Kang HS, et al. Hematologic profile of preterm fetuses Perinatology 됨이보고되었다 백혈구증가증 (leucocytosis) 및백혈구감소증 (leukopenia), 유핵적혈구 (nucleated erythro

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1 pissn eissn Original article Perinatology Vol. 29, No. 1, March, 2018 The Effect of Acute Histologic Chorioamnionitis on Hematologic Profile of Preterm Fetuses Hye-Sim Kang, MD 1,3, Jeong Woo Park, MD 1,2, Hee Sun Kim, MD 4 1 Department of Obstetrics and Gynecology, Jeju National University Hospital, Jeju, 2 Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 3 Jeju National University College of Medicine and Graduate School of Medicine, Jeju, 4 Department of Obstetrics and Gynecology, Ilsan- Paik Hospital, Inje University College of Medicine, Goyang, Korea Received: 25 September 2017 Revised: 24 October 2017 Accepted: 8 December 2017 Correspondence to Jeong Woo Park, MD Department of Obstetrics and Gynecology, Jeju National University Hospital, 15 Aran 13-gil, Jeju 63241, Korea Tel: Fax: jwjwpark@gmail.com Copyright 2018 by The Korean Society of Perinatology 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: To characterize the hematologic profile of preterm fetuses delivered spontaneously with acute histologic chorioamnionitis (HCA). Methods: This was a retrospective cohort study. The relationship between the presence of acute HCA and the change of hematologic profile was examined in 109 singleton pregnant women who were admitted and delivered between weeks of gestation. Cases without results of placental histologic examination, cord blood cell count, and the differential count were excluded. From the cord blood, hemoglobin concentration, hematocrit, mean corpuscular volume, total leucocyte count and the differential count, platelet count, normoblast count, and umbilical arterial ph were obtained. All the observed values were corrected for gestational age by calculating a ratio between the observed and mean expected value for gestational age. Results: 1) The prevalence of acute HCA was 60.6% (66/109); 2) newborns with acute HCA had a higher median corrected leucocyte counts and corrected percentage of neutrophil in the differential count and a lower median corrected percentage of lymphocyte in the differential count than those without acute HCA; 3) neutrophilia was significantly frequent in newborns with acute HCA than in those without acute HCA; and 4) acute HCA was not associated with detectable changes in percentage of monocyte, eosinophil, basophil, and normoblast in the differential count, hemoglobin concentration, hematocrit, erythrocyte counts, mean corpuscular