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1 대한요로생식기감염학회지 : 제 4 권제 2 호 2009년 10월 Korean J UTII Vol. 4, No. 2, October 2009 종설 임신과요로감염 부산대학교의학전문대학원비뇨기과학교실 김태남 신동길 이상돈 이정주 [Abstract] Pregnancy and Urinary Tract Infection Tae Nam Kim, Dong Gil Shin, Sang Don Lee, Jeong Zoo Lee From the Department of Urology, Pusan National University School of Medicine, Busan, Korea Urinary tract infections (UTIs) represent the most common bacterial infection in pregnant and non-pregnant women. Physiologic changes of pregnancy increase a woman s susceptibility to UTIs. Progesterone effects and mechanical compression by the gravid uterus impair emptying of the bladder and lead to increased bladder residual volume and vesicoureteral reflux. Relative stasis of urine in the ureters results in hydronephrosis. Furthermore, pregnancy-related changes in glomerular filtration rate increases the urinary glucose concentration and alkalinity, thereby facilitating bacterial growth. The signs and symptoms of UTIs vary by the type of infection. UTIs in pregnancy is classified by the site of bacterial proliferation as follows: asymptomatic bacteriuria, cystitis, pyelonephritis. (Korean J UTII 2009;4: ) Key Words: Urinary tract infection, Pregnancy 서 요로감염은임신의흔한합병증으로하부요로감염 ( 무증상세균뇨및방광염 ) 과상부요로감염 ( 신우신염 ) 으로분류된다. 무증상세균뇨와방광염의발생빈도는가임및임신여성에서비슷하지만신우신염의발생빈도는임신여성에서증가한다. 이는임신에따른산모의해부학적및생리학적변화에따른것으로여겨지며, 1 가임여성과는다르게임신여성 론 교신저자 : 이정주, 부산대학교의학전문대학원비뇨기과학교실부산시서구구덕로 305 우 Tel: , Fax: toohotman@hanmail.net 141 에서는하부요로감염이상부요로감염으로진행하는중요한위험인자가된다. 2 만약산모가신우신염에이완된다면심각한악영향이산모와태아모두에게나타날수있으므로증상의여부와상관없이하부요로감염의적절한조기진단및치료가필요하다. 이에저자들은최근문헌고찰을통하여임신과요로감염에대한최근지견을정리해보고자한다. 본론 1. 병인건강한인체의요로생식기는무균상태이며, 장내

2 142 대한요로생식기감염학회지 : 제 4 권제 2 호 2009 년 10 월 Table 1. Microbiology of bacteriuria in pregnancy Gram-negatives Microorganisms Enterobacteriaceae (90%) Others Gram-positives Other organisms E. coli, Klebsiella, Enterobacter P. mirabilis, Pseudomonas, Citrobacter Staphylococcus saprophyticus Group B Streptococcus Gardnerella vaginalis Ureaplasma urealyticum *Data from Gilstrap 3rd LC, Ramin SM. Urinary tract infections during pregnancy. Obstet Gynecol Clin North Am 2001;28(3):581-91; MillarCox SM. Urinary tract infections complicating pregnancy. Infect Dis Clin North Am 1997;11(1):13-26; Le J, Briggs GG, McKeown A, et al. Urinary tract infections during pregnancy. Ann Pharmacother 2004;38(10): Table 2. Urinary tract changes in