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1 pissn eissn Original article Vol. 29, No. 1, March, The Comparison of Efficiency of Oral Ibuprofen and Intravenous Indomethacin for Patent Ductus Arteriosus in Very Low Birth Weight Infants Jong Woan Yun, MD, Hyun A Park, MD, Jong Hee Hwang, MD, PhD Department of Pediatrics, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea Received: 20 September 2017 Revised: 21 October 2017 Accepted: 27 October 2017 Correspondence to Jong Hee Hwang, MD, PhD Department of Pediatrics, Ilsan Paik Hospital, Inje University College of Medicine, 170 Juhwa-ro, Ilsanseogu, Goyang 10380, Korea Tel: Fax: jhhwang@paik.ac.kr Copyright 2018 by The Korean Society of This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( 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. Objective: Intravenous indomethacin is the conventional treatment for closure of patent ductus arteriosus (PDA) in preterm infants. However, there are very few studies about oral ibuprofen in preterm infants with PDA. Therefore, this study was done to evaluate the efficacy and side effects of oral ibuprofen compared to intravenous indomethacin in very low birth weight (VLBW) infants. Methods: From March 2008 to August 2012, medical records of 103 infants with VLBW who had PDA in Inje University Ilsan Paik Hospital were reviewed retrospectively. The medical treatment was given to the 90 infants with hemodynamically significant PDA. Patients were divided into the intravenous indomethacin (IV indo) group (n=27) and the oral ibuprofen (per oral [PO] ibu) group (n=63). Demographic findings and factors associated with PDA were compared between these groups. Results: There were no significant differences in the mean gestational age, birth weight, and demographic findings between the two groups. The conditions such as respiratory distress syndrome and PDA size were not different before treatment. The rate of ductal closure was 100% in IV indo and 95% in PO ibu. 3 infants in only PO ibu needed surgical closure. Blood urea nitrogen and Creatinine levels did not increase significantly in PO ibu compared with IV indo, and there was no notable increase in necrotizing enterocolitis or oliguria incidence in this group either. There were no significant differences in the mortality and late complications. Conclusion: Oral ibuprofen is as efficacious as intravenous indomethacin with similar adverse effects. Key Words: Ductus arteriosus, Patent, Ibuprofen, Indomethacin 서론 동맥관개존 (patent ductus arteriosus) 은미숙아에서흔히발생하는중요한질환의하나 로출생체중 1,500 g 미만의극소저체중출생아 (very low birth weight infants) 의 30%, 재 태기간 28 주미만미숙아의 65% 에서발생하는것으로보고하고있으며, 32 주이상신생아 의 20% 에서발병하는것으로보고하고있다. 1,2 동맥관개존은미숙아나신생아호흡곤란증 이동반된경우에는폐쇄가지연될수있으며, 개존크기가큰경우에는심혈관계에영향을 주어폐부종, 폐출혈및심부전을유발하여생명에위협을줄수있다. 특히, 극소저체중출 생아의경우혈액학적으로증상이있는동맥관개존으로인해괴사성장염, 뇌실내출혈, 뇌 실주위백질연화증의이환율및사망률에영향을주는것으로보고하고있어임상적인상태 를고려하여적절한치료가필요하게된다. 3 동맥관개존의약물적치료방법으로 cyclooxygenase 억제제인인도메타신 (indome thacin) 과이부프로펜 (ibuprofen) 이주로사용되고있으며, 4 최근에는아세트아미노펜 (acetaminophen) 의사용연구도보고되고있다. 3 인도메타신은주로정주용으로사용되고있으 며치료효과에대해서는많은연구가이루어졌으나경구용이나정주용이부프로펜의효과