volume, platelet counts, or umbilical arterial ph. Conclusion: The hematologic profile of preterm fetuses delivered spontaneously with acute HCA is characterized by significant changes in the total leucocyte count, neutrophil percentage, and lymphocyte percentage. Key Words: Hematologic test, Preterm, Chorioamnionitis, Fetus 서론 급성조직학적융모양막염 (acute histologic chorioamnionitis) 은태반의급성염증성변 화를의미하며조기분만된태반에서흔하게관찰되는소견이다. 1-3 급성조직학적융모양막 염은조산아에서감염으로인한여러주산기합병증및뇌성마비의위험인자로알려져있으 며양수내백혈구증가및여러전염증성시토카인 (proinflammatory cytokine) 의증가와밀 접한관련이있음이밝혀져있다. 1,4-7 이러한염증성변화들은결국태아염증반응을유발하 게되고, 태아염증반응은태아염증반응증후군 (fetal inflammatory response syndrome) 으 로명명되는전신질환으로설명되는데이는태아혈액내인터루킨 (interleukin)-6 농도가 >11 pg/ml 인경우로정의한다. 8 자궁내감염시, 태아에서전염증성시토카인의합성이촉 진되고증가된태아혈액내시토카인에의해성인에서의전신염증반응증후군 (systemic inflammatory response syndrome) 과유사한급성염증반응이일어나는것으로받아들여 지고있다. 전신염증반응증후군으로진단된환자에서혈액계수 (hematologic profile) 의변화가관찰

2 Kang HS, et al. Hematologic profile of preterm fetuses Perinatology 됨이보고되었다 백혈구증가증 (leucocytosis) 및백혈구감소증 (leukopenia), 유핵적혈구 (nucleated erythrocyte) 의출현등은좋지않은예후와도관련이있음이알려져있다. 11,14 또한신생아에서중성구증가증 (neutrophilia) 이호흡곤란증후군, 신생아패혈증, 뇌손상과관련되어있다는여러저자의보고가있었다 년 Romero 등은태아염증반응증후군을가진태아에서신생아및성인에서보이는이러한혈액학적변화와유사한반응이일어남을보고하였다. 20,21 Romero 등 20 의보고에의하면, 태아염증반응증후군으로진단된태아에서염증반응증후군이없는태아에비교해전체백혈구수및중성구수가유의하게증가하고유핵적혈구수는증가하는경향성이있다고하였다. 한편다른연구에서는조기진통으로조산한태아에서태아염증반응증후군유무에따른제대동맥혈내 ph값은차이가없었다. 21 또한한연구에서는조직학적융모양막염이존재할때제대혈내염증성시토카인및대사물의변화가있다고보고하였다. 22 그러나급성조직학적융모양막염의유무에따른신생아의혈액계수변화에대해서는부분적인혈액계수항목에대한연구가일부있었고모든혈액계수에대해비교한연구는거의없었다. 2015년 Kim 등 23 은 34주이전조산한태아중, 제대염 (funisitis) 유무에따른모든태아혈액계수의변화를조사하여보고하였다. 그러나제대염은태아염증반응증후군의태반염증성변화의대응물 (counterpart) 로간주되고있다. 24 또한조산태아에서제대염은심한태아염증반응증후군과관련이깊다. 25 따라서제대염이있을때, 태아혈액계수가태아염증반응증후군에서보이는변화와비슷한양상을보이는것은당연하다고할수있고 Kim 등 26 의보고는이를확인한것이라고본다. 제대염과비교하였을때, 급성조직학적융모양막염은상대적으로모체부분의태반염증이며경한염증단계로받아들여진다. 급성조직학적융모양막염이있을때태아혈액계수항목의전체적인변화를조사한연구는지금까지는없었다. 이에본연구의저자들은 24-32주사이에조기진통및조기양막파열로조산한단태임신태아에서급성조직학적융모양막염이있으면서혈액계수의변화를보이는태아에서더불량한신생아예후를보일것이라는가설을검증하기위한선행연구로서조직학적융모양막염과태아혈액계수의변화사이의관련성을조사하고자하였다. 대상및방법 본연구는조산한여성의태반의조직학적소견과출생시제대혈내의혈액계수의변화와의연관성을알아보기위하여 1998년 1월부터 2006년 12월까지서울대학교병원에서임신 24주에서 32주사이에조산한임신부들및그조산아를대상으로하였다. 본연구대상의선정조건은다음과같다 : 1) 단태임신 ; 2) 임신 24 주에서 32주사이에조산한경우 ; 3) 의학적적응증으로조산하지않은경우 ; 4) 분만후태반의조직검사가시행된경우 ; 5) 분만직후제대혈에서전체혈구계산 (complete blood cell count) 을시행하여결과가있는경우 ; 6) 주요선천기형 (major con genital anomalies) 이없고자궁내태아사망 (intrauterine fetal death) 이아닌경우 ; 7) Rh 동종면역 (isoimmunization) 이없는경우 ; 8) 태아수혈 (fetal transfusion) 을시행하지않은경우로하였다. 연구대상은태반의조직학적검사에의한급성조직학적융모양막염의존재유무에따라두군으로나누었다. 혈구계산및감별계산 (differential count) 결과가둘다없는경우는연구대상에서제외시켰다. 연구수행과정에서모든임상자료와검체는충분한설명에근거한동의 (informed consent) 를환자로부터받고, 서울대학교병원생명윤리심의위원회의승인 (IRB No ) 하에수집하였다. 