pregnancy Urinary tract Kidney Anatomic & physiologic change Increased renal length Increased glomerular filtration rate by 30% to 50% Collecting system Ureters Bladder Decreased peristalsis Decreased peristalsis Mechanical obstruction Displacement superiorly and anteriorly Smooth muscle relaxation * Data from Waltzer WC. The urinary tract in pregnancy. J Urol 1981;125(3): 세균총이요도를통해방광으로침범할경우세균뇨가발생한다. 3 임신및가임여성에서세균뇨를발생시키는균주는비슷하며, 1 E. coli가가장흔하다 (Table 1). 4 그외 Gardnerella vaginalis, lactobacilli, Chlamydia trachomatis 및 Ureaplasma urealyticum과같은균주들이세균뇨에흔하게나타난다. E. coli를제외한위의균주들에의한세균뇨의임상적의의는논란중에있으나최근몇몇연구들은이런균주들에의한세균뇨의치료가산모의건강에좋은영향을미친다는임상결과를보고하였다. 5,6 2. 비뇨기계의변화세균뇨의빈도는임신및가임여성에서비슷하나 급성신우신염의발생빈도는임신여성이가임여성보다훨씬높다. 7 산모의해부학및생리학적변화가신우신염의발생빈도를높이는것으로여겨진다. 1 이런비뇨기계변화는신장, 집뇨계, 요관및방광등전방위적으로나타난다 (Table 2). 신장은길이가 1cm 가량증가하며, 8 사구체여과률은 30 50% 가량증가한다. 9 이런변화는산모의약물농도를결정할때중요한데, 사구체여과률이증가함으로써약물의소변내지속시간을감소시킨다. 10 신우및요관은임신 7주부터직경이늘어나며, 1 임신주수가증가할수록더욱늘어나는데이는자궁크기의증가에의한기계적폐색및 progesterone에의한신우와요관의평활근이완에따른것이다. 또한평활근이완으로인해요관연동운동의감소, 4 방광용적의증

3 김태남외 : 임신과요로감염 143 가및소변정체가발생하며, 방광의위치는임신기간내내골반앞쪽및위쪽으로이동한다 요로감염과항생제사용임신중발생한신우신염치료시산모와태아모 두에게안전한약제를사용해야한다. 대부분의항생제는태반을통과하므로태아에게해로운약제사용은피해야한다. Penicillin, cephalosporin 및 nitrofurantoin은수십년간임신중안전하게사용되고있으나, 11 fluoroquinolones, chloramphenicol, erythromycin 및 tetracycline과같은약제는태아에악영향을미치 Table 3. Antimicrobials in pregnant women Drug Fetal toxicity Comments Safe in pregnancy Penicillins Penicillin G Ampicillin Amoxicillin Cephalosporins Cephalexin Cefaclor Clindamycin Used for Group B Streptococcus Increasing bacterial resistance Increasing bacterial resistance Not active against Enterococcus Used extensively Effective against gram-negatives Used for Group B Streptococcus in penicillin-allergic patients Use cautiously in pregnancy Nitrofurantoin 3 rd trimester: theoretical risk of fetal hemolytic anemia when mother has G6PD deficiency Not effective in pyelonephritis. Not active against Proteus. Hemolytic anemia in maternal G6PD deficiency. Rare maternal pulmonary reaction Aminoglycosides Theoretical risk of fetal oto- and nephrotoxicity May cause maternal oto- and nephrotoxicity Sulfisoxazole Trimethoprim 1 st trimester: antifolate metabolism associated with theoretical increased risk of neural tube defects Increasing E. coli resistance. Hemolytic anemia in 3rd trimester: may lead to neonatal hyperbilirubinemia with G6PD deficiency kernicterus 1 st trimester: antifolate metabolism associated with theoretical increased risk of neural tube defects Increasing E. coli resistance. May cause maternal megaloblastic anemia Avoid in pregnancy Fluoroquinolones Chloramphenicol Irreversible arthropathy in animal studies Gray baby syndrome Erythromycin May cause maternal cholestasis Tetracycline Discoloration of deciduous teeth May cause maternal acute fatty liver degeneration *Data from Schaeffer AJ. Infections of the urinary tract. In: Walsh PC, Retik AB, Vaughan ED Jr, editors. Campbell's Urology. 8th edition. Philadelphia: WB Saunders; 2002: ; Dashe JS, Gilstrap 3rd LC. Antibiotic use in pregnancy. Obstet Gynecol Clin North Am 1997;24(3):

4 144 대한요로생식기감염학회지 : 제 4 권제 2 호 2009 년 10 월 므로산모에게사용해서는안된다 (Table 3). 또한약물의혈중및조직농도가임신에따른생리학적변화로 ( 산모의채액량증가, 신혈류의증가, 사구체여과률증가및태아로약물이동등 ) 인해일반인보다낮다는사실을고려하여처방해야한다. 3,11 1) Penicillin 의치료제로사용되지않는다. Penicillin에과민반응혹은내성을나타낼때좋은대체약으로사용되지만 Proteus 균주는치료하지못한다. 10 드물게아주심각한합병증이발생할수있는데 glucose-6-phosphate dehydrogenase 결핍이있는산모에사용될경우폐렴을비롯한폐질환및용혈성빈혈을유발할수있으므로사용에주의해야한다. 2 Penicillin은수십년간임신여성의요로감염에안전하게사용되었으며태아에악영향을미치지않는걸로알려져있다. 10 Ampicillin은 penicillin의주사용제로임신여성에서신장을통한빠른배출이일어나므로증량하여사용한다. 12 Ampicillin의경구용인 amoxicillin은용량증가는필요없으며임신중요로감염에가장많이사용되었다. 그러나 ampicillin 및 amoxicillin에대한내성이증가하였기때문에항생제감수성검사를병행해야한다. 13 Penicillin G는여전히효과적이며특히현재에도 group B Streptococci에의한세균뇨의특효약으로사용되고있다 11 2) Cephalosporin Cephalosporin도임신여성의요로감염에흔히사용되고있으며신우신염과일차치료에내성을보이는요로감염에좋은효과를나타낸다. 14 Cephalexin은 1 세대 cephalosporin으로경구용으로가장널리사용되었다. 15 3세대 cephalosporin은그람음성균에뛰어난효과를나타내며그람양성균일부에도효과를나타낸다. 그러나 cephalosporin계열의항생제는 Enterococcus에효용이없으며, 11 임신중신장을통한배출이증가되면서반감기가짧아지므로용량조절에신경써야한다. 16 3) Nitrofurantoin 4) Macrolides Clindamycin은 penicillin에과민반응이있는산모에서 group B Streptococci 치료에사용된다. 산모에사용시용량은증가시킬필요가없으며기형유발은없는것으로알려져있다. 18 5) Aminoglycoside 임신여성에서신우신염치료를위해주로 ampicillin과병용하여사용되고있다. 신실질에고농도로존재하기때문에특히신우신염치료에유용하며, 14 가장많이사용되는약제는 gentamicin이다. Aminoglycoside는태반을통과하는것으로알려졌으며태아에이독성이나신독성유발이가능하지만, 현재까지보고된연구는없으며, 선천성기형도유발하지않는것으로알려져있다. 11 6) Sulfonamide E. coli에대한내성과독성때문에 1차치료제로권유되지않는다. 임신첫 3개월 (1 st trimester) 에는항엽산작용을하여태아기형을유발할수있으며, 19 임신 3기 (3 rd trimester) 에는 albumin을 bilirubin으로대체시켜고빌리부빈혈증및황달을유발할수있다. 11 드물게 glucose-6-phosphate dehydrogenase 결핍산모에서태아의용혈성빈혈도보고되고있다. Nitrofurantoin은소변에적절한치료농도로존재하며태아기형과관련이없는것으로알려져있어무증상세균뇨나방광염치료에사용되고있다. 17 그러나조직내로의투과도는약하여급성신우신염 7) Trimethoprim E. coli에대한내성이많아서일차치료제로사용되지않는다. 기형유발은보고된바없지만엽산

