통적으로뇌초음파가주된뇌영상도구로임상에서사용되었으나최근뇌자기공명영상 (magnetic resonance imaging, MRI) 의사용이점차늘어나고있다. 뇌의이상소견을찾아내 고신경발달학적예후를예측하기위해뇌초음파와뇌 MRI 중어느방법이더유리한가를비교 한여러연구들이있었고, 18,20-24 대다수의연구에서뇌 MRI 가뇌초음파보다더높은해상도로

Park SH, et al. Dose Brain MRI before Discharge at NICU Predict Neurodevelopmental Outcomes in VLBW Infants? 뇌구조를보여주며, 미숙아의퇴원후신경발달에대한예후를더정확하게예측할수있다고보고하였다. 11,12,20-22,25-27 이에본연구는신생아집중치료실에서치료받고퇴원한극소저체중출생아를대상으로퇴원전에시행된뇌 MRI가교정연령 12 개월과 24 개월에서의신경발달결과를예측할수있는지알아보고자하였다. 대상및방법 2010 년 1월부터 2014 년 12 월까지분당서울대학교병원신생아집중치료실에입원하여치료를받은출생체중 1,500 g 미만의극소저체중출생아중퇴원전에뇌 MRI를시행한환아를확인하고이들중교정연령 12 개월과 24 개월에추적관찰을위해외래를방문한환아를대상으로하였다. 교정연령 12 개월에는교정연령 10-14 개월에추적관찰된환아들을, 교정연령 24 개월은교정연령 20-28 개월에추적관찰된환아들을포함하였다. 입원기간및외래추적관찰동안의의무기록을후향적으로분석하였다. 본연구는분당서울대학교병원임상연구윤리위원회의승인하에진행되었다 ( 과제번호 : B-1607-355-105). 1. 임상자료조사대상아의신생아호흡곤란증후군, 기관지폐이형성증, 동맥관개존증, 미숙아망막증, 패혈증, 신생아괴사성장염, 뇌실내출혈, 뇌실주위백질연화증등의이환여부를조사하였다. 신생아호흡곤란증후군은호흡곤란이존재하고, 산소의존도의증가를보이면서다른호흡곤란의원인이없이가슴 x-ray에서양측폐의과립상침윤, 폐용적감소와공기기관지음영을보이는경우로정의하였다. 4 기관지폐이형성증은 2001년에 National Institute of Child Health and Development Workshop에서합의된내용을바탕으로 28 월경후연령 (postmenstrual age) 36주이전에최소 28일이상산소의존성을보이는경우로정의하였으며, 월경후연령 36 주의산소의존성에따라경증 (fraction of inspired oxygen, FiO2=0.21), 중등증 (0.21<FiO2<0.3), 중증 (FiO2 0.3 또는인공호흡기를필요로하는경우 ) 으로분류하였다. 동맥관개존증은임상증상및심초음파를통해진단하였으며, 미숙아망막증은안과전문의가망막검사를통해진단하였다. 패혈증은전신증상및혈액검사에서이상소견을보이면서혈액배양검사에서균이배양되는경우로정의하였다. 신생아괴사성장염은 Bell 등 29 의분류를기준으로하였으며복부 X-ray 에서괴사성장염에합당한소견을보였을경우로정의하였다. 뇌실내출혈, 뇌실주위백질연화증은출생후 3일이내, 생후 7일과이후환아상태에따 라 1-2 주간격에따라시행된뇌초음파를통해진단하였고, 이중뇌실내출혈은고도뇌실내출혈인 grade III 와 IV를따로분류하였다. 2. 뇌 MRI 월경후연령 35 주가넘으면보호자의동의하에퇴원전에뇌 MRI를시행하였다. 뇌 MRI는 1.5 Tesla Intera Achieva (Philips Medical system, Best, the Netherlands) 로시행하였고, 본연구를위해횡단면 (axial), 관상면 (coronal) 또는시상면 (saggital) 의 T1- 강조영상 (T1-weighted conventional spin echo image: 4 mm thickness, repetition time 500 ms, echo time 11 ms) 과 T2- 강조영상 (T2-weighted fast spin echo image: 4 mm thickness, repetition time 3,000 ms, echo time 80 ms) 을관찰하였다. 뇌 MRI는영상의학과전문의의판독을바탕으로백질과회백질이상유무를확인하였으며, 뇌 MRI 에서이상이있는경우를이상소견 (any abnormality) 이라고정의하였다. 그리고 Woodward 등 11 이제안한뇌 MRI에대한점수체계를바탕으로백질의이상은백질신호이상의정도 (the nature and extent of white matter signal abnormality), 뇌실주위백질의용량감소 (the loss in the volume of periventricular white matter), 낭성이상의정도 (the extent of any cystic abnormalities), 뇌실확장 (ventricular dilatation), 뇌량두께감소 (the thinning of the corpus callosum) 등의 5가지척도에의해등급화하였으며, 각각의중증도를이상없음 (none), 경증 (mild), 중등증 (mo derate), 중증 (severe) 으로분류하여분석하였다 (Fig. 1). 회백질의이상은회백질신호이상의정도 (the extent of gray matter signal ab normality), 회백질성숙의정도 (the quality of gyral ma turation), 거미막밑공간의크기 (the size of the subarachnoid space) 등의 3가지척도에의해등급화되어정상 (normal), 비정상 (abnormal) 으로분류하여분석하였다. 