2 Yun JW, et al. The comparison of efficiency of oral ibuprofen and intravenous indomethacin 에대한연구는상대적으로적고특히국내에서는경구용이부프로펜에대한연구는제한적이다. 이에본연구에서는극소저체중출생아를대상으로동맥관개존에서정주용인도메타신과경구용이부프로펜의효과및부작용에대해비교하여경구용이부프로펜의유효성에대해서알아보고자한다. 대상및방법 2008년 3월부터 2012년 8월까지인제대학교일산백병원신생아집중치료실에입원한출생체중 1,500 g 미만의극소저체중출생아중동맥관개존을가진 103명을대상으로의무기록을가지고후향적으로조사하였다. 동맥관개존의진단은출생후 48시간이내에심초음파검사를통해이루어졌으며, 수축기또는지속성심잡음, 넓은맥압이나심첨부의과도한박동, 저혈압, 호흡곤란증상의악화, 단순흉부방사선검사에서폐부종이나심비대의소견이나타나는경우중 2가지이상의임상소견이존재하는경우에혈액학적으로의미있는증상을가진동맥관개존으로정의하고약물요법을시행하였다. 환자들은정주용인도메타신을사용한군 (intravenous indomethacin) 과경구용이부프로펜을사용한군 (Oral ibuprofen) 으로나누어비교하였으며선천성기형을가진환자나약물치료시작전에혈소판감소증 (<50,000/μL), 핍뇨 (<1 ml/kg/hr), 혈청크레아틴 (creatinine) 의상승 (>1.8 mg/dl), 출혈경향, 괴사성장염이나장천공이있는경우에는대상에서제외하였다. 또한대상환자중출생체중 1,000 g 미만의초극소저체중출생아 (extremely low birth weight infants) 를따로분류하여비교하였다. 약물치료방법으로인도메타신 (Indocin, Merck & Co., Inc, West Point, PA, USA) 은 12시간간격으로 3회정주하였으며출생후나이에따라용량을다르게조절하였다. 출생 48시간이전은각각 0.2 mg/kg, 0.1 mg/kg, 0.1 mg/kg으로 3회투여하였고, 생후 7일이내인경우 0.2 mg/kg씩 3회, 7일이후에는 0.2 mg/kg, 0.25 mg/kg, 0.25 mg/kg로 3회투여하였다. 이부프로펜 (Brufen syrup, Samil, Seoul, Korea) 은 24시간간격으로각각 10 mg/kg, 5 mg/kg, 5 mg/kg의저용량으로 3회경구투여하였다. 약물을투여한지 24시간이후부터동맥관의폐쇄및약물의반복투여여부를확인하기위해심초음파검사를다시시행하였으며반복적인약물투여에도불구하고동맥관이폐쇄되지않고지속적으로임상소견이호전되지않는경우에는동맥관결찰술의수술적치료를시행하였다. 대상환자들의인구학적특징으로재태기간, 출생체중, Apgar 점수, 분만형태, 성별등을비교하였으며주산기인자로서 조기양막파수, 임신성고혈압, 산전스테로이드투여, 조직학적 융모양막염의빈도를조사하였다. 또한신생아호흡곤란증후군, 폐고혈압증, 침습적기계환기요법, 산소투여, 중심정맥도관 사용, 기관지폐형성이상, 패혈증, 미숙아망막증, 3 단계이상의 뇌실내출혈및뇌실주위백질연화증등의이환율과사망률을 조사하였다. 약물요법에대한효과를비교하기위해약물투여 횟수및동맥관결찰술의빈도그리고부작용을비교하기위해 서첫번째약물주기투여후폐출혈, 핍뇨 (<1 ml/kg/hr), 혈청 요소질소 (blood urea nitrogen) 및혈청크레아티닌농도, 위장 관출혈, 괴사성장염발생등의빈도를조사하였다. 통계적처리는 SPSS version 21.0 (IBM Corp., Armonk, NY, USA) 을사용하여군간의인자들을비교분석하였다. 표본수에 서두군간에차이가있고정주용인도메타신을사용한군에서 표본수가적은관계로비모수적검정법을통하여분석을시행 하였으며, 종속변수가범주형변수인경우는 Fisher s exact test, 연속형변수는 Kruskal-Wallis test 를이용하였으며유의 수준은 P<0.05 로하였고, 관찰값은평균 ± 표준편차로제시하였 다. 결과 1. 임상적특징 동맥관개존을가진 103 명의환아중 90 명 (87%) 에서의미있 는증상으로약물요법이필요하였고, 약물요법이시행된 90 명 PDA in VLBW infants (n=103) Medical treatment for symptomatic PDA (n=90) 1st cycle (n=23) IV indomethacin (n=27) Responder (n=87) 2nd cycle (n=4) Non responder (n=3) 1st cycle (n=47) Observation (n=13) PO ibuprofen (n=63) 2nd cycle (n=16) Ligation (n=3) Fig. 1. Diagram of patent ductus arteriosus in very low birth weight infants. PDA, patent ductus arteriosus; VLBW, very low birth weight; IV, intravenous; PO, per oral

