380 Hanyang Medical Reviews Vol. 29 No. 4, 2009 본론 1. 유아기의신경발달에대한예후초극소저출생체중아에서유아기에나타나는신경학적후유증으로는뇌성마비, 경련, 시각및청력장애등의주요장애를들수있으며, 이들의 20~25% 에서볼수있다. 최근 3

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1 HANYANG MEDICAL REVIEWS Vol. 29 No. 4, 초미숙아의신경발달에대한예후 Neurodevelopmental Outcomes of Extremely Preterm Infants 이연경관동대학교의과대학제일병원소아청소년과 Yeon Kyung Lee, M.D. Department of Pediatrics, Cheil General Hospital, School of Medicine, Kwandong University, Seoul, Korea 책임저자주소 : , 서울시중구묵정동 1-19 관동의대제일병원소아청소년과 Tel: , 7562, Fax: ykleeped@hanmail.net 투고일자 : 2009 년 8 월 25 일, 심사일자 : 2009 년 9 월 18 일, 게재확정일자 : 2009 년 10 월 2 일 Abstract Recently, advances in perinatal and neonatal intensive care during the last decades have led to a dramatic increased survival of extremely preterm and extremely low birth weight infants (ELBWI, ). These have influenced the rates of neonatal morbidity and neurodevelopmental impairment. Neurodevelopmental outcome is being used as the most important measure of successful neonatal care and has to be assessed, not only in the short term, but also in the long term. Long-term follow-up of ELBWI is necessary to identify neurodevelopmental outcomes with a wide array from major neurosensory disability to high prevalence/ low severity dysfunction in early childhood, school age and young adulthood. 서론일반적으로출생체중 1,000 g 미만의신생아를초극소저출생체중아 (extremely low birth weight infant, ELBWI) 라고하며, 재태기간 28주미만의신생아를초미숙아 (extremely preterm infant), 그중에서도출생체중 750~800 g 미만, 재태기간 25주미만을 micropremie 라고한다. 최근주산의학및신생아집중치료의급속한발전으로초미숙아의생존율이증가하고있다. NICHD (National Institute of Child Health and Human Development) 에따르면, 1990 년대중반이후로는 85% 이상의극소저출생체중아의생존율을보고하고있고, 750~1,000 g 사이는 88%, 750 g 미만의 micropremie 에서는 50% 이상의생존율을보고하고있다. 1 국내의경우에는아직여기까지는이르지못하지만, 1990 년후반의초극소저출생체중아생존율이 45% 에서 2000 년초반에는 62% 정도로급격히향상되고있는추세이다. 2 그러나생존하는초미숙아의증가로인해이들신생아에서의신경학적후유증의발생빈도증가에대한우려와함께장기적인신경발달에대한예후에관심이높아지고있다. 지금까지미숙아에대한신경학적평가는주로뇌성마비, 지능저하, 시각및청력손실등의주요신경장애에중점을두어이루어졌으나, 생존하는초미숙아의연령이증가되면서주요신경장애가없는경우에서도정상출생체중아에비해지능및학습능력의저하, 운동및행동장애등의빈도가높아학령기를거쳐성인에이르는장기간에걸친평가가이루어지고있다. 이에본장에서는생존하는초극소저출생체중아의유아기, 학령기, 성인기에따른신경발달학적예후에대하여알아보고자한다. Key Words: Neurodevelopmental outcome, Extremely preterm, Extremely low birth weight infants