뇌 MRI 에서경증이상의백질이상이있는경우를백질의이상소견 (any white matter abnormalities) 으로정의하였다. 3. 신경학적결과신경학적결과로는교정연령 12 개월과 24 개월에서의뇌성마비여부를확인하고인지발달과운동발달정도를평가하기위해베일리발달검사 (Bayley Scale of Infant Development-II, BSID- II) 결과를확인하였다. 뇌성마비는비진행성중추신경계장애로최소 1개이상의사지에서비정상적인근육긴장도와행동및자세의장애를가지는경우로정의하였으며, 4 신생아분과전문의, 소아신경분과전문의또는소아재활의학과전문의의신경학적, 이학적검사를통해진단하였다. BSID-II 는작업치료사에의해이루어졌으며인지발달지수 (mental developmental index), 운동발달지 228 www.e-kjp.org

2016 December;27(4):227-235 Fig. 1. Representative images of white matter abnormalities on brain MRI (axial T2-weighted and coronal T1-weighted images): A, normal white matter; B, mild abnormalities with ventricular dilatation; C, moderate abnormalities with cystic periventricular leukomalacia, hydrocephalus; D, severe abnormalities with diffuse signal abnormalities, decreased WM volume and multiple parenchymal cystic changes 수 (psychomotor development index) 를분석에이용하였다. 각발달지수는 85 점이상이면정상, 70 점에서 84 점사이이면경한발달지연 (mild developmental delay), 69 점이하면심한발달지연 (moderate to severe developmental delay) 으로정의하였으며, 30 발달지수 84 점이하를발달지연 (any developmental delay) 으로정의하였다. 4. 통계분석수집된자료에대한통계적분석은 SPSS for Windows version 21.0 (IBMCorp., Armonk, N, USA) 을이용하였다. 범주형변수의분석은 Chi-square test 또는 Fisher s exact test 를사용하여분석하였으며, 연속형변수는모수집단의경우 t-test 또는 mannwhitney test 를, 비모수집단의경우에는 ANOVA test 또는 Kruskal-Wallis test 를사용하여분석하였다. 뇌 MRI 소견과신경발달학적결과의독립적인연관성을보기위해로지스틱회귀분석을사용하여교란변수의영향을보정하였다. P value 값이 0.05 미만인경우에통계적유의성을인정하였다. 결과 1. 외래추적관찰 2010 년 1월부터 2014 년 12 월까지신생아집중치료실에서치료를받은극소저체중출생아는총 285 명이었으며, 이중입원기간동안사망한환아는 24 명 (8.4%), 타병원으로전원을간환아는 6 명 (2.1%), 퇴원한생존아는총 255명 (89.5%) 이었다. 생존환아중퇴원전뇌 MRI 를시행한환아는 182 명 (71.4%) 으로뇌MRI 시행시중위월경후연령 (median postmenstrual age) 은 37 +5 주 (35 +0-47 +5 주 ) 였다. 이중교정연령 12 개월에외래추적관찰이되었던환아는 142 명 (78%), BSID-II 까지시행한환아는 37명 (20.3%) 으로 BSID-II 시행시중위교정연령은 11.0개월 (10.0-13.4 개월 ) 이었다. 그리고교정연령 24개월에외래추적관찰이되었던환아는 81 명 (44.5%), BSID-II까지시행한환아는 18 명 (9.9%) 으로 BSID-II 시행시중위교정연령은 21.4 개월 (20.4-26.0개월 ) 이었다 (Fig. 2). 2. 퇴원전시행한뇌 MRI 국소저체중출생아에서퇴원전뇌 MRI 를총 182 명이시행하였으며, 이중뇌 MRI 에서이상소견을보였던환자는 79 명 (43.4%) 이었다. 그리고백질의이상소견을보였던환자는총 45 명 (24.7%) 이었으며, 회백질의이상소견을보였던환아는총 2명 (1.1%) 이었다. www.e-kjp.org 229

Park SH, et al. Dose Brain MRI before Discharge at NICU Predict Neurodevelopmental Outcomes in VLBW Infants? Fig. 2. The study population, Brain MRI was performed in 71.4% of eligible infants before discharge at NICU, and 78%, 44.5% of infants attended follow-up clinics at 12months, 24months corrected age. 이를백질이상의중증도에따라분류시이상없음이 137 명 (75.3 %), 경증이 29 명 (15.9%), 중등증이 8 명 (4.4%), 증증이 8 명 (4.4%) 이 었으며회백질이상의중증도에따라분류시정상이 181 명 (99.4%), 비정상이 1 명 (0.6%) 이었다. 뇌 MRI 상이상이있으나백질이나회백질이상에서제외된환자 들은주로점같은뇌실질출혈, 뇌실막하배기질에국한된출혈 (germinal matrix hemorrhage), 적은양의뇌실내출혈, 단두등 의모양이상 (brachycephalic configuration) 등의소견을보였 다. 3. 