3 2018 March;29(1):33-38 중에서정주용인도메타신을사용한경우는 27명 (30%), 경구용이부프로펜을사용한경우는 63명 (70%) 이었다 (Fig. 1). 두군간의재태기간, 출생체중, Apgar 점수, 분만형태, 성별, 조기양막파수, 임신성고혈압및조직학적융모양막염의빈도등은차이가없었다. 또한신생아호흡곤란증후군및폐고혈압증의빈도, 침습적인기계환기사용기간, 산소치료기간및중심정맥관사용기간등도두군간에유의한차이가없었다. 또한 46 명의초극소저체중출생아를대상으로다시두군으로나누어비교하였을때경구용이부프로펜을사용한군에서조기양막파수의빈도및남아의빈도가통계적으로나았으며 (P<0.05), 다른인자에서는유의한차이를보이지않았다 (Table 1). 2. 동맥관치료효과극소저체중출생아에서약물투여시작전동맥관크기는두군간에유의한차이가없었으며, 1차약물투여로동맥관이폐쇄된빈도도두군간에유의한차이는없었다. 2차이상의약물투여가필요한경우는정주용인도메타신치료군의 15% (4/27명), 경구용이부프로펜치료군의 28% (16/63명) 였으며수술적치료가필요한경우는 3명으로모두경구용이부프로펜을사용한군이었으나통계적으로두군간에유의한차이는없었다. 전체적으로약물투여에대한동맥관폐쇄효과는경구용이부프로펜치료군의 95%, 정주용인도메타신치료군의 100% 빈도를보였다. 초극소저체중출생아의경우에도치료반응은두군간 Table 1. Characteristics of Very Low Birth Infants with Symptomatic Patent Ductus Arteriosus Table 2. Efficacy of Intravenous Indomethacin versus Oral Ibuprofen for Patent Ductus Arteriosus in Very Low Birth Weight Infants IV indomethacin Oral ibuprofen P-value Initial PDA Size (mm) 1.9± ± ± ± st cycle 23 (85) 10 (83) 47 (72) 21 (62) nd cycle 4 (15) 2 (17) 16 (28) 13 (38) Ligation operation 0 (0) 0 (0) 3 (5) 2 (6) Abbreviations: IV, intravenous; BW, birth weight; PDA, patent ductus arteriosus. IV Indomethacin Oral Ibuprofen P-value Gestational age (wks) 27±3 25±2 27±3 25± Birth weight (g) 1,014± ± ± ± Apgar score 1 minute 4±2 3±2 4±2 3± minutes 7±2 6±1 7±1 6± Male 11 (41) 10 (83) 34 (54) 16 (47) Inborn 26 (96) 12 (100) 60 (95) 34 (100) Cesarean section 16 (59) 6 (50) 44 (70) 25 (74) PIH 2 (7) 1 (10) 10 (16) 4 (13) PROM 15 (44) 7 (64) 11 (20) 6 (18) Pathologic chorioamnionitis 9 (33) 5 (46) 16 (25) 13 (41) Prenatal steroid 11 (41) 5 (46) 23 (36) 10 (32) RDS 26 (96) 12 (100) 63 (100) 34 (100) PPHN 2 (3) 1 (8) 3 (5) 0 (0) Intubation duration (days) 51±49 71±57 49±38 66± Oxygen duration (days) 68±50 86±57 44±54 65± PCVC duration (days) 54±36 66±46 49±27 57± Abbreviations: BW, birth weight; PIH, pregnancy induced hypertension; PROM, premature rupture of membrane; RDS, respiratory distress syndrome; PPHN, persistent pulmonary hypertension; PCVC, percutaneous central venous catheterization

4 Yun JW, et al. The comparison of efficiency of oral ibuprofen and intravenous indomethacin 에유의한차이가없었다 (Table 2). 고찰 3. 약물요법의부작용약물투여후흔히발생할수있는혈청단백질요소나혈청크레아티닌수치의증가정도는높지는않았으며두군간에도유의한차이는없었다. 핍뇨의빈도는경구용이부프로펜을투여한군에서빈도가더많았으나통계적인차이는없었다. 그외폐출혈, 위장관출혈, 괴사성장염의발생빈도도두군간에유의한차이는없었다 (Table 3). 4. 이환율과사망률중등도이상의기관지폐형성이상, 패혈증, 3단계이상이나수술적치료가필요한미숙아망막증, 뇌실내출혈, 낭성뇌실주위백질연화증등의빈도는두군간에유의한차이가없었다. 사망률의차이도두군간에나타나지않았으며, 초극소저체중출생아에서도이환율과사망률의빈도는유의한차이가없었다 (Table 4). 국내신생아집중치료실에서는동맥관개존의치료약물로 2009년도이전까지는주로정주용인도메타신을사용하였다가이후정주용인도메타신의수입이제한되면서 2010년부터는경구용이부프로펜의사용이증가하게되었고, 최근 2-3년사이에는정주용이부프로펜의구입이용이해지면서점차정주용이부프로펜의사용이증가하고있는실정이다. 