임신부와조산아의인구학적및임상적특성은의무기록의검토를통해확인하였다. 저자들은임신부의나이, 미분만부 (nulliparity) 여부, 분만주수, 출생체중, 조산의원인 ( 자연조산인지의학적적응증에의한조산인지여부 ), 제대동맥혈 ph, 제왕절개유무, 분만전코르티코스테로이드 (corticosteroid) 사용유무, 분만전항생제투여, 자궁수축억제제사용, 양수내감염 (intra-amniotic infection) 유무, 중성구증가증및중성구감소증의빈도, 분만시제대혈내백혈구계산 (total leucocyte count) 및감별계산 (differential count), 적혈모세포 (normoblast), 적혈구계산 (erythrocyte count), 혈색소농도 (hemoglobin concentration), 적혈구용적률 (hematocrit), 평균적혈구용적 (mean corpuscular volume), 혈소판계산 (platelet count) 을조사하였다. 혈구계산수치는임신주수에따라변하기때문에측정치는측정치와임신주수에따라기대되는평균치의비 (ratio) 를계산하여분만주수에따라교정하였다. 그러나제대혈내호산구 (eosino phil) 및호염기구 (basophil) 수는임신주수에따라변하지않는다고알려져있으므로교정값을구하지않았다. 27 제대혈내백혈구계산및감별계산, 적혈모세포계산, 적혈구계산, 혈색소농도, 적혈구용적률, 평균적혈구용적, 혈소판계산, 제대동맥 ph의임신주수에따른참고치는이전연구들을통해얻었다 중성구증가증은재태주수대비 95백분위수초과로, 중성구감소증은 40

3 2018 March;29(1):39-47 재태주수대비 5백분위수미만으로정의하였다. 27 태반조직표본에서제대 (umbilical cord), 융모판 (chorionic plate), 태반막 (placental membranes) 에서조직을얻어 10% 포르말린에고정시킨후파라핀에포매 (embedding) 시켰다. 준비된조직블록의절편을헤마톡실린-에오신 (hematoxylin-eosin) 으로염색하였다. 급성조직학적융모양막염의진단기준은 1995년 Yoon 등 1 이보고한바와같이, 상기조직샘플중적어도어느하나에서급성염증성병변이존재하는경우로하였다. 조기진통의진단은적어도 20분동안 4회또는 1시간동안 8회의규칙적인자궁수축이있으면서자궁경부의변화가있는경우로하였고, 조기양막파열은분만진통이전에양막이파열되었다는병력과무균소독된질경검사를통한질강내양수확인, 니트라진 (nitrazine) 및양치상화 (ferning) 검사등으로양막파열여부를확인하여진단하였다. 임상적융모양막염 (clinical chorioamnionitis) 의진단은임신부의체온이 37.8 C 이상이면서자궁압통, 악취나는질분비물, 태아빈맥, 모체빈맥, 모체백혈구증가증중두가지이상의소견을보이는경우로하였다. 양수내감염유무는모든대상환자에서사전동의을얻은후, 복부양수천자를통하여얻은양수를즉시혈액배양병에담아마개를씌워차단하고호기성, 혐기성및마이코플라즈마 (mycoplasma) 에대하여이미보고된방법에의해배양하였다. 1 연속형변수의비교는 student t-test 또는 Mann-Whitney U-test를사용하였고, 범주형변수의비교는 chi-square test 또는 Fisher s exact test로분석하였다. P값이 0.05 미만인경우를통계적으로유의하다고판정하였다. 통계프로그램은 SPSS version 19.0 (SPSS Inc., Chicago, IL, USA) 를사용하였다. 결과 연구기간동안임신 24주에서 32주사이의생존아를분만한단태임신은총 366예였다. 이중에서자발적인조산이아닌모체및태아의적응증을이유로조산한경우, 태반의조직학적검사결과가없는경우, 제대혈검사결과가없는경우, 주요선천기형, 자궁내태아사망, Rh 동종면역, 태아수혈을시행한경우를제외한 109명이포함기준을충족하였다. 연구대상가운데급성조직학적융모양막염의유병률은 60.6% (66/109) 였고양수내감염률은 20.3% (15/74) 였다. 조산의원인중조기진통으로분만한임신부는 56% (61/109) 였으며, 조기양막파열은 44% 를차지하였다. 급성조직학적융모양막염의빈도는조기양막파열군에서조기진통군에비해약간더높게관찰되었으나통계적유의성은없었다 (68.8% [33/48] vs. 54.1% [33/61], P=0.120). Table 1. Demographic and Clinical Characteristics of the Study Population according to the Presence or Absence of Acute Histologic Chorioamnionitis Absent (n=43) Acute histologic chorioamnionitis Present (n=66) Maternal age (yrs) 30.2 ( ) 31.5 ( ) Nulliparity 24/43 (55.8) 28/66 (42.4) Etiology of preterm birth Preterm labor 28/43 (65.1) 33/66 (50.0) PROM 15/43 (34.9) 33/66 (50.0) Cesarean delivery 26/43 (60.5) 28/66 (42.4) Antenatal corticosteroids use 32/43 (74.4) 52/66 (78.8) Antenatal antibiotics use 22/43 (51.2) 53/66 (80.3) Tocolytics