뇌 MRI 이상소견과신경발달학적결과 교정연령 12 개월까지추적관찰이되었던환아 142 명중뇌성마 비로진단되었던환아는총 10 명 (7.0%) 이었으며이중 2 명이이후 추적관찰이되지않았으나새로 1 명이뇌성마비로진단되어교정 연령 24 개월까지추적관찰이되었던환아 81 명중뇌성마비로진 단된환아는총 9 명 (11.1%) 이었다. 뇌성마비는대부분재활의학과 전문의를통해근긴장도증가및저하, 경직소견등의소견에따 라진단되었으며, 총 11 명의뇌성마비환아를뇌성마비의종류에 따라분류한결과하지마비가 6 명, 편마비가 3 명, 사지마비가 2 명 이었다. 뇌 MRI 에서이상소견을보였던환자는교정연령 12 개월에 58 명 (58/142, 40.8%), 교정연령 24 개월에 37 명 (37/81, 45.7%) 으로, 교정 연령 12 개월과 24 개월모두에서뇌성마비의발생빈도가유의하게 Table 1. Abnormalities on Brain MRI and Neurodevelopmental Outcome at 12 and 24 Months Corrected Age At 12 months corrected age 높았다 (P<0.001, P=0.001). 뇌 MRI 에서이상소견을보였던환자 군에서인지발달지연은교정연령 12 개월과 24 개월에서많이발생 하는경향을보였고 (P=0.053, P=0.052), 운동발달지연은교정연령 12 개월과 24 개월에서모두유의하게많이발생하였다 (P=0.043, P= 0.023) (Table 1). Normal MRI 4. 뇌 MRI 백질이상소견과신경발달학적결과 뇌 MRI 에서백질의이상소견을보였던환자는교정연령 12 개월 에 37 명 (37/142, 26.1%), 교정연령 24 개월에 23 명 (23/81, 28.4%) 으 로, 뇌 MRI 에서백질의이상소견을보인환자군에서교정연령 12 개월과 24 개월에모두뇌성마비의발생빈도가유의하게높았다 (P<0.001, P<0.001). 백질의이상소견을보인환자군에서교정연령 12 개월에운동발달지연이유의하게많이발생하였으며 (P=0.040) 심한인지발달지연이많이발생하는경향을보였다 (P=0.053) (Table 2). 그러나뇌 MRI 에서회백질의이상을보였던환자는 2 명 으로그수가너무적어분석에서제외하였다. Any abnormal MRI P value Cerebral palsy (%) 0/84 (0.0) 10/58 (17.2) <0.001 Any cognitive delay (%)* 3/12 (25.0) 9/25 (36.0) 0.503 Moderate to severe cognitive delay (%)* 0/12 (0.0) 3/25 (12.0) 0.217 Any motor delay (%)* 5/12 (41.7) 19/25 (76.0) 0.043 Moderate to severe motor delay (%)* 2/12 (16.7) 8/25 (32.0) 0.332 At 24 months corrected age Cerebral palsy (%) 0/44 (0.0) 9/37 (24.3) 0.001 Any cognitive delay (%) 1/6 (16.7) 8/12 (66.7) 0.052 Moderate to severe cognitive delay (%) 1/6 (16.7) 7/12 (58.3) 0.103 Any motor delay (%) 1/6 (16.7) 9/12 (75.0) 0.023 Moderate to severe motor delay (%) 1/6 (16.7) 8/12 (66.7) 0.052 *37 infants were assessed with the Bayley Scales of Infant Development-II at 12 months corrected age. 18 infants were assessed with the Bayley Scales of Infant Development-II at 24 months corrected age. 뇌 MRI 에서의백질이상의중증도에따라분류시교정연령 12 개월에서는이상없음이 105 명 (105/142, 73.9%), 경증이 24 명 (24/ 142, 16.9%), 중등증과증증이 13 명 (13/142, 9.2%) 이었으며, 교정 연령 24 개월에서는이상없음이 58 명 (58/81, 71.6%), 경증이 16 명 (16/ 81, 19.8%), 중등증과증증이 7 명 (7/81, 8.6%) 이었다. 백질이 상의중증도에따른신경발달학적결과를분석하였을때, 교정연 령 12 개월과 24 개월에서모두백질이상의중증도에따른뇌성마비 230 www.e-kjp.org

