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1 KMJ Original Article Clinical Features and Factors Associated with the Frequency of Phototherapy in Premature Birth Gestation < 35 Weeks and Birth Weight 2,500 g So Yoon Choi 1, Ho Yeon Hwang 1, Yoo Rha Hong 1, Yu Jin Jung 2 1 Department of Pediatrics, College of Medicine, Kosin University, Gospel Hospital, Busan, Korea, 2 Department of Pediatrics, College of Medicine, Inje University, Haeundae Paik Hospital, Busan, Korea 임신기간 35 주미만인미숙아에서광선치료횟수에미치는인자와임상적특징 최소윤 1 황호연 1 홍유라 1 정유진 2 1 고신대학교복음병원소아청소년과, 2 인제대학교해운대백병원소아청소년과 Objectives: Clinical features according to the frequency of phototherapy and clinical risk factors on the number of phototherapy were investigated in premature births with gestation <35 weeks and birth weight 2,500 g. Methods: The 186 infants with gestation <35 weeks and birth weight 2,500 g were admitted to the neonatal intensive care unit of Kosin University Gospel Hospital from March 2009 to August The 171 infants were alive and had jaundice requiring phototherapy. Phototherapy was usually started to 50-70% of the maximal bilirubin level. They were divided into two groups according to the frequency of phototherapy as single phototherapy group (group I) and multiple phototherapy group (group II). We retrospectively reviewed the medical records of all patients. Results: The mean gestational age and birth weight of group I were 31.0±2.9 weeks and 1,596±485 g and those of group II were 31.1±2.6 weeks and 1,592±430 g. Compared with group I, albumin and Apgar score at 1 minute of group II were significantly higher and the day of peak bilirubin was also late. Duration of phototherapy in group II was statistically longer than that groupⅠ but duration of ventilator and aminophylline use for apnea was significantly shorter. The frequency of antibiotic use, incidence of bronchopulmonary dysplasia (BPD), and intraventricular hemorrhage (IVH) of group II were significantly lower than those of group I. Conclusions: The day of peak bilirubin was late and the frequency of antibiotic use, incidence of BPD, and IVH were low in group II. The aggressive phototherapy may be considered in premature births with jaundice. Key Words: Jaundice, Phototherapy, Premature birth 임신나이 35주이상신생아에서황달이발생하였을때광선치료의적응증은임신나이, 생후나이와위험인자유무에따라서달라진다. 