use 34/43 (79.1) 46/66 (69.7) Clinical chorioamnionitis 1/43 (2.3) 4/66 (6.1) Gestational age at delivery (wks) 29.7 ( ) 28.2 ( ) Birthweight (g) 1,410.0 ( ,610.0) 1,150.0 ( ,020.0) AF WBC count 20 cells/mm 3 * 8/23 (34.8) 32/51 (62.7) Positive AF culture* 3/23 (13.0) 12/51 (23.5) Values are presented as median (range) or number (%). Abbreviations: PROM, premature rupture of membranes; AF, amniotic fluid; WBC, white blood cell. *Transabdominal amniocentesis was performed only in 40 women from whom we received a written consent. In women without acute histologic chorioamnionitis, 61% (14/23) were diagnosed as having preterm labor. Fifty three percent (27/51) had preterm labor in women with acute histologic chorioamnionitis. P-value 41

4 Kang HS, et al. Hematologic profile of preterm fetuses Perinatology 급성조직학적융모양막염이있었던군에서분만주수및출생체중의중앙값은더낮고임상적융모양막염, 양수내백혈구수입방밀리미터당 20개이상및양수내감염의빈도는태반염증이있는군에비해더높았다. 이중분만주수, 출생체중, 양수내백혈구수는통계적으로유의한차이가있었다 (Table 1). 급성조직학적융모양막염의존재유무에따른제대혈내각혈액계수의절대값과교정값, 백혈구감별계산에서백혈구종류에따른각혈액계수의백분위수와교정백분위수를비교하였다 (Table 2). 급성조직학적융모양막염이있었던태아에서제대혈내백혈구수의절대값및교정백혈구수의중앙값은통계적으로유의하게높았다 (Fig. 1). 급성조직학적융모양막염이있을때중성구증가증이더빈번하게관찰되었으나중성구감소증은차이가없었다. 제대혈내백혈구감별계산에서중성구백분위수및교정중성구백분위수는급성조직학적융모양막염이존재할때증가하였으나 (Fig. 2), 림프구백분위수및교정림프구백분위수는모두감소하였다 (Fig. 3). 한편, 백혈구감별계산중, 단핵구, 호산구, 호염기구백분위수는두군간에차이가없었다 (Table 2). 제대혈내림프구수, 단핵구수, 호산구수및호염기구수의절대값은급성조직학적융모양막염과무관하였다 (data not shown). 적혈구와관련된혈액계수중에서적혈구수, 혈색소농도, 적 혈구용적률은급성조직학적융모양막염이있었던태아에서태반염증이없었던군과비교하였을때감소하는경향이었으나모두통계적으로유의한차이는없었다. 평균적혈구용적, 혈소판수, 제대동맥 ph값도두군간에차이가없었다. 적혈구관련모든혈액계수, 혈소판수, 제대동맥 ph값을주수를보정하여계산하였을때에도두군간에유의한차이를보이지않았다 (Table 2). 고찰 본연구에서는임신 24-32주사이에자연조산을한단태임신태아에서태반의급성조직학적융모양막염이있을때, 제대혈내혈액계수의분명한변화가있음을확인하였다. 급성조직학적융모양막염이있는태아에서제대혈내백혈구수, 중성구수및백분위값이유의하게증가하였다. 반면림프구백분위수는유의한감소를보였다. 급성조직학적융모양막염이존재할때적혈구수, 혈색소농도, 적혈구용적률이통계적으로유의하지는않지만감소하는경향을보였다. 그외백혈구감별계산에서단핵구, 호산구및호염기구백분율, 혈소판수, 제대동맥혈 ph값은두군간에유의한차이가없었다. A Fig. 1. Comparison of the fetal blood absolute and corrected leucocyte counts. (A) Fetuses with acute histologic chorioamnionitis had higher median absolute leucocyte counts than those without acute histologic chorioamnionitis (absolute leucocyte count median 10.5 [range, ] vs. 6.6 [range, ] 10 9 /L, P<0.001). (B) Corrected leuco cyte counts by gestational age was also higher in fetuses with acute histologic chorioamnionitis (corrected leucocyte count median 2.31 [range, ] vs [range, ], P<0.001). HCA, histologic chorioamnionitis. B 42