2016 December;27(4):227-235 의발생에유의한차이가있었다 (P<0.001). 중등증이상의백질이 상을보이는환자군에서백질이상이없거나경증인환자군에비해 교정연령 12 개월에심한인지발달지연을보였으나 (P<0.001), 교정 연령 24 개월에서는인지발달지연발생의차이가없었다. 또한운동 발달지연은교정연령 12 개월와 24 개월에서모두백질이상의중증 도에따른차이가없었다 (Table 3). Table 2. White Matter Abnormalities on Brain MRI and Neurodevelopmental Outcome at 12 and 24 Months Corrected Age At 12 months corrected age No white Any white matter matter abnormalities abnormalities P value Cerebral palsy (%) 0/105 (0.0) 10/37 (27.0) <0.001 Any cognitive delay (%)* 6/20 (30.0) 6/17 (35.3) 0.732 Moderate to severe cognitive delay (%)* 0/20 (0.0) 3/17 (17.6) 0.053 Any motor delay (%)* 10/20 (50.0) 14/17 (82.4) 0.040 Moderate to severe motor delay (%)* 4/20 (20.0) 6/17 (35.3) 0.297 At 24 months corrected age Cerebral palsy (%) 0/58 (0.0) 9/23 (39.1) <0.001 Any cognitive delay (%) 4/9 (44.4) 5/9 (55.6) 0.647 Moderate to severe cognitive delay (%) 3/9 (33.3) 5/9 (55.6) 0.357 Any motor delay (%) 3/9 (33.3) 7/9 (77.8) 0.065 Moderate to severe motor delay (%) 3/9 (33.3) 6/9 (66.7) 0.169 *37 infants were assessed with the Bayley Scales of Infant Development-II at 12 months corrected age. 18 infants were assessed with the Bayley Scales of Infant Development-II at 24 months corrected age. 5. 뇌 MRI 이상소견과신경발달학적결과와의독립적연관성뇌 MRI 이상소견과교정연령 12 개월과 24 개월의신경발달학적결과와의독립적인연관성을분석하기위해극소저체중출생아의신경발달학적결과에영향을미칠수있는교란변수로출생체중, 재태연령, 성별, 다태아여부, 기관지폐이형성증, 동맥관개존증, 출생후스테로이드사용, 패혈증, 신생아괴사성장염과초음파검사로확인된뇌실내출혈, 뇌실주위백질연화증을선정하였다. 이들교란변수의영향을보정한후뇌 MRI 의이상소견은교정연령 12 개월에서의운동발달지연과유의한연관성을보였다 (odds ratio (OR) 12.9, 95% confidence interval (CI) 1.1-151.3). 뇌 MRI 에서의백질의이상소견은교정연령 12 개월에서의뇌성마비와유의한연관성을보였으며 (OR 32.9, 95% CI 2.0-547.8), 중등증이상의백질이상의경우교정연령 12 개월과 24 개월모두에서뇌성마비와유의한연관성이있었다 (OR 800.5, 95% CI 6.9-92,665.7; OR 52.0, 95% CI 1.3-2,168.2). 그러나뇌 MRI 에서의백질의이상소견은교정연령 12 개월과 24개월모두에서인지발달지연또는운동발달지연과독립적으로유의한연관성이없었다 (Tables 4, 5). 고찰 극소저체중출생아에서퇴원전에시행된뇌 MRI 가교정연령 12 개월및 24 개월에서의신경발달학적결과를예측할수있는지를알아본본연구에서뇌 MRI 에서발견된중등증이상의백질이상은교정연령 12 개월과 24 개월의뇌성마비를유의하게예측하였다. Table 3. Severity of White Matter Abnormality on Brain MRI and Neuro developmental Outcome at 12 and 24 Months Corrected Age At 12 months corrected age White matter abnormality None Mild Moderate to severe Cerebral palsy (%) 0/105 (0.0) 3/24 (12.5) 7/13 (53.8) <0.001 Any cognitive delay (%)* 6/20 (30.0) 2/11 (18.2) 4/6 (66.7) 0.118 Moderate to severe cognitive delay (%)* 0/20 (0.0) 0/11 (0.0) 3/6 (50.0) <0.001 Any motor delay (%)* 10/20 (50.0) 9/11 (81.8) 5/6 (83.3) 0.121 Moderate to severe motor delay (%)* 4/20 (20.0) 2/11 (18.2) 4/6 (66.7) 0.057 At 24 months corrected age Cerebral palsy (%) 0/58 (0.0) 4/16 (25.0) 5/7 (71.4) <0.001 Any cognitive delay (%) 4/9 (44.4) 2/6 (33.3) 3/3 (100.0) 0.151 Moderate to severe cognitive delay (%) 3/9 (33.3) 2/6 (33.3) 3/3 (100.0) 0.105 Any motor delay (%) 3/9 (33.3) 4/6 (66.7) 3/3 (100.0) 0.105 Moderate to severe motor delay (%) 3/9 (33.3) 3/6 (50.0) 3/3 (100.0) 0.135 *37 infants were assessed with the Bayley Scales of Infant Development-II at 12 months corrected age. 18 infants were assessed with the Bayley Scales of Infant Development-II at 24 months corrected age. P value www.e-kjp.org 231