5 김태남외 : 임신과요로감염 145 관련대사를방해함으로서이론적으로신경관결손을위험성을증가시킬수있으므로, 12 임신첫 3 개월에는사용해서는안된다. 20 8) Quinolone 이약제는신장조직에고농도로존재하기때문에신우신염치료에좋은약제이나동물실험에서연골발달의장애를유발한다는연구결과가있다. 현재까지산모에서태아의연골발달장애가보고된적은없지만임신기간중사용을피해야한다. 3 2) 역학임신자체가무증상세균뇨의위험요소는아니며임신및가임여성에서발생빈도는 4 6% 로비슷하다. 24 사회경제적상태가무증상세균뇨의위험요소중하나이며빈곤층여성이그렇지않은여성보다세균뇨의발생빈도가 5배가높다는보고도있다 다른위험요소로는당뇨, sickle cell disease 및 trait, 2회이상의출산경험, 요로감염의과거력및해부학적혹은기능적요로계기형등이있다. 1,25 9) Tetracycline 3) 의의 Tetracycline은임신주수 5개월이후에사용될경우배냇니의착색을유발할수있기때문에임신중에는사용하지않는다. 1,11 Tetracycline이사기질형성저하증및비골성장억제를일으킨다는초기연구가있은뒤 Porter 등 21 은이런사실이사실이아님을밝혔지만, 미국식약품안정청에서는 tetracycline을여전히 category D로분류하여임신중사용을금하고있다 임신중무증상세균뇨의의의와치료 1) 정의무증상세균뇨는분류상무증상요로감염에포함되는데빈뇨, 절박뇨, 배뇨통, 농뇨혹은혈뇨등과같은증상이나징후없이의미있는세균뇨를나타내는경우에해당한다. 의미있는세균뇨란중간뇨채취를통한 2번의연속적인소변검사에서 1ml의소변내에단일병균이 10 5 colony-forming units 이상존재할때로정의한다. 23 그러나도뇨를통한소변채취시나증상이동반된경우 1mL 소변내에 10 2 이상의단일세균이존재할경우에도의미있는세균뇨라할수있다. 일반적으로무증상세균뇨는임상적으로중요성을가지지못하나산모의경우는그렇지않다. 세균뇨에서신우신염으로의발전은임신여성이가임여성보다높으며, 무증상세균뇨를치료하지않을경우 20 40% 의산모에서신우신염으로진행하지만, 2,4,27 세균뇨를조기치료할경우신우신염의발병률을 90% 감소시키는것으로알려져있다. 28 세균뇨와신우신염의관계는잘알려져있지만세균뇨가임신에미치는다른부작용에대한내용은아직미약한실정이다. 다양한연구에서무증상세균뇨가태아의미성숙, 저체중, 성장장애및주산기사망과관련있음이나타났으나, 29 사회경제적상황등공존하는위험요소가태아의미치는악영향을완전히배제할수없기때문에명확한결과를알수없는실정이다. 현재까지이런연관성은논란중에있다. 1 Group B Streptococcus는양막의조기파열, 조산, 주산기폐혈증, 뇌막염및폐렴과관련이있으며초기진단시혹은분만시작전에반드시치료해야한다. 2 4) 조기검진미국산부인과협회 (American College of Obstetricians and Gynecologists) 는최근모든산모에서무증상세균뇨의조기검진을권유했다. 3,254명의산모를대상으로시행한대규모연구에서세균뇨의적

6 146 대한요로생식기감염학회지 : 제 4 권제 2 호 2009 년 10 월 Table 4. Regimens for asymptomatic bacteriuria & acute cystitis Antimicrobial Single-dose regimens Short-course regimens Amoxicillin 3 g or 2 g plus 1 g probenecid mg tid 3 or 7 days 3 g two doses 12 h apart Amoxicillin/clavulanic acid - 250/125 mg tid 7 days Nitrofurantoin 200 mg 100 mg qid 3 or 7 days Sulfisoxazole 2 g 1 g then 500 mg qid 7 days Cephalexin 2-3 g or 2 g plus 1 g probenecid mg qid 7 days Trimethoprim/ Sulfamethoxazole 320/1600 mg 320/1600 mg bid 3 days *Data from Patterson TF, Andriole VT. Detection, significance, and therapy of bacteriuria in pregnancy. Update in the managed health care era. Infect Disclin North Am 1997;11(3): ; Le J, Briggs GG, Mckeown A, et al. Urinary tract infections during pregnancy. Ann Pharmacother 2004;38(10): ; Connolly A, Thorp JM Jr. Urinary tract infections in pregnancy. Urol Clin North Am 1999;26(4):779-87; Ovalle A, Levancini M. Urinary tract infections in pregnancy. Curr Opin Urol 2001;11(1):55-9. 