5 2018 March;29(1):39-47 A Fig. 2. Comparison of the fetal blood percentage of neutrophil in the differential count and corrected neutrophil counts. (A) Median percentage of neutrophil was higher in fetuses with acute histologic chorioamnionitis than in those without acute histologic chorioamnionitis (median percentage of neutrophil in the differential count 53.5% [range, ] vs. 32.5% [range, ], P<0.001). (B) Corrected median percentage of neutrophil counts was also higher in fetuses with acute histologic chorioamnionitis (corrected median percentage of neutrophil counts 5.51 [range, ] vs. 2.20, [range ], P<0.001). HCA, histologic chorioamnionitis. B A Fig. 3. Comparison of the fetal blood percentage of lymphocyte in the differential count. (A) Median percentage of lymphocyte was lower in fetuses with acute histologic chorioamnionitis than those without acute histologic chorioamnionitis (median percentage of lymphocyte in the differential count 32.4% [range, ] vs. 53.0% [range, ], P<0.001). (B) Corrected percentage of lymphocyte counts was also lower in fetuses with acute histologic chorioamnionitis (corrected median percentage of lymphocyte counts 0.41 [range, ] vs [range, ], P<0.001). HCA, histologic chorioamnionitis. B 43

6 Kang HS, et al. Hematologic profile of preterm fetuses Perinatology Table 2. Hematologic Profile of the Fetuses according to the Presence or Absence of Acute Histologic Chorioamnionitis Absent (n=43) Acute histologic chorioamnionitis Present (n=66) Leucocyte ( 10 9 /L) 6.6 ( ) 10.5 ( ) <0.001 Corrected leucocyte 1.11 ( ) 2.31 ( ) <0.001 Neutrophilia 25/36 (69.4) 52/57 (91.2) Neutropenia 1/36 (92.8) 0/57 (0.0) Percentage of neutrophil (%)* 32.5 ( ) 53.5 ( ) <0.001 Corrected percentage of neutrophil* 2.20 ( ) 5.51 ( ) <0.001 Percentage of lymphocyte (%)* 53.0 ( ) 32.4 ( ) <0.001 Corrected percentage of lymphocyte* 0.69 ( ) 0.41 ( ) <0.001 Percentage of monocyte (%)* 7.2 ( ) 7.1 ( ) Corrected percentage of monocyte* 2.38 ( ) 2.37 ( ) Percentage of eosinophil (%)* 2.6 ( ) 1.6 ( ) Percentage of basophil (%)* 0.1 ( ) 0.17 ( ) Nucleated RBC (/100WBCs) 10.5 ( ) 0.9 ( ) Corrected nucleated RBC 0.58 ( ) 0.04 ( ) Erythrocyte ( /L) 3.60 ( ) 3.42 ( ) Corrected erythrocyte 0.99 ( ) 0.97 ( ) Hemoglobin (g/dl) 13.6 ( ) 12.8 ( ) Corrected hemoglobin 1.04 ( ) 0.98 ( ) Hematocrit (%) 41.5 ( ) 39.8 ( ) Corrected hematocrit 1.00 ( ) 0.95 ( ) MCV ( /L) ( ) ( ) Corrected MCV 0.96 ( ) 0.97 ( ) Platelet ( 10 9 /L) ( ) ( ) Corrected platelet 0.88 ( ) 0.98 ( ) Umbilical arterial ph 7.29 ( ) 7.30 ( ) II Corrected umbilical arterial ph 0.99 ( ) 0.99 ( ) II Values are presented as median (range) or number (%). Abbreviations: RBC, red blood cell; WBC, white blood cell; MCV, mean corpuscular volume. *Percentage in the differential cell count. Available in 36. Available in 57. Available in 40. II Available in 65. P-value Kim 등 26 의보고에의한양수내상행감염의과정을살펴볼때, 우선양막내미생물이출현하게되면, 양수내전염증성시토카인및화학주성 (chemotaxis) 인자의농도가증가한다. 