1 그러나임신나이 35주미만인신생아에서는아직까지국제적으로인정되고있는가이드라인은아직없고, 최대황달수치의 50-70% 에달하는혈청빌리루빈수치를보일때에광선치료를시작한다는문헌이있어서현재일부에서인용되어쓰이고있다. 2 그래서광선치료시작을결정하는것이임상의에따라차이가있을수있다. 광선치료가신생아황달을치료하는기본치료방법이며교환수혈이요구되는심한 Corresponding Author: Yu Jin Jung, Department of Pediatrics, College of Medicien, Inje University, Haeundae Paik Hospital, 1435, Jwa-dong, Haeundae-gu, Busan, , Korea TEL: FAX: hasaohjung@hanmail.net Received: August 7, 2012 Revised: October 22, 2012 Accepted: October 25,

2 황달을예방할수있는방법임에도불구하고임상의에따라다르고, 92개신생아실의담당임상가들의응답한바에의하면광선치료의기준이되는혈청빌리루빈수치도매우다양하여환아의임상적상태에따라광선치료가시작된다고하였다. 3 또한광선치료에의해묽은변, 안구손상, 피부발진, 발열, 탈수, 오한, 직접빌리루빈증가인경우 Bronze baby 증후군과같은부작용을동반할수있어 1,2 치료방침에따른광선치료의시작시기를고려해볼필요가있겠다. 본연구자들은미숙아와저체중출생아가만삭아보다뇌손상과관계된빌리루빈수치에도달할위험이높으므로임신나이 35주미만이고출생체중 2,500 g 이하미숙아를대상으로광선치료횟수에영향을주는인자들을살펴보고광선치료횟수에따른환아들의임상적특징들을알아보고자하였다. 연구대상및방법 2009 년 3월 1일부터 2010 년 8월 31일까지본원신생아중환자실에입원한임신나이 35주미만이고출생체중 2,500 g 이하미숙아 186명중생존하여퇴원한 176명중에서 1회이상광선치료를시행받은 171명을대상으로하였다. 동일기간에서광선치료를시행받지않은미숙아환아 5명, 사망한환아 9명및전원된환아 1명은제외되었다. 황달은혈중빌리루빈농도가최대황달농도의 50% 를넘으면신생아황달로진단하였다. 광선치료의기준은황달수치가최대황달농도의 50-70% 범위에서결정되었고광선치료의중단시기는최대황달농도의 50% 미만에서이루어졌다. 본연구에서대상환아의대부분이광선치료를받았기때문에광선치료 1회시행받은군 (group I) 과다시발생한황달을치료하기위해광선치료를 2회이상시행받은군 (group II) 으로나누어산과적요인및출생당시와출생후임상적특징과위험요소 등을조사하였다. 산모의임신성당뇨와임신성고혈압, 산전항생제, 스테로이드및 MgSO 4 사용여부, 조기양막파수 (>24 h) 등의산과적인요인과임신나이, 출생체중, 성별, 분만방법, 출생당시 ph 와 PCO 2, 1분과 5분아프가점수, 신생아호흡곤란증후군, 동맥관개존증, 최대황달농도와시기, 최대황달농도시기의알부민, 광선치료기간과시작시기, 최대체중감소 % 와시기, 출생체중으로의회복시기, 수유시작시기, 수유곤란, 완전장관영양시기, 총정맥영양투여기간, 괴사성장염, 인공호흡기치료기간, 무호흡기간, 기관지폐형성이상, 미숙아망막증, 항생제사용, 패혈증, 뇌실내출혈과뇌실주위백질연화증등의출생당시와이후의임상적특징들과위험요소등을후향적으로조사하였다. 광선치료는모델명 PIT-220TLR (Atom Medical Corp., Japan) 기기를사용하였다. 그리고이연구는본원임상시험및의학연구윤리심사위원회에서 2012년승인받았다 (No ). 광선치료를 1회시행받은군과 2회이상시행받은군으로나누어조사한항목들을 Microsoft Excel 에입력하여관리하였다. 연속형변수는 Student s t-test를사용하여두군을비교하였고범주형변수는 Chi-square test 를사용하였다. 자료통계결과는 P < 0.05 미만인경우를통계학적으로유의한것으로정의하였으며 PASW (Version 19.0) 프로그램을이용하였다. 결과 총 171명중광선치료를 1회시행받은환아가 98명 (57.3%), 2회시행받은환아가 52명 (30.4%), 3회시행받은환아가 13명 (7.6%), 4회이상시행받은환아가 8명 (4.7%) 이었다 (Fig. 1). 1회광선치료군 98명 (57.3%) 과 2회이상광선치료군 73명 (42.7%) 으로나누어분석하였다. 1회광선치료군의임신나이는 31.0±2.9주, 출생체중은 1,596±485 g으로 2회이상광선치료군의임신 134