실제로, Lee 등 5 의연구에서도 2013년부터 2014년까지한국신생아네트워크 (Korea Neonatal Network) 에서 2,386명의극소저체중출생아를대상으로동맥관개존의치료를분석하였을때, 801명에서약물치료가필요하였고그중 98% 에서이부프로펜 ( 경구용 34%, 정주용 63%, 혼합투여 1%) 을 1.7% 에서정주용인도메타신을사용한것으로보고하였다. 특히, 이부프로펜은인도메타신에비해서뇌관류및뇌대사, 신장이나장관혈류에영향을적게주기때문에위장관출혈이나신손상의부작용이적은것으로보고하고있으며, 6-8 안정성에대한연구가이루어지면서최근국내외적으로사용이증가하고있는추세이다. 본원신생아집중치료 Table 3. Side Effect of Intravenous Indomethacin versus Oral Ibuprofen for Patent Ductus Arteriosus in Very Low Birth Weight Infants IV Indomethacin Oral Ibuprofen P-value BUN after 1st cycle use (mg/dl) 21±10 23±13 20±10 23± Creatinine after 1st cycle use (mg/dl) 1.2± ± ± ± Oliguria 11 (21) 7 (64) 14 (42) 10 (74) Pulmonary hemorrhage 0 (0) 0 (0) 3 (5) 3 (9) GI hemorrhage 3 (11) 2 (17) 2 (3) 1 (3) NEC 0 (0) 0 (0) 0 (0) 0 (0) Abbreviations: IV, intravenous; BW, birth weight; BUN, blood urea nitrogen; GI, gastrointestinal; NEC, necrotizing enterocolitis. Table 4. Mortality and Morbidity of Intravenous Indomethacin versus Oral Ibuprofen for Patent Ductus Arteriosus in Very Low Birth Weight Infants IV Indomethacin Oral Ibuprofen P-value BPD ( moderate) 8 (30) 3 (25) 28 (44) 12 (35) Sepsis 7 (26) 5 (40) 17 (27) 14 (41) ROP ( stage 3) 6 (22) 5 (40) 8 (13) 6 (18) ROP (laser operation) 7 (26) 5 (40) 8 (13) 6 (18) IVH ( grade III) 1 (4) 1 (8) 4 (6) 2 (6) Cystic PVL 4 (15) 1 (8) 4 (6) 3 (9) Mortality 4 (15) 2 (17) 8 (13) 9 (26) Hospital stay (days) 90±51 106±58 91±52 109± Abbreviations: BW, birth weight; PIH, pregnancy induced hypertension; PROM, premature rupture of membrane; RDS, respiratory distress syndrome; PPHN, persistent pulmonary hypertension; PCVC, percutaneous central venous catheterization

5 2018 March;29(1):33-38 실에서도 2010년도부터정주용인도메타신의공급부족으로인해저용량 (10 mg/kg, 5 mg/kg, 5 mg/kg) 의경구용이부프로펜을사용하게되었고집중적으로경구용이부프로펜을사용하게된시점을기준으로전후 2년간의환자를대상으로연구를하였다. 본연구의대상환자수가경구용이부프로펜치료군이정주용인도메타신을사용한군에비해서 2배가까이많았는데, 이는 2010년이후병상확장으로인해서입원환자수가증가한영향이있으며, 극소저체중출생아치료전략의시기별변화영향을적게주기위해서대상환자수보다는시기를정하여연구를진행하였다. 본연구에서경구용이부프로펜은초극소및극소저체중출생아의동맥관을폐쇄하는데유용한효과를보였고부작용이나이환율도인도메타신과비교하여유사한소견을나타내었다. 비록경구용이부프로펜군에서수술적인치료가필요하였으나통계적인차이는보이지않았다. Aly 등 9 도재태기간 35주이하의미숙아를대상으로시행한무작위대조연구에서경구용이부프로펜과정주용인도메타신의효과를비교하였을때, 경구용이부프로펜치료군의 83%, 정주용인도메타신치료군의 78% 에서폐쇄가되었다고보고하면서동맥관의치료로경구용이부프로펜이쉽게투여될수있는장점을가지면서유효성이있다고하였다. Lee 등 10 은 88명의극소저체중출생아를대상으로후향적연구를하였고, 경구용이부프로펜치료군의 70.5%, 정주용인도메타신치료군의 61.5% 에서수술적치료없이동맥관이폐쇄되었다고하였다. 국내의연구에서도 Lee 등 11 이 36주미만의미숙아를대상으로시행한무작위대조연구에서경구용이부프로펜이유용한효과를보였고, 52명의극소저체중출생아를대상으로후향적인조사를시행한 Lee 등 12 의연구에서도경구용이부프로펜이효과적이었다고보고하였다. Yang 등 13 은 48명의초극소저체중출생아를대상으로후향적으로연구하였을때, 경구용이부프로펜치료군의 81.8%, 정주용인도메타치료군의 88.5% 에서폐쇄가되었다고보고하였는데본연구에서초극소저체중출생아는경구용이부프로펜치료군의 94%, 정주용인도메타신치료군의 100% 에서폐쇄가되어더유효한결과를나타내었다. 미숙아에서이부프로펜의효과와부작용을비교연구한코크란자료 6,14,15 에서도이부프로펜이인도메타신과유사한효과를보이면서괴사성장염이나일시적인신기능부전의위험성을감소시킨다고하였고, 이부프로펜도투여방법에따라경구와정주투여를비교하였을때모두동맥관폐쇄에유사한효과를나타낸다고하였다. 