Park SH, et al. Dose Brain MRI before Discharge at NICU Predict Neurodevelopmental Outcomes in VLBW Infants? Table 4. Associations between Perinatal Clinical Characteristics and Radiologic Findings and Neurodevelopmental Outcome at 12 Months Corrected Age Measure Clinical characteristics No. of infants (%) Cerebral palsy Any cognitive delay Odds ratio (95% confidence interval) Moderate to severe cognitive delay Any motor delay Moderate to severe motor delay Gestational age (per week) 0.8 (0.7-1.1) 1.0 (0.8-1.3) - 1.0 (0.8-1.2) 0.9 (0.7-1.1) Birth weight (per 100 g) 1.0 (1.0-1.0) 1.0 (1.0-1.0) - 1.0 (1.0-1.0) 1.0 (1.0-1.0) Male sex 60 (42.3) 0.6 (0.1-2.3) 0.3 (0.1-1.4) - 0.8 (0.2-3.3) 0.7 (0.2-3.5) Multiple birth 35 (24.6) 1.3 (0.3-5.5) 2.3 (0.5-9.8) - 1.7 (0.4-7.8) 3.5 (0.8-16.2) Moderate-severe BPD 45 (31.7) 2.3 (0.6-8.4) 1.1 (0.3-4.3) - 1.1 (0.3-4.6) 1.7 (0.4-7.4) Hemodynamically significant PDA 54 (38.0) 1.1 (0.3-4.1) 2.5 (0.6-10.2) - 3.9 (0.9-18.0) 1.5 (0.3-6.3) PDA ligation 17 (12.0) 3.6 (0.8-15.6) 1.5 (0.2-10.2) - 3.2 (0.3-30.4) 17.3 (1.6-184.4) Postnatal corticosteroid 38 (26.8) 1.9 (0.5-7.2) 1.3 (0.3-5.7) - 1.7 (0.4-7.8) 1.9 (0.4-8.8) Sepsis 12 (8.5) 5.7 (1.3-26.6) 14.3 (1.4-149.2) - 2.4 (0.2-24.1) 5.4 (0.7-38.6) NEC 11 (7.7) 1.4 (0.2-11.8) 2.1 (0.4-11.3) - 1.5 (0.2-8.8) 1.1 (0.2-6.9) Cranial ultrasonographic findings High-grade IVH 7 (4.9) 28.7 (5.2-157.9) 1.2 (0.1-14.8) - 1.1 (0.1-13.3) 6.5 (0.5-81.4) PVL 9 (6.3) 4.5 (0.8-25.1) 1.7 (0.2-12.0) - 2.4 (0.2-24.1) 2.0 (0.3-14.2) MRI findings Any abnormality 58 (40.8) 15.8 (1.9-128.1) 2.8 (0.5-15.8) - 4.4 (1.0-19.3) 2.4 (0.4-13.4) Any white matter abnormality 37 (26.1) 35.0 (4.3-288.4) 1.6 (0.4-6.8) - 4.7 (1.0-21.4) 2.2 (0.5-9.6) Moderate-severe white matter abnormality 13 (9.2) 49.0 (10.1-238.2) 6.9 (1.0-45.6) - 3.2 (0.3-30.4) 8.3 (1.2-56.7) Adjusted MRI findings* Any abnormality 58 (40.8) 12.1(0.9-156.3) 1.1 (0.1-11.3) - 12.9 (1.1-151.3) 3.4 (0.2-67.5) Any white matter abnormality 37 (26.1) 32.9 (2.0-547.8) 1.5 (0.2-2.0) - 10.1 (0.9-119.2) 1.7 (0.1-50.9) Moderate-severe white matter abnormality 13 (9.2) 800.5 (6.9-92,665.7) 16.5 (0.1-3,823.2) - 3.4 (0.1-231.0) 15.3 (0.5-490.4) Abbreviations: BPD, bronchopulmonary dysplasia; PDA, patent ductus arteriosus; NEC, necrotizing enterocolitis; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia. *Covariate factors included in the logistic- regression models were abnormality of cranial ultrasonographic findings (high grade IVH or PVL) and perinatal clinical characteristics including gestational age, birth weight, male sex, multiple birth, the presence of BPD, PDA, sepsis and NEC, use of postnatal corticosteroid. 