3 Clinical Features Associated with the Frequency of Phototherapy in Prematurity Fig. 1. Summary of preterm infants by the frequency of phototherapy Abbreviations: GA, Gestational age; BW, Birth weight; PT, Phototherapy Table 1. Demographic factors of preterm infants by the frequency of phototherapy (mean±sd) Characteristics Group I (n=98) Group II (n=73) P-value Gestational age (weeks) 31.0± ±2.6 NS Birth weight (gram) 1,596±485 1,592±430 NS Cesarean section, n (%) 67 (68.4%) 46 (63.0%) NS Male, n (%) 48 (49.0%) 41 (56.2%) NS Apgar score, 1min, median (range) 6 (1-9) 7 (2-9) <0.05 Apgar score, 5min, median (range) 8 (5-9) 8 (4-9) NS Antenatal steroids, n (%) 66 (67.3%) 54 (74.0%) NS Intrapartum antibiotics, n (%) 44 (44.9%) 38 (52.1%) NS PROM (>24 h), n (%) 28 (28.6%) 26 (35.6%) NS GDM, n (%) 4 (4.1%) 2 (2.8%) NS PIH, n (%) 11 (11.2%) 3 (4.1%) NS Abbreviations: PROM, premature rupture of membranes; GDM, gestational diabetes mellitus; PIH, pregnancy induced hypertension. 나이 31.1±2.6주, 출생체중 1,592±430 g과비슷하였다 (Table 1). 산모의임신성당뇨와임신성고혈압, 산전항생제, 스테로이드및 MgSO 4 사용, 조기양막파수 (>24 h) 와같은산과적요인은두군간에차이가없었다 (Table 1). 성별, 135

4 분만방법, 출생당시 ph와 PCO 2, 5분아프가점수, 최대황달농도, 광선치료시작시기, 출생체중으로의회복시기, 완전장관영양시기와총정맥영양투여기간, 수유곤란, 괴사성장염, 신생아호흡곤란증후군, 동맥관개존증, 미숙아망막증, 패혈증, 뇌실주위백질연화증등과같은출생당시와출생후임상적특징들과위험요소등에두군간에유의한차이가없었다 (Table 1, 2, 3). 2회이상치료군을 1회치료군과비교하여최대황달농도가발생한시기 (6.7±5.3 vs. 3.8±1.5) 와광선치료기간 (8.6±3.7 vs. 5.0±2.2) 이통계적으로차이가있었으 며, 알부민농도 (3.2±0.4 vs. 2.9±0.3) 와 1분아프가점수 (7 vs. 6) 도높게나왔다. 그리고인공호흡기치료기간 (0.7±3.4 vs. 3.2±10.3) 과무호흡기간 (27.2±23.9 vs. 38.1±29.2) 이의미있게짧았다. 수유시작시기 (1.5±1.0 vs. 1.9±2.1) 도의미있게일찍시작되었다 (Table 1, 2). 2회이상치료군에서 1회치료군보다기관지폐형성이상 (6.8% vs. 19.6%), 항생제사용여부 (50.7% vs. 68.4%) 와뇌실내출혈 (5.6% vs. 18.6%) 이통계학적으로의미있게낮았다 (Table 3, 4). Table 2. Clinical features of preterm infants by the frequency of phototherapy (mean±sd) Group I (n=98) Group II (n=73) P-value ph at birth 7.3± ±0.1 NS PCO 2 at birth 49.1± ±11.1 NS Peak bilirubin (mg/dl) 8.9± ±2.4 NS The day of peak bilirubin (day) 3.8± ±5.3 <0.05 Albumin (g/dl) 2.9± ±0.4 <0.05 Duration of PT (days) 5.0± ±3.7 <0.05 Duration of ventilator (days) 3.2± ±3.4 <0.05 Duration of AMP for apnea (days) 38.1± ±23.9 <0.05 Day of maximal weight loss (day) 5.4± ±1.5 NS Day of recovery to birthweight (day) 13.7± ±4.6 NS The day of first feed (day) 1.9± ±1.0 <0.05 Day of full feeding (day) 22.4± ±13.4 NS Duration of TPN (days) 20.4± ±14.7 NS Abbreviations: PT, Phototherapy; AMP, aminophylline; TPN, total parenteral nutrition. Table 3. Outcomes of preterm infants by the frequency of phototherapy Group I (n=98) Group II (n=73) P-value RDS, n (%) 23 (23.5%) 12 (16.4%) NS Symptomatic PDA, n (%) 26 (28.3%) 20 (30.8%) NS Sepsis, n (%) 15 (15.5%) 7 (9.9%) NS ROP stage 3, n (%) 9 (11.1%) 4 (6.3%) NS BPD, n (%) 19 (19.6%) 5 (6.8%) <0.05 Use of antibiotics, n (%) 67 (68.4%) 37 (50.7%) <0.05 IVH Grade 2, n (%) 18 (18.6%) 4 (5.6%) <0.05 PVL, n (%) 5 (9.4%) 3 (6.3%) NS Abbreviations: RDS, respiratory distress syndrome; PDA, patent ductus arteriosus; ROP, retinopathy of prematurity; BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia. Table 4. Logistic regression results of outcomes Β SE β Wald Statistic OR (95% CI) BPD ( ) Use of antibiotics ( ) IVH Grade ( ) 136

5 Clinical Features Associated with the Frequency of Phototherapy in Prematurity 고찰 본연구에서는연구기간동안대상환아의 97% 가 1회이상의광선치료가필요한황달이관찰되었다. 만삭아의 60%, 미숙아의 80% 까지 3 황달이발견되는것보다높은비율을보였다. 이는임상의들이광선치료를동일한기준에서시작할수있도록사전에결정하고예방적방법과치료적방법을구분하여이루어진연구들과는달리, 본연구는최대황달수치의 50-70% 에달하는혈청빌리루빈수치를보일때에광선치료를시작한다는가이드라인 2 으로임상의들에따라서환아들의임상적상태를고려하여광선치료가이루어졌다는차이점이있기때문인것으로여겨진다. 임신나이가더낮을수록출생체중이더적을수록황달의발생률이높지만, 본연구에서는 1회광선치료군의임신나이와출생체중이 2회이상광선치료군과차이를보이지않았다. 그리고광선치료횟수에산과적요인들이영향을줄수있는지보기위해비교해보았으나두군간에차이는보이지않았다. 광선치료의적용에위험인자에따라서고빌리루빈혈증의치료범위가차이가있는데, 2 이러한위험인자에도산과적요인은포함되지않는것으로보아황달이관찰될때환아들의임상적건강상태를살펴보는것이중요하리라여겨진다. 출생이후빌리루빈대사는위장관을통해간접빌리루빈의형태로배설되고탈수나칼로리부족에의한체중감소가병적황달의위험인자가되므로 2 두군간의수유와체중변화를비교해보았다. 2회이상광선치료군에서첫수유가일찍시작되었음에도불구하고광선치료횟수와기간이더길었다. 첫수유시기가두군간에통계학적인차이를보였지만완전경관영양에도달하는시기와총정맥영양투여시기가의미있게차이가나지않았고, 2회이상광선치료군에서여러요인들에의해체중감소가발생되었을수도있겠지만광선치료와연관된불감손실양의증가 4 와출생체중으로의회복이늦게일어난이유들에영향을받았기때문인것으로생각해볼수있겠다. 본연구에서광선치료를 2회이상시행한군에서무호흡치료를위한아미노필린투여기간이의미있게짧았 다. 미숙아에서무호흡은흔히관찰되는질환인데, 높은혈청의빌리루빈이뇌간의자율신경의기능을억제하여황달이있는미숙아에서는무호흡이악화될수있다. 5 그러므로미숙아에서무호흡의발생을감소시키는기전으로고빌리루빈혈증을치료하기위해서는여러번의광선치료가필요해도황달치료가적절하게이루어지는것이중요하다. Choi 등 6 은빌리루빈 / 알부민비가증가함에따라대뇌피질세포의세포독성이증가하였으므로빌리루빈과동시에같이존재하는알부민의양이대뇌피질의세포손상과관계있다고하였다. 본연구에서도 2회이상광선치료군에서결과적으로알부민수치가통계학적으로높게나왔다. 이는알부민의높은수치가뇌세포독성을낮추는효과가있는것으로생각해볼수도있겠다. 그러나알부민수치를빌리루빈을측정할때마다검사를한것이아니므로전향적인방법을통해추가적인연구가이루어져야할것이다. 또한미숙아에서는혈청빌리루빈농도가광선치료기준에도달하지못하더라도빌리루빈이뇌에침착되어있는경우가있어 7 황달이관찰되었을때광선치료의필요성을고려해야하겠다. 