2 380 Hanyang Medical Reviews Vol. 29 No. 4, 2009 본론 1. 유아기의신경발달에대한예후초극소저출생체중아에서유아기에나타나는신경학적후유증으로는뇌성마비, 경련, 시각및청력장애등의주요장애를들수있으며, 이들의 20~25% 에서볼수있다. 최근 30여년동안의신생아집중치료의발달로초미숙아의생존율뿐만아니라주요신경학적장애의발생율에도변화가있었다 년대에는폐표면활성제, 산전스테로이드투여, 미숙아의만성폐질환에대한스테로이드투여등에힘입어 1980 년대에비해생존율이현저하게향상되었으나, 그와더불어주요신경학적장애율도증가하였다. 하지만 2000 년대에들어와서는 1990 년대중반이후와생존율에있어서는큰차이를보이지않았으나, 주요신경학적장애율은오히려감소하는경향을보이는데, 이는산전스테로이드의확대, 미숙아만성폐질환에대한스테로이드제한, 뇌출혈및패혈증의감소등에기인하는것으로생각된다. 3 국내에서도전등에의한보고에서,2000 년이후에출생한 1,000 g 미만의초극소저출생체중아의생존율은 1990 년대에비해증가하였으며, 평균출생체중및재태주수가상대적으로더작았음에도불구하고, 오히려뇌성마 비의발생율은감소하였다 년대에태어난초극소저출생체중아를대상으로한 NICHD 의첫다기관연구에따르면, 교정연령 18~22 개월에추적관찰가능한 1,151 명에서의신경학적장애발생빈도는뇌성마비 17%, shunt 를필요로하는뇌수종 4%, 만성경련은 5% 였고, Bayley II Mental Developmental Index (MDI) 가 70미만이 37%, Bayley II Psychomotor Developmental Index (PDI) 가 70미만이 29%, 편측또는양측실명 3%, 보청기를필요로하는청각장애가 3% 였다. 5 초미숙아에서유아기의주요신경학적장애는보고자에따라차이가있어뇌성마비는 5~22%, 시력및청력소실은각각 0~10%, 1~6%, MDI<70 인인지장애는 15~37% 였다 (Table 1). 3-9 이는연구기관마다의생존율, 연구시기, 신생아기합병증, 사회경제적인요인, 검사연령, 신경발달평가방법, 장애진단기준등이영향을주었을것으로생각된다. 또한재태주수 25주미만의 micropremie 의 Epicure 연구에서는교정연령 30개월에반수에서신경학적장애를보였으며, 이중반수에서는심각한장애를보였고, 10 Kilbride 등은출생체중 800 g 미만의 micropremie 에있어환경적요인이신경학적예후에미치는영향을알아보기위하여그들의만삭아형제, 자매와의비교연구에서 micropremie 들은그들의형제, 자매보다학령전기 (5세 ) 에지능지수, 운동, 수용언어능력이떨어졌으며, 지능과언어는미숙아로인한요인뿐아니라사회경제적요인의영향을받았으나, 운동능력은사회경제적 Table 1. Early Childhood Outcomes of ELBWI Authors Population Birth years BW/GA Age at F/U (months) Outcomes (%) CP Blind Deaf MDI<70 Robertson et al. (1994) 6 Hack et al. (1996) 7 Jacobs et al. (2000) 8 Vohr et al. (2000) 5 Wilson-Costello et al. (2007) 3 Jeon et al. (2007) 4 Park et al. (2008) 9 Two center Multicenter Korea Korea ~ ~ ~ ~ ~ ~ ~ ~ ~2006 <750 g <750 g 23~26 wks 24~ ~ ~ Abbreviations : BW, birth weight; GA, gestational age; F/U, follow up; CP, cerebral palsy; MDI, mental developmental index

3 Neurodevelopmental Outcomes of Extremely Preterm Infants 381 Table 2. Trends in Cerebral Palsy of ELBWI Authors Population Birth Years BW/GA Trend/CP rate Emsley et al. (1998) 12 Jacobs et al. (2000) 8 England Two centers 1984~ ~25 wks No change over time CP rate 21% in 1984~ % in 1990~ ~ ~26 wks No change in CP rate CP rate 12% in 1982~ % in 1990~1994 Salokorpi et al. (2001) 13 Mikkola et al. (2005) 14 Hintz et al. (2005) 15 Finland 1991~ ~ ~1999 No change over time CP rate 21% in 1984~ % in 1990~1994 No change over time CP rate 23% in % in 1997~1999 Wilson-Costello et al. (2007) 16 Jeon et al. (2007) 4 Korea 1982~2002 Significant increase followed by decrease (P=0.01) CP rate 8% in % in 1990~1999 5% in ~2004 Significant decrease over time CP rate 22% in 1994~1999 8% in Abbreviations : BW, birth weight; GA, gestational age; CP, cerebral palsy 요인이아닌미숙아자체와관계가있는것으로보고하였 다. 11 뇌성마비는유아기의대표적인신경학적장애로, 초극소 저출생체중아의 10~20% 에서진단되어지며, 1980 년에서 2000 년대에이르면서시기별로뇌성마비의빈도추이에대 한다양한보고가있다 (Table 2). 