무작위대조연구에서 Cherif 등 16 은경구와정주용이부프로펜의폐쇄효과는각각 70% 로유사하였으나부작용은정주용이부프로펜에서더많았다고하였고, Gokmen 등 17 은극소저체중출생아의무작위연구에서경구및정주용이부프로펜간에부작용의발생빈도차이는없으나경구투여방법 (84.6%) 이정주투여방법 (62.0%) 보다효과가더좋았다고보고하였다. Oncel과 Erdeve 18 도동맥관치료에있어서경구투여방법으로는이부프로펜이효과적이면서부작용이적어서첫번째로고려될수있다고하였다. Erdeve 등 19 은 80명의초극소저체중출생아를대상으로무작위대조연구를하였는데, 이부프로펜의 1차투여후폐쇄여부를비교하였을때, 경구용투여방법 (83.3%) 이정주용투여방법 (61.7%) 보다폐쇄빈도가통계적으로유의하게높았다고보고하였다. Barzilay 등 20 은 34주미만의미숙아 ( 평균재태기간 27.8주, 출생체중 1,052 g) 를대상으로 10 mg/kg의단일용량이부프로펜을경구투여한후혈액농도를시간에따라측정하였을때, 투여후 8시간경에최고농도에도달하였으며혈중농도-시간곡선하면적 (area under the curve 24 hours) 이 Van Overmeire 등 21 의정주용이부프로펜투여와비교하였을때높은수치를나타내고있어동맥관의폐쇄에더좋은효과를줄수있다고하였다. 22 Ohlsson 등 14 은이부프로펜의경구와정주투여방법에따른위장관의부작용을비교하려하였으나명확한연구가아직은없는것으로보고하였고, Oncel과 Erdeve 18 는위장관출혈이나괴사성장염의발생을줄이기위해경관투여시약물의삼투압을낮춰주기위해서 1-2 ml의증류수를같이흘려주는것을권장하기도하였다. 최근국내에서는정주용이부프로펜의구입이용이해지면서그사용빈도가증가하고있으나정주투여는건강보험급여기준으로재태기간 34주미만의미숙아로제한하고있어서후기미숙아의경우에는경구용이부프로펜을사용할수밖에없는실정이다. 여러연구에의하면재태기간 32주이상의신생아도 20% 에서의미있는동맥관개존이발생하며, 경구용이부프로펜은만삭아동맥관개존의 75% 에서도폐쇄효과를보이는것으로보고하고있어, 4,6,7,23 후기미숙아나만삭아에서도경구용이부프로펜이유용하게사용될수있을것이다. 또한투여방법이정주투여와비교하였을때비침습적이기때문에말초혈관을유지하는과정에서발생하는통증을감소시키는데도움이될수있을것이다. 본연구에서는경구용이부프로펜투여가초극소및극소저체중출생아의동맥관폐쇄에유효한효과를나타내고있어효율성이나경제적인면에서지속적으로유의하게사용될수있을것으로생각된다. 그러나본연구는경구용이부프로펜의효과에제한되어있어서추후정주용이부프로펜을사용한대상과임상적효과및부작용에대한추가연구가더필요할것이다

6 Yun JW, et al. The comparison of efficiency of oral ibuprofen and intravenous indomethacin References 1) Koch J, Hensley G, Roy L, Brown S, Ramaciotti C, Rosenfeld CR. Prevalence of spontaneous closure of the ductus arteriosus in neonates at a birth weight of 1000 grams or less. Pediatrics 2006;117: ) Ellison RC, Peckham GJ, Lang P, Talner NS, Lerer TJ, Lin L, et al. Evaluation of the preterm infant for patent ductus arteriosus. Pediatrics 1983;71: ) Benitz WE, Bhombal S. The use of non-steroidal anti-inflammatory drugs for patent ductus arteriosus closure in preterm infants. Semin Fetal Neonatal Med 2017;22: ) Hamrick SE, Hansmann G. Patent ductus arteriosus of the preterm infant. Pediatrics 2010;125: ) Lee JA, Kim MJ, Oh S, Choi BM. Current status of therapeutic strategies for patent ductus arteriosus in very-low-birth-weight infants in Korea. J Korean Med Sci 2015;30 Suppl 1:S ) Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2010;(4):CD ) Keating P, Verhagen E, van Hoften J, ter Horst H, Bos AF. Effect of indomethacin infused over 30 minutes on cerebral fractional tissue oxygen extraction in preterm newborns with a patent ductus arteriosus. Neonatology 2010;98: ) Patel J, Roberts I, Azzopardi D, Hamilton P, Edwards AD. Randomized double-blind controlled trial comparing the effects of ibuprofen with indomethacin on cerebral hemodynamics in preterm infants with patent ductus arteriosus. Pediatr Res 2000;47: ) Aly H, Lotfy W, Badrawi N, Ghawas