황달의발생과관계있는 ABO 나 Rh 부적합에의한용혈을보인환아는본연구에서는없었고교환수혈이필요한경우도발생하지않았다. 광선치료의발달로황달이있는미숙아에서교환수혈을하는횟수가눈에띄게줄었다고하였으며, 8,9 1,500 g 미만의생존한미숙아 1,213명중에서도교환수혈은한명에서도일어나지않았다고하였다. 9 그리고적극적인광선치료가핵황달과같은합병증의발생률도줄이고신경학적예후를예방할수있다고하였다. 10 그래서출생체중및임신나이에따라광선치료및교환수혈을하게되는황달농도가정해져있다고한다. 본연구에서도환아들의장기적인신경학적예후를추적해보아야하겠지만 2회이상광선치료군에서 2단계이상의뇌실내출혈의빈도가낮게보이는것으로보아광선치료의적극적인시행을고려해야하겠다. 또한뇌실내출혈과같은인자가 34주미만의미숙아에서는황달원인중의하나일수도있는데, 출생체중 1,500 g 미만미숙아를대상으로한조사에서생후 12시간내에일찍 137

6 광선치료를시작하여빌리루빈수치를낮게유지시키는것이더나은신경학적예후를가지게한다고하였다. 3 그러므로미숙아에서임상적상태를고려하여황달을일찍의심하여진단하고광선치료의시작시기와반복되는광선치료의횟수에대해서적극적으로생각해보아야할것이다. 본연구에서통계적자료를제시하지는않았지만, 27 주미만미숙아 22명을대상으로미숙아망막증의발생과최대총혈청빌리루빈농도와의관계에서통계학적의미가없었다. 23 주에서 26주사이의 157 명의미숙아를대상으로한연구에서도총혈청빌리루빈수치와미숙아망막증과관계가없다고하였다. 11 그러나 27주이상미숙아 149 명중에서미숙아망막증이 2명의환아에게발생하였고, 미숙아망막증이발생한환아의평균최대총빌리루빈농도가미숙아망막증이없는환아들보다의미있게낮았다. 빌리루빈은강력한항산화제이고 12,13 신생아에서는산화방지제로서생리적역할을가지있으므로 14,15 광선치료를통해총혈청빌리루빈수치를낮게유지하는것은미숙아망막증의발생을촉진할수도있겠다. 10 임신나이별로혈청빌리루빈농도에따른미숙아망막증발생과의관계는전향적인방법을통해추가적으로연구가이루어져야할것이다. 그리고최대빌리루빈농도의발생시기가늦고더높은빌리루빈농도를보인 2회이상광선치료군에서인공호흡기치료기간이짧고기관지폐형성이상의빈도가낮은것으로미숙아치료에있어서빌리루빈의항산화제역할을고려해보아야할것이다. 13 그러므로광선치료시작을최대황달농도의 50-70% 범위에서낮은기준으로할것인지, 높은기준으로할것인지에대한광선치료의시작시기에논의가필요할것으로보인다. 미숙아에서는동맥관개존증의높은발생률과진단되는시기가광선치료기간과관계가있다고한다. 16,17 이는광선치료를하는동안체온, 말초혈액의흐름, 위장관의운동성및장관내혈액관류의변화로신장의혈액양이감소하고심박출양이감소하기때문이라고한다. 4 하지만본연구에서는두군간에동맥관개존증의발생률에차이가없었고광선치료중에 16 명이진단받았으나통계 적인차이를보이지않았다. 그리고본연구에서자료를제시하지않았지만 2회이상광선치료시행군 (group II) 에서 3회, 4회이상광선치료횟수가증가하여도임신나이와출생체중이차이를보이지않았다. 하지만최대황달발생시기와출생체중으로의회복시기가의미있게늦게나타났다. 그러므로미숙아에서는 1회광선치료이후에도고빌리루빈혈증이발생할수있고출생체중으로의회복시기가늦은미숙아일수록황달이다시관찰될수있음을고려하여황달의진단및치료에관심을기울여야할것이다. 본연구의제한점은후향적인방법으로이루어진것으로광선치료의시작점이환아의의학적상태와임상의에따라동일하지않다는점이있다. 그리고미숙아의제한된조건으로황달이관찰될때마다빌리루빈수치검사를시행할수없었기에최대황달농도의수치에차이가발생할수있다. 본연구에서는 2회이상광선치료를시행했던환아들에서기관지폐형성이상과뇌실내출혈의빈도가낮고항생제사용기간이짧았다. 반복되는광선치료횟수에도불구하고임상적인이로운점이있고적극적인황달치료로미숙아에서장기적인예후에도움이될수있을것이라여겨진다. 그리고보다적극적인광선치료의필요성에대해서는전향적인방법들을통해연구해보아야할것이다. 참고문헌 1. American Academy of Pediatrics Subcommitee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114: Kliegman RM. Jaundice and hyperbilirubinemia in the newborn. In : Kliegman RM, Stanton RM, St. Geme JW, Schor NF, Behrman RE, editors. Nelson Textbook of Pediatrics. 19th ed. Philadelphia: WB Saunders Co, 2011: de Almeida MF. When should we start phototherapy in preterm newborn infant? J Pediatr (Rio J) 2004;80: Benders MJ, van Bel F, van de Bor M. The effect of phototherapy on renal blood flow velocity in preterm infants. Biol Neonate 138