4, 8, 출생체중이더작 을수록뇌성마비의발생율은높지만, 앞서언급한 NICHD 보고에서초극소저출생체중아의 100 g 단위의체중별로세 분화한뇌성마비발생율은 401~500 g 군에서 29 % 로가장 높았으나, 다른체중군들에서는 15~21% 로 100 g 단위로나 눈체중군에대한뇌성마비발생율의일정한경향은없었 다. 5 Athetoid 또는 ataxic 형보다 spastic 형이많고, 출생체 중 1,000 g 이하로출생한신생아의뇌성마비위험인자로는 뇌실내출혈 III, IV, 뇌실주변백질연화증, 뇌실확장증, 남 아, 만성폐질환, 결찰을필요로하는동맥관개존증, 후기 4, 15, 17 패혈증, 따라잡기성장의실패등이있다. 유아기의인지장애는 Bayley II MDI 로교정연령 6 개월 에서 3 세사이의인지능력을측정하여 70 미만인경우에심 한장애가있는것으로평가하는데, 초극소저출생체중아 의 NICHD 연구에서교정연령 18~22 개월의평균 MDI 는 76 이었으나, 5 기관마다차이가있어 Park 등, Wilson- Costello 등은 83~84 로보고하였다. 3, 9 인지장애율은 25 주미만이거나초극소저출생체중아의경우 15~37% 였으나, 3, 5-9 이시기의인지능력평가는운동, 언어, 사회감정적발 달에대한의존도가높아학동기이후의인지발달의예견 인자가되지못하며정확도가떨어진다. 또한시력및청력등의감각기능의장애는초미숙아에 있어인지및운동장애보다드물지만, 매우중요한후유장 애로시력소실이 0~10%, 보청기를필요로하는청력소실이 1~6% 정도보고되고, 3-8 근시및사시등의가벼운시력장애 5, 10 는 9~25%, 약간의청력장애는 11~13% 까지보고되며, 일시적인전도장애로인한청력장애까지포함하면 28% 까지보고한경우도있다 학령기의신경발달에대한예후 학령기예후는초미숙아의지속적인추적관찰에서중요 한표식자이며, 대부분이정상체중으로출생한경우와의 비교연구이다. 최근에는분명한신경학적장애를갖지않았 던아이라도학교에입학한후에학습장애, 행동장애등의 문제가생기고있어이에대한관심이높아지고있으며, 초

4 382 Hanyang Medical Reviews Vol. 29 No. 4, 2009 Table 3. School Age Outcomes of ELBWI Authors Population Birth years BW/GA Age at F/U Outcomes Whitfield et al. (1997) ~ g 9 years Lower mean IQ: 99 vs 112 More attention problem: 33 vs 4% More learning disability: 47 vs 18% 14% with ELBW had multiple disabilities Horwood et al. (1998) 20 New Zealand years Higher rates of behavioral problems Poorer school performance More special education: 31 vs 9% More school problems: 71 vs 42% More subnormal IQ: 36 vs 11% Buck et al. (2000) ~1986 <28 wks vs term 10 years More grade repetition: 33 vs 18% More special education: 20 vs 5% More rehabilitation: 47 vs 18% Anderson et al. (2003) 22 Australia 1991~ years Significantly lower IQ and achievement Saigal et al. (2003) 23 International,, Holland 1977~1987 8, 11 years High rates of cognitive deficit IQ < 70: 15-27% Special education: 39-62% Hack et al. (2005) 24, 1992~ years Significantly lower IQ IQ < 70: 18 vs 4% More limitations Mikkola et al. (2005) 14, Finland 1996~ years Cognitive impairment: 9% Mean IQ: 96 Functional abnormalty: 39% BW, birth weight; GA, gestational age; F/U, follow up; NBW, normal birth weight 미숙아의학령기예후에대한연구들이보고되고있다. 이들연구에서초극소저출생체중아는주요신경장애가없는경우에도정상아에비해인지장애, 학습장애, 주의력결핍, 행동장애의빈도가높았다 (Table 3). 14, 년에서 1995 년사이에출생한초극소저출생체중아를대상으로 Hack 등에의한학령기예후연구에서심각한신경학적장애가 16% 에서보였으며, 신체적, 정신적지연, 의사소통문제등의기능성장애 64% ( 정상체중군 20%), 일상생활에서의도움을필요로하는의존성 48% ( 정상체중군 23%), 물리치료, 작업치료, 특수학교등의보통이상의서비스를필요로하는경우가 65% ( 정상체중군 27%) 였으며, 이러한차이는주요신경학적장애가없는초극소저출생체중아에서도뚜렷하였다. 24 Marlow 등은 25주미만의 micropremie 를대상으로교정연령 30개월과 6세에서의신경학적장애의관련성을분석하여, 30개월에심한장애를보였던경우에 6세에서중등도이상의장애를나타낸경우는 86% 로높은예견성을보였으나, 30개월에정상이었던경우의 24% 에 서도 6 세경에중등도이상의장애를나타내어학령기추적관찰의중요성을강조하였다. 25 학령기의인지기능은 Stanford-Binet Intelligence Scale, Wechsler Intelligence Scale for Children (WISC-III), Kaufman Assessment Battery of Childhood 등의검사를 통해, Intelligence Quotient (IQ) 로평가되어진다. 평균 IQ 는 82~105 정도로정상체중아에비해 IQ 가낮은인지장 애의비율이높다. 19, 20, 그러나정상 IQ 에서도학습및 행동장애를보이는경우가많아 IQ 가특별한학습장애나 행동장애를대변하지는못한다. 또한주의력결핍 - 과잉운동 장애, 전반적인분노, 우울증, 정신사회적으로적응을못하 며, 친구가적고, 자기주장이적으며, 부끄러워하고, 자폐 적인성향을갖거나 Asperger 장애등의빈도가높기에이 러한행동장애의조기발견과치료에관심을가져야한다