그러나뇌 MRI 에서의중등증이상의백질이상과교정연령 12 개월과 24 개월에서의인지발달지연이나운동발달지연과의유의한연관성은관찰되지않았다. 뇌 MRI 에서의중등증이상의백질이상과교정연령 12 개월과 24 개월에서의뇌성마비와의연관성은극소저체중출생아의신경발달학적결과에영향을미칠수있을것으로판단되는인자들인출생체중, 재태연령, 성별, 다태아여부, 기관지폐이형성증, 동맥관개존증, 출생후스테로이드사용, 패혈증, 괴사성장염과초음파검사로확인된뇌실내출혈, 뇌실주위백질연화증의영향을통계적으로보정한후에도유의하였다. 이는기존의선행연구와일치하는결과로 Woodward 등 11 은재태연령 30 주미만의미숙아를대상으로뇌 MRI와교정 24 개월에서의신경발달결과를연구하였고, 백질이상의중증도가심할수록 BSID 의인지 / 운동발달지수가감소하며인지 / 운동발달지연과뇌 성마비의비율이증가한다고하였다. 재태연령 32 주미만의미숙아를대상으로교정연령 4세와 6세의지적능력, 언어발달, 실행능력등의신경인지결과를확인한다른연구에서도 14 백질이상이없는환자는만삭출생아인대조군과차이를보이지않았으나, 백질이상을보인환자는대조군에비해분명한신경인지발달장애를보였다고보고하였다. Skiöld 등 25 역시재태연령 27 주미만의미숙아를대상으로한연구에서중등도이상의백질이상은교정 30 개월의뇌성마비와뚜렷한연관성이있다고보고하였으며, Miller 등 12 은백질의이상이교정연령 12-18 개월에서의인지발달지연과신경운동이상과분명한연관성이있음을보고하였다. 이전연구 4,9,11-17 에서신경학적예후에영향을미치는인자로재태기간, 출생체중, 기관지폐이형성증, 동맥관개존증, 다태아, 출생후스테로이드사용, 뇌초음파상이상등이보고되었으나본연구에 232 www.e-kjp.org

2016 December;27(4):227-235 Table 5. Associations between Perinatal Clinical Characteristics and Radiologic Findings and Neurodevelopmental Outcome at 24 Months Corrected Age Measure Clinical characteristics No. of infants (%) Cerebral palsy Any cognitive delay Odds ratio (95% confidence interval) Moderate to severe cognitive delay Any motor delay Moderate to severe motor delay Gestational age (per week) 0.8 (0.6-1.1) 1.1 (0.8-1.5) 1.2 (0.9-1.7) 1.1 (0.8-1.5) 1.2 (0.9-1.7) Birth weight (per 100 g) 1.0 (1.0-1.0) 1.0 (1.0-1.0) 1.0 (1.0-1.0) 1.0 (1.0-1.0) 1.0 (1.0-1.0) Male sex 37 (45.7) 1.1 (0.3-4.3) 1.0 (0.1-9.2) 0.3 (0.0-4.0) 0.8 (0.1-7.0) 1.0 (0.1-9.2) Multiple birth 23 (28.4) 1.3 (0.3-5.7) 0.4 (0.1-2.7) 0.6 (0.1-4.0) 1.7 (0.3-11.1) 2.5 (0.4-16.9) Moderate-severe BPD 30 (37.0) 2.4 (0.6-9.5) 0.2 (0.0-1.8) 0.3 (0.0-2.5) 1.1 (0.2-7.5) 0.6 (0.1-4.2) Hemodynamically significant PDA 35 (43.2) 1.8 (0.4-7.1) 4.0 (0.6-28.4) 2.5 (0.4-16.9) 7.0 (0.9-56.9) 4.0 (0.6-28.4) PDA ligation 12 (14.8) 3.5 (0.7-16.5) 4.0 (0.3-48.7) 3.0 (0.2-40.9) 3.0 (0.3-36.3) 4.0 (0.3-48.7) Postnatal corticosteroid 25 (30.9) 3.3 (0.8-13.3) 0.2 (0.0-1.8) 0.3 (0.0-2.5) 0.4 (0.1-3.0) 0.2 (0.0-1.8) Sepsis 7 (8.6) 1.4 (0.2-12.9) 2.3 (0.2-31.0) 0.6 (0.0-7.7) 1.8 (0.1-23.7) 2.3 (0.2-31.0) NEC 8 (9.9) 1.2 (0.1-10.7) 2.3 (0.2-31.0) 1.3 (0.1-24.4) 0.8 (0.0-14.8) 1.0 (0.1-18.9) Cranial ultrasonographic findings High-grade IVH 6 (7.4) 11.5 (1.9-67.0) 4.0 (0.3-48.7) 5.4 (0.4-66.7) 3.0 (0.3-36.3) 1.0 (0.1-9.2) PVL 6 (7.4) 11.5 (1.9-69.9) 1.0 (0.1-18.9) 1.3 (0.1-24.4) 0.8 (0.0-14.8) 1.0 (0.1-18.9) MRI findings Any abnormality 37 (45.7) 12.6 (1.5-106.0) 4.4 (0.6-34.0) 3.0 (0.4-22.7) 6.7 (0.8-55.0) 4.4 (0.6-34.0) Any white matter