M, Abdel-Meguid IE, Hammad TA. Oral Ibuprofen and ductus arteriosus in premature infants: a randomized pilot study. Am J Perinatol 2007;24: ) Lee CH, Chen HN, Tsao LY, Hsiao CC, Lee ML. Oral ibuprofen versus intravenous indomethacin for closure of patent ductus arteriosus in very low birth weight infants. Pediatr Neonataol 2012;53: ) Lee SJ, Kim JY, Park E, Sohn S. The pharmacological treatment of patent ductus arteriosus in premature infants with respiratory distress syndrome: oral ibuprofen vs. indomethacin. Korean J Pediatr 2008;51: ) Lee J, Choi M, Shim GH, Song YH, Chey MJ. Oral ibuprofen versus intravenous indomethacin for the treatment of patent ductus arteriosus in very low birth weight infants. Neonatal Med 2013;20: ) Yang EM, Song ES, Choi YY. Comparison of oral ibuprofen and intravenous indomethacin for the treatment of patent ductus arteriosus in extremely low birth weight infants. J Pediatr (Rio J) 2013;89: ) Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2013;(4):CD ) Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database Syst Rev 2015;(2):CD ) Cherif A, Khrouf N, Jabnoun S, Mokrani C, Amara MB, Guellouze N, et al. Randomized pilot study comparing oral ibuprofen with intravenous ibuprofen in very low birth weight infants with patent ductus arteriosus. Pediatrics 2008;122:e ) Gokmen T, Erdeve O, Altug N, Oguz SS, Uras N, Dilmen U. Efficacy and safety of oral versus intravenous ibuprofen in very low birth weight preterm infants with patent ductus arteriosus. J Pediatr 2011;158: e1. 18) Oncel MY, Erdeve O. Oral medications regarding their safety and efficacy in the management of patent ductus arteriosus. World J Clin Pediatr 2016;5: ) Erdeve O, Yurttutan S, Altug N, Ozdemir R, Gokmen T, Dilmen U, et al. Oral versus intravenous ibuprofen for patent ductus arteriosus closure: a randomised controlled trial in extremely low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2012;97:F ) Barzilay B, Youngster I, Batash D, Keidar R, Baram S, Goldman M, et al. Pharmacokinetics of oral ibuprofen for patent ductus arteriosus closure in preterm infants. Arch Dis Child Fetal Neonatal Ed 2012;97:F ) Van Overmeire B, Touw D, Schepens PJ, Kearns GL, Anker JN. Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus. Clin Pharmacol Ther 2001;70: ) Sharma PK, Garg SK, Narang A. Pharmacokinetics of oral ibuprofen in premature infants. J Clin Pharmacol 2003;43: ) Neumann R, Schulzke SM, Bührer C. Oral ibuprofen versus intravenous ibuprofen or intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants: a systematic review and metaanalysis. Neonatology 2012;102:

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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