다음과정으로감염에대한일차면역방어체계인중성구의출현이증가하게된다. 따라서본연구에서급성조직학적융모양막염이존재할때, 출생시제대혈내백혈구수및중성구수의증가는상기태반연구와 Romero 등 20 의태반염증반응증후군에서와 Kim 등 23 의제대염에서제대혈내태아혈액계수변화연구결과와일치하는결과를보여주었다. 중성구증가증은급성조 직학적융모양막염이있을때에는거의 90% 이상에서관찰되었다. 중성구는감염에대한급성염증성반응과숙주방어기제에서중심적인역할을담당하고있다. 조산태아의혈액내백혈구중에서는림프구가가장지배적인형태이다. 27,29 임신 32주이후부터중성구수가증가하기시작하여만삭이되었을때에는중성구가가장지배적인형태가되는것으로알려져있다. 27,31 또한급성조직학적융모양막염이있을때출생시채취한신생아혈액내백혈구및중성구가증가한다는관찰결과는자궁내염증및감염에노출되었거나세균혈증소견을보이는조산한태아 44

7 2018 March;29(1):39-47 및신생아의혈액에서백혈구및중성구수가증가하였다는여러연구의결과와일치한다. 2011년 Wirbelauer 등 19 은급성조직학적융모양막염을보이는 1,500 g 미만으로출생한극소저체중출생아 (very low birthweight infant) 에서출생후 1시간이내에얻은혈액내백혈구수와중성구수가조직학적융모양막염이없었던군에비해유의하게증가하였음을확인하였다. 그러나유핵적혈구수는두군사이에차이가없었다고보고하였다 년 Kim 등 32 은태아염증반응증후군의조직학적대응부 (counterpart) 이자급성조직학적융모양막염의심한형태라고할수있는제대염이존재할때임신부가아닌태아제대혈내단핵구및과립구의세포표면항원의면역표현형이변한다는사실을증명하였다. 특히과립구의 CD14, CD64, CD66b 그리고단핵구의 CD64의평균통로밝기 (mean channel brightness) 의중앙값이유의하게증가하였다는것을증명하였다. 32 이연구결과의의의는본연구결과와비교하였을때, 비록급성조직학적융모양막염이있을때, 단핵구와같이그절대적인숫자의변화가관찰되지않은혈구세포라고할지라도기능적인측면에서여러변화가있음을증명한것이라고할수있다. 1997년 Leikin 등 33 은조기진통및조기양막파열로조산하고급성조직학적융모양막염이확인된신생아에서출생후 24시간이내에채혈하여시행한혈액검사에서유핵적혈구수가유의하게증가하였음을보고하였다. 본연구에서는급성조직학적융모양막염이있었던군에서출생직후채취한제대혈내백혈구수와중성구는유의하게증가하였고림프구백분위수는감소하였으나유핵적혈구수에서의의미있는변화는없었다. 앞서말한 Wirbelauer 등 19 의연구결과와는일치하였으나 Leikin 등 33 의보고와는다른관찰결과였다. 자궁내염증및감염의결과라고할수있는태아염증반응증후군또는태반염증의존재유무에따른유핵적혈구수의차이에있어서성인에서의전신염증반응증후군에서와는달리일관되지않은결과가나오는이유는태아에있어서시토카인이나염증매개성물질들이적혈구조혈과정에영향을미치는정도가성인에비해미약하기때문으로생각된다. 또한적혈구형성인자 (erythropoietin) 는태반을넘어가지않으므로태아는태아의간또는신장에서생성하는적혈구형성인자의영향만을받게되는데이는태아가성숙함에따라생산량이증가하는것으로알려져있다. 34 본연구가임신 24-32주사이의조산아를연구대상으로하였기때문에유핵적혈구수에대한영향이보다덜반영되었을것으로보인다. 또다른설명으로는, 본연구대상군에서유핵적혈구수가이미알려진임신주수에따른유핵적혈구수기준치와는많은차이를보였다. 28,29 특히 Table 2에서유핵적혈구교정값을보았을때, 급성조직학적융모양막염유 무에무관하게양군모두다른선행연구에서알려진평균값기준치절반또는훨씬못미치는수치를보여주었으며오히려급성조직학적융모양막염이있는군에서더낮은수치를보였던점은본연구결과와다른연구들과차이가있는부분이었다. 본연구는임신 24-32주사이의자연조산아에서급성조직학적융모양막염유무에따른백혈구수및감별계수, 적혈모세포, 적혈구, 혈색소농도, 혈소판, 적혈구용적률, 평균적혈구용적, 제대동맥 ph 등거의모든혈액계수를동시에비교한첫번째연구이다. 이에앞서 Kim 등 23 이보고한제대염이있을때태아혈액계수의변화와거의유사한결과를보여준다. 이러한연구결과의의미는태아염증반응증후군의대응부라고할수있는제대염즉비교적심한태반염증형태를보일때태아혈액계수의분명한변화를보여준다는기존연구결과와비교하였을때, 비교적초기단계의경한태반염증형태까지포함하는조직학적융모양막염이존재할때에도이러한태아혈액계수의변화는이미시작된다는점을보여주었다고할수있다. 본연구의약점으로는많은연구대상환자에서채혈을하기전에항생제, 스테로이드, 자궁수축억제제를포함한약물을사용하였다는점이다. 특히세팔로스포린계항생제의사용은드물지만호산구증가증, 백혈구감소증그리고 1% 미만에서무과립구증이발생할수있는것으로알려져있다. 35,36 본연구대상군에서급성조직학적융모양막염이있는군에서조기양막파열빈도가더높았으며, 따라서항생제의사용빈도가더높았다. 그러나호산구수백분율에는통계적으로유의한차이를보이지않았으며조직학적융모양막염이없었던군에서약간더높은경향을보여주었다. 또한중성구감소증도조직학적융모양막염군에서는관찰되지않았다. 또한본연구대상군에서급성조직학적융모양막염의유병률은 60.6% (66/109) 로높았다. 1979년 Russell 37 의보고에의하면분만주수 32주미만에서급성조직학적융모양막염의빈도는 43.2% (70/162) 였다. 또한이연구에의하면, 분만주수가낮을수록태반염증의빈도는증가하였고구체적으로 21-24주에는 94%, 25-28주에는 40%, 29-32주에는약 35% 에의빈도를보였다. 그리고이연구에서는조기진통및조기양막파열뿐만아니라다른의학적적응증에의한조산을포함하는모든조산아의태반염증유무를확인하여보고한연구이며태반의염증은임신성고혈압질환과같은의학적적응증에의한조산보다조기진통및조기양막파열과같은자연조산에서태반염증의빈도가높음이잘알려져있다. 38 본연구에서는 32주이하의자연조산한경우만연구대상으로하였으므로문헌에알려진 43% 보다는약간더높은빈도로본연구의대상군에서태반의조직학적융모양막염이있을것으로예상할수있다. 따라서본 45