abnormality 23 (28.4) 33.1 (3.8-287.2) 1.0 (0.2-6.4) 1.5 (0.2-9.8) 4.5 (0.6-34.6) 2.5 (0.4-16.9) Moderate-severe white matter abnormality 7 (8.6) 43.8 (6.4-299.8) 4.0 (0.3-48.7) 5.4 (0.4-66.7) 3.0 (0.3-36.3) 4.0 (0.3-48.7) Adjusted MRI findings* Any abnormality 37 (45.7) 7.4 (0.3-206.4) 11.2 (0.3-368.5) 17.5 (0.0-9032.6) - - Any white matter abnormality 23 (28.4) 18.3 (0.8-441.3) 2.1 (0.1-34.6) 4.1 (0.0-903.4) - - Moderate-severe white matter abnormality 7 (8.6) 52.0 (1.3-2,168.2) 32.0 (0.1-18,151.1) 125.1 (0.0-3,876,076.2) - - Abbreviations: BPD, bronchopulmonary dysplasia; PDA, patent ductus arteriosus; NEC, necrotizing enterocolitis; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia. *Covariate factors included in the logistic- regression models were abnormality of cranial ultrasonographic findings (high grade IVH or PVL) and perinatal clinical characteristics including gestational age, birth weight, male sex, multiple birth, the presence of BPD, PDA, sepsis and NEC, use of postnatal corticosteroid. 서는패혈증과동맥관개존증결찰술, 고도뇌실내출혈, 뇌실주위백질연화증만이그연관성이확인되었다. 이는뇌혈류에급격한변화를야기하여뇌신경손상을유발할수있는상황 12,13 과백질이상으로진행할가능성이있는뇌의변화가신경학적예후와직접적인관련이있음을나타내며, 최근뇌신경손상을최소화하기위한신생아소생술및집중치료가발전함에따라이전신경발달의나쁜예후인자로알려졌던짧은재태기간과적은출생체중등이신경학적예후와그연관성이사라진것으로보인다. 또한대부분의기존연구와는달리, 본연구에서는뇌 MRI 와인지 / 운동발달지연의관련성을확인할수없었다. 뇌 MRI의중등증이상의백질이상이교정연령 12 개월에서의심한운동발달지연과관련이있던반면교정 24 개월에서는관련이없었는데, 이는교정연령 12 개월까지추적관찰된환자들의수 (142 명 ) 에비해교정연 령 24 개월까지추적관찰된환자들의수 (81 명 ) 가대폭줄어든것이결과에영향을주었을가능성이있을것으로생각된다. 또한뇌성마비에대한평가는일반적인외래진찰에서도가능한데비해인지발달정도를평가하기위해사용된 BSID-II는따로마련된공간, 시간과인력이필요하였는데, 이로인해교정연령 12 개월과 24 개월에외래추적관찰시 BSID-II 까지시행한환자들의비율이각각 26.1%, 22.2% 로외래를방문한환자들의일부에서만인지발달정도평가가가능했었다는점도뇌 MRI의중등증이상의백질이상과교정 24 개월에서의심한운동발달지연간에유의한상관관계가없다는결과가도출된것에영향을주었을것으로생각된다. 일반적으로극소저체중출생아들의장기추적관찰에있어서추적관찰의비율이떨어질수록신경발달지연이나장애의발생빈도의파악이어려워지는것은당연하나실제로장기추적관찰비율 www.e-kjp.org 233

Park SH, et al. Dose Brain MRI before Discharge at NICU Predict Neurodevelopmental Outcomes in VLBW Infants? 이신경발달지연이나심한장애의유병률에어느정도로영향을끼치는지는정확히파악하기어렵다. 일부연구에서는심한신경학적장애를가진환아가추적관찰이되지않을가능성이높다고보고하였고, 31,32 Castro 등 33 이초극소저체중출생아를대상으로조사한연구에서는 18-22 개월의추적관찰에적극적으로참여한군이추적관찰이되지않은군보다오히려더나쁜신경발달을보였다고보고하였다. 본연구에서신생아집중치료실에서퇴원전확인한뇌 MRI 에서백질이상이있는환자는 24.7% 로확인되었으며이중중등증이상의백질이상을보인환자는 8.8% 였다. 이전연구에서 Woodward 등 11 은백질의이상이있는환아가 72% 로, 이중경도의백질이상이 51%, 중등도의백질이상이 17%, 중증의백질이상이 4% 였다고보고하였고, Inder 등 13 은경도의백질이상이 50%, 중등도이상의백질이상이 20% 였다고보고하였다. 이러한비율의차이는각연구별대상자군간의차이와추적관찰중발생한선택편향에따른결과로보인다. Woodward 등 11 은뇌 MRI의백질이상에따른뇌성마비의양성예측도 (positive predictive value, PPV) 를 31.4%, 음성예측도 (negative predictive value, NPV) 를 94.5% 로보고하였으며, Skiöld 등 25 은중등증이상의백질이상에따른뇌성마비의 PPV 를 50%, NPV 를 97.5% 로보고하였다. 본연구에서는뇌 MRI 에서중등증이상의백질이상에따른뇌성마비에대한 PPV는교정연령 12개월에 53.8%, 교정연령 24 개월에 71.4% 로확인되었으며, NPV 는교정연령 12개월에 97.7%, 교정연령 24 개월에 94.6% 로확인되었다. 