5 Neurodevelopmental Outcomes of Extremely Preterm Infants 383 Table 4. Young Adult Age Outcomes of ELBWI Authors Population Birth years BW Age at F/U Outcomes Hack et al. (2004) ~ years Neurosensory impairment: 12 vs 1% Lower mean IQ: 81 vs 92 Graduation from high school 72 vs 83% 4 year college enrollment 10 vs 40% Unemployment 14 vs 13% Grunau et al. (2004) ~1986 <800 g 17 years Lower cognitive scores and academic skills More internalizing, externalizing problems Lower scholastic, athletic, job, and romantic competence Lefebvre et al, (2005) ~ years Lower mean IQ: 94 vs 108 IQ <85: 19 vs 2% Requirement for special classes 33 vs 9% 31, 32 Saigal et al. (2006, 2007) 1977~ years Neurosensory impairment: 27 vs 2% Graduation from high school 82 vs 87% Permanent employment 48 vs 57% Higher functional limitations No difference of self-reported quality of life BW, birth weight; F/U, follow up; NBW, normal birth weight 3. 성인기의신경발달에대한예후 초극소저출생체중아의생존율이높아지고, 그들이성장 함에따라학령기이후의추적관찰을통해성인기에이르 는장기간에걸친평가가이루어지고있다 (Table 4) 이 러한연구들은지역, 연구방법, 생존율, 재태주수및사회 경제적환경에따라차이가있으나, 궁극적으로초극소저 출생체중아의신경학적장애는성인기까지지속되었으며, 전반적으로정상체중으로출생한군에비하여지능및교 28, 31 육성취도가낮았으나취업률의차이는보이지않았다. 정신행동학적측면에서불안증이나우울증의빈도가높았 으나주요정신과적장애의차이는없었고, 33 알코올및약 물남용등의위험성은낮았으며, 범죄율의차이는없었 다. 34 또한초극소저출생체중아가성인이되어느끼는삶 의질은정상체중아군에비해차이가없었고, 스스로만족 할수있는생활을하고있다고느끼는것으로보고되고있 32, 35 다. 결론 초미숙아치료의궁극적인목표는생존율향상과장기적 으로신경학적발달장애가없도록하는것이며, 그러기위해서는조기출산을줄이고미숙아로인한합병증, 특히뇌손상을줄일수있는치료의개발과장기적인추적관찰을통한치료에대한평가가필요하다. 또한장기적인신경학적발달장애를결정하는요인으로미숙아자체의생물학적요인뿐아니라, 사회경제적인환경적요소가중요한역할을하기에, 조기교육프로그램을통해이에대한접근이필요하며, 장기적으로추적관찰하여초미숙아에대한계속적인지지와신경학적장애를줄일수있는방법에대한연구가지속되어야할것으로생각된다. References 1. Fanaroff AA, Stoll BJ, Wright LL, Carlo WA, Ehrenkranz RA, Stark AR, Bauer CR, Donovan EF, Korones SB, Laptook AR, Lemons JA, Oh W, Papile LA, Shankaran S, Stevenson DK, Tyson JE, Poole WK; NICHD Neonatal Research Network. Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol 2007;196:147.e Kim KS, Bae CW. Trends in survival rate for very low

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386-390.hwp 386 HANYANG MEDICAL REVIEWS Vol. 29 No. 4, 2009 우리나라 미숙아의 통계와 의료비용 Statistics and Medical Cost of Preterm in Korea 윤혜선 을지대학교 노원을지병원 소아청소년과학교실 Hye Sun Yoon, M.D., Ph.D., Department of Pediatrics, Nowon