8 Kang HS, et al. Hematologic profile of preterm fetuses Perinatology 연구에서대상으로한분만주수에서약 60% 의태반염증유병 률은기존문헌의알려진유병률에비하면많이높다고할수는 없을것으로사료된다. 결론적으로, 급성조직학적융모양막염이있는자연조산아 의혈액계수상특징으로는백혈구수의증가, 중성구백분위수 의증가와림프구백분위수의감소이다. 그리고적혈구생성및 동맥혈 ph 값에미치는영향은미미하다는점이다. 급성조직학 적융모양막염이있을때거의대부분에서중성구증가증이확 인되었다. 본연구는급성조직학적융모양막염이있는조산아 에서모든혈액계수의변화를동시에보여준첫번째연구라는 점에서의의가있겠다. 감사의글 이연구는 2017 년도제주대학교병원연구비로수행되었다. References 1) Yoon BH, Romero R, Kim CJ, Jun JK, Gomez R, Choi JH, et al. Amniotic fluid interleukin-6: a sensitive test for antenatal diagnosis of acute inflammatory lesions of preterm placenta and prediction of perinatal mor bidity. Am J Obstet Gynecol 1995;172: ) Chang JW, Yoon BH, Syn HC. The relationship between the presence, severity and pattern of acute placental inflammation and amniotic fluid interleukin-8 in preterm labor. Korean J Obstet Gynecol 1999;42: ) Kim JC, Yoon BH. The relationship between amniotic fluid white blood cell count and the presence and severity of acute placental inflammation in preterm premature rupture of membrane. Korean J Obstet Gynecol 2000;43: ) Murphy DJ, Sellers S, MacKenzie IZ, Yudkin PL, Johnson AM. Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet 1995;346: ) Watterberg KL, Demers LM, Scott SM, Murphy S. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 1996;97: ) Lee JS, Choi SJ, Moon SO, Yang SH, Lee KS. The association of histologic chorioamnionitis and bronchopulmonary dysplasia in prematurity. Korean J Obstet Gynecol 2002;45: ) Park KH, Yoon BH, Jun JK, Park JS, Kim GJ, Lee HK et al. The relationship between amniotic fluid tumor necrosis factor-, histologic chorioamnionitis, and congenital sepsis in preterm labor. Korean J Obstet Gynecol 2001;44: ) Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. The fetal inflammatory response syndrome. Am J Obstet Gynecol 1998;179: ) Fung YL, Fraser JF, Wood P, Minchinton RM, Silliman CC. The systemic inflammatory response syndrome induces functional changes and relative hyporesponsiveness in neutrophils. J Crit Care 2008;23: ) Groselj-Grenc M, Ihan A, Pavcnik-Arnol M, Kopitar AN, Gmeiner-Stopar T, Derganc M. Neutrophil and monocyte CD64 indexes, lipopolysaccharide-binding protein, procalcitonin and C-reactive protein in sepsis of critically ill neonates and children. Intensive Care Med 2009;35: ) Grimm RH Jr, Neaton JD, Ludwig W. Prognostic importance of the white blood cell count for coronary, cancer, and all-cause mortality. JAMA 1985;254: ) Mammen EF. The haematological manifestations of sepsis. J Antimicrob Chemother 1998;41 Suppl A: ) Koussoulas V, Tzivras M, Karagianni V, Spyridaki E, Plachouras D, Giamarellou H, et al. Monocytes in systematic inflammatory response syndrome: differences between sepsis and acute pancreatitis. World J Gastroenterol 2006;12: ) Stachon A, Segbers E, Holland-Letz T, Kempf R, Hering S, Krieg M. Nucleat ed red blood cells in the blood of medical intensive care patients indicate increased mortality risk: a prospective cohort study. Crit Care 2007;11: R62. 15) Nupponen I, Pesonen E, Andersson S, Mäkelä A, Turunen R, Kautiainen H, et al. Neutrophil activation in preterm infants who have respiratory distress syndrome. Pediatrics 2002;110(1 Pt 1): ) Papoff P, Christensen RD, Calhoun DA, Juul SE. Granulocyte colonystimulating factor, granulocyte macrophage colony-stimulating factor and neutrophils in the bronchoalveolar lavage fluid of premature infants with respiratory distress syndrome. Biol Neonate 2001;80: ) Schrama AJ, de Beaufort AJ, Poorthuis BJ, Berger HM, Walther FJ. Secretory phospholipase A(2) in newborn infants with sepsis. J Peri natol 2008;28: ) Selimović A, Skokić F, Selimović Z, Bazardzanović M. The predictive values of total white blood count and differential count in the diagnosis of early-onset neonatal sepsis. Med Arh 2008;62: ) Wirbelauer J, Thomas W, Speer CP. Response of leukocytes and nucleated red blood cells in very low-birth weight preterm infants after exposure to intrauterine inflammation. J Matern Fetal Neonatal Med 2011; 24: ) Romero R, Savasan ZA, Chaiworapongsa T, Berry SM, Kusanovic JP, Hassan SS, et al. Hematologic profile of the fetus with systemic inflammatory response syndrome. J Perinat Med 2011;40: ) Romero R, Soto E, Chaiworapongsa T, Berry SM, Hassan SS, Kusanovic JP, et al. Blood ph and gases in fetuses in preterm labor with and without a systemic inflammatory response syndrome. J Matern Fetal Neonatal Med 2012;25: ) Kang MS, Kim YH, Kim CH, Kim KM, Cho MK, Kim JW, et al. Changes of interleukin-6, C-reactive protein, and lipid peroxide levels in the umbilical venous plasma of preterm birth with or without chorioamnionitis. Korean J Perinatol 2007;18: ) Kim EN, Kim CJ, Park JW, Yoon BH. Acute funisitis is associated with distinct changes in fetal hematologic profile. J Matern Fetal Neonatal 46

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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