이는뇌 MRI 에서중등증이상의백질이상이있을때교정연령 12 개월및 24 개월에뇌성마비가높은수준으로예측된다는것을의미한다. 그러나뇌 MRI 의중등증이상의백질이상이모두뇌성마비로진행하는것은아니며, 백질이상이없는군에서도심한인지발달지연과심한운동발달지연을보인환자들이있다는것에주목할필요가있다. Woodward 등 11 은뇌의백질이상이없던군의 15% 에서뇌성마비를포함한신경학적장애가있었으며, 중증의백질이상을보인환아의 33% 에서는신경학적장애가보이지않았다고보고하였다. 또한 Skiöld 등 25 의연구에서는뇌성마비의환자들의 1/3 이정상뇌 MRI 소견을보였으며, Mirmiran 등 12 역시 7 명의뇌성마비환자들중 1명은정상 MRI 를보였다고보고하였다. 따라서뇌 MRI 를바탕으로신경발달학적예후에대한예측을할때위음성 (false negative), 위양성 (false positive) 의가능성이있음을항상고려해야한다. 뇌 MRI 는신경발달학적예후에대한정보를주지만, 이러한정보는뇌초음파결과, 신경학적진찰소견, 환자의의학적정보등의다양한요소들을통합하여해석해야할것으로생각된다. 이번연구는단일기관의의무기록고찰을통한후향적연구로 신경발달학적평가를교정연령 12 개월과 24 개월두번에걸쳐확 인하였다. 그러나뇌성마비의증상이만 2-3 세까지도뚜렷하게나 타나지않을가능성이있고, 22 본연구에서비교적이른시점인교 정연령 12 개월에뇌성마비진단여부를확인함으로인해뇌성마비 의발생을실제보다적게평가했을가능성이있다. 또한회백질의 이상에대한분석은회백질에이상을보였던환자수가적어시행되 지못했으며, 신경발달학적예후로뇌성마비와 BSID-II 를통한인 지및행동발달지연을평가하였지만시각및청각장애등의감각 신경장애와뇌전증에대해조사하지못한것이본연구의한계점 이라고할수있다. 또한앞서언급한바와같이추적관찰환자의 이탈비율이높고 BSID-II 의순응도가낮았기때문에본연구의결 과를일반화시키는것에는제약이따른다. 아직각병원간에미숙아들에서의뇌 MRI 시행기준이다르기 는하나, 최근장기신경발달학적예후를예측하기위해퇴원전뇌 MRI 의시행이늘어나고있다. 이에본연구는극소저체중출생아 에서퇴원전뇌 MRI 에서중등증이상의백질이상소견이있는경 우교정연령 12 개월과 24 개월에뇌성마비를높은수준으로예측할 수있음을밝힘에따라극소저출생체중아에서퇴원전뇌 MRI 를 시행하는하나의근거로사용될수있을것으로생각된다. References 1) Horbar JD, Carpenter JH, Badger GJ, Kenny MJ, Soll RF, Morrow KA, et al. Mortality and neonatal morbidity among infants 501 to 1500 grams from 2000 to 2009. Pediatrics 2012;129:1019-26. 2) Kim KS, Bae CW. Trends in survival rate for very low birth weight infants and extremely low birth weight infants in Korea, 1967-2007. Korean J Pediatr 2008;51:237-42. 3) Aarnoudse-Moens CS, Weisglas-Kuperus N, van Goudoever JB, Oosterlaan J. Meta-analysis of neurobehavioral outcomes in very pre term and/or very low birth weight children. Pediatrics 2009;124:717-28. 4) Shankaran S, Johnson Y, Langer JC, Vohr BR, Fanaroff AA, Wright LL, et al. Outcome of extremely-low-birth-weight infants at highest risk: gesational age < or =24 weeks, birth weight < or =750 g, and 1-minute Apgar < or =3. Am J Obstet Gynecol 2004;191:1084-91. 5) Anderson PJ, Cheong JL, Thompson DK. The predictive validity of neonatal MRI for neurodevelopmental outcome in very preterm children. Semin Perinatol 2015;39:147-58. 6) de Kieviet JF, Piek JP, Aarnoudse-Moens CS, Oosterlaan J. Motor development in very preterm and very low-birth-weight children from birth to adolescence: a meta-analysis. JAMA 2009;302:2235-42. 7) Marlow N, Wolke D, Bracewell MA, Samara M, Group EPS. Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med 2005;352:9-19. 8) Larroque B, Ancel PY, Marret S, Marchand L, Andre M, Arnaud C, et al. 234 www.e-kjp.org

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