7 Clinical Features Associated with the Frequency of Phototherapy in Prematurity 1998;73: Mesner O, Miller MJ, Iben SC, Prabha KC, Mayer CA, Haxhiu MA, et al. Hyperbilirubinemia diminishes respiratory drive in a rat pup model. Pediatr Res 2008;64: Choi CW, Min KW, Kim MN, Hwang JH, Shim JW, Koh SY, et al. Bilirubin cytotoxicity in primary mouse cerebral cortical cell culture. J Korean Soc Neonatol 2003;10: Choi CW, Hwang JH, Kang S, Shim JW, Chung SH, Koh SY, et al. Effect of hyperbilirubinemia on the brainstem auditory evoked response in newborn piglets. J Korean Soc Neonatol 2003;10: O'Shea TM, Dillard RG, Klinepeter KL, Goldstein DJ. Serum bilirubin levels, intracranial hemorrhage, and the risk of developmental problems in very low birth weight neonates. Pediatrics 1992;90: Maisels MJ. Phototherapy--traditional and nontraditional. 2001; 21 Suppl 1:S93 7; discussion S Maisels MJ, Watchko JF. Treatment of jaundice in low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2003;88: DeJonge MH, Khuntia A, Maisels MJ, Bandagi A. Bilirubin levels and severe retinopathy of prematurity in week estimated gestational age infants. J Pediatr 1999;135: McDonagh AF. Is bilirubin good for you? Clin Perinatol 1990;17: Dani C, Martelli E, Bertini G, Pezzati M, Filippi L, Rossetti M, et al. Plasma bilirubin level and oxidative stress in preterm infants. Arch Dis Child Fetal Neonatal Ed 2003;88: Hegyi T, Goldie E, Hiatt M. The protective role of bilirubin in oxygen-radical diseases of the preterm infant. J Perinatol 1994;14: Gopinathan V, Miller NJ, Milner AD, Rice-Evans CA. Bilirubin and ascorbate antioxidant activity in neonatal plasma. FEBS Lett 1994;349: Rosenfield W, Sadhev S, Brunot V, Jhaveri R, Zabaleta I, Evans HE. Phototherapy effect of the incidence of patent ductus arteriosus in premature infants: prevention with chest shielding. Pediatrics 1986;78: Barefield ES, Dwyer MD, Cassady G. Association of patent ductus arteriosus and phototherapy in infants weighing less than 1000 grams. J Perinatol 1993;13:

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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