절한검진시기는임신 16주이며, 4,30 소변배양검사가표준검사이고임신첫 3개월내에모든산모는세균뇨검사를받을것을권유했다. 2 한번의소변검사에서소변 1ml 당 10 5 이상의세균뇨가나오면 80% 의정확성을나타내는반면, 같은균주가 2번의검사에서나오는경우정확성은 95% 까지높아진다. 23,31 한번의검사만으로세균뇨를진단할경우소변채취시오염되거나산모의일시적세균뇨로인해과잉진단을유발할수있으므로, 32 확진을위해배양검사가병행되어야한다. 그러나무증상세균뇨가임신에미칠수있는악영향때문에배양검사에의한확진이전에치료에시작해야한다. 33 초기소변배양검사가음성일경우, 소변배양검사를다시시행하는것은권유되지않는데초기배양검사에서음성을나타내는 1 2% 산모에서임신기간중신우신염으로진행하기때문이다. 34 예외적으로반복적요로감염의과거력이나요로계의이상이동반된경우남은임신기간동안추적소변배양검사가요구된다. 소변배양검사의높은검사비로인해비용-효과적측면에서많은다양한방법들이연구되었다. 그러나이런검사들은소변배양검사만큼신뢰성을주지는못했다. 예를들어농뇨의경우모든세균뇨에동반되는징후가아니며특이성역시높지않았 으며, McNair 등 35 은임신여성에서 53% 에육박하는 dipstick 위음성을보고했다. 결국 Wadland 등 36 은세균뇨조기검진시세균배양검사를실시하는것이비용-효과적이라고보고했으며표준진단방법으로세균배양검사를권유했다. 5) 치료무증상세균뇨의조기진단및치료는증상을동반한요로감염과이로인한합병증발생을감소시켜준다. Sweet 등 7 은무증상요로감염을치료할경우신우신염의발병률을 % 에서 0 5.3% 까지낮춘다고보고했다. 치료기간은일일일회복용법부터일주간치료하는방법등다양한치료법이있다 (Table 4). 일회치료법의완치률은 50 60% 로보고되며, 37 3일간항생제사용시 70 80% 에서효용이있는걸로알려져있다. 3일을초과한치료기간으로완치률은향상되지않기때문에, 38 3 일간치료법이통상적으로권유된다. 1 치료 1주후소변배양검사로반드시세균뇨가박멸되었는지를추적관찰해야한다 % 환자에서단기간치료법이실패하는데이럴경우배양검사에따라감수성있는항생제로 7 10일치료받는것을권유한다. 39

7 김태남외 : 임신과요로감염 147 6) 재발방지 3) 의의 소변배양검사에서음성이나온후에매일저용량의 nitrofurantoin (50 100mg) 을저녁에한번예방적으로경구투여하는것이좋다. 1,40 이런예방적항생제투여를하지않을경우 3분의 1 가량의산모에서재발하는양상을보였다. 2,32 치료후예방적항생제를복용하지않는산모의경우소변배양검사를자주실시하는것이바람직하며, 반복적, 지속적세균뇨가있는산모의경우에는출산이후에도소변배양검사로추적관찰해야하며 3 6개월뒤비뇨기계에대한검사를하는것이바람직하다. 41 급성신우신염을치료하지않은경우 20 50% 태아가미성숙아로출산한다. 42 신우신염이발생한경우세균에의해 phospholipase A2가생산되고이에따라 prostaglandin이활성화되어조기진통을유발하여조산하는것으로생각한다. 26 신우신염의합병증으로저체중아출산및주산기사망이발생했다는보고도있지만, 42 아직까지합병증에대해서정립되지않았다. 그러나다출산산모에서신우신염이발생하면빈혈, 고혈압, 일시적신부전, 급성호흡곤란증후군및폐혈증이발생한다 하부요로감염 ( 급성방광염 ) 4) 치료 임신기간중급성방광염의빈도는 1 2% 가량이다. 급성방광염은세균뇨와방광염의징후 ( 혈뇨, 농뇨 ) 및증상 ( 빈뇨, 급박뇨, 배뇨통 ) 으로진단한다. 급성방광염의치료는무증상세균뇨의치료와동일하며 (Table 2), 추적관찰은반드시실시해야한다. 급성방광염을않은산모의 3분의 1정도에서임신기간중재발하기때문이다 상부요로감염 ( 급성신우신염 ) 1) 역학임신기간중 1 2% 에서신우신염이발생하지만무증상세균뇨를치료하지않은산모의경우 20 40% 에서신우신염이발생한다. 2 신우신염은소변정체와수신증이가장뚜렷한임신 3기에호발한다. 3 2) 진단 신우신염에걸린모든산모는입원및항생제정맥치료를받아야한다. 3 초기치료는통상적으로 ampicillin과 gentamicin 혹은 cephalosporin의병합요법으로시작한다. 단일제재로 2세대혹은 3세대 cephalosporins이사용될수있다. 2 위항생제치료로 95% 의산모에서 72시간이내에효과가나타나지만, 43,44 치료에반응하지않을경우소변배양검사에따라감수성있는항생제로바꾸어치료한다. 배양검사에따른적절한항생제사용에도불구하고치료경과가좋지않다면초음파를사용하여요로결석, 요로계기형및신농양등을배제해야한다. 45 항생제치료후발열증상이사라지면경구용항생제를사용한 2주간의외래치료가가능하며, 이후에도출산후까지예방적항생제를사용해야한다. 46,47 무증상세균뇨와급성방광염처럼급성신우신염도추적관찰이중요한데, 신우신염의과거력이있는산모의경우재발의위험성이증가하기때문이다. 42 세균뇨와신우신염에합당한증상및징후를종합하여진단한다. 증상및징후는가임기여성과유사하며발열, 오심, 구토, 오한및갈비척추각동통을나타낸다. 결론요로감염은임신기간중흔한합병증이며산모와태아의건강에심각한영향을미칠수있다. 무증상

8 148 대한요로생식기감염학회지 : 제 4 권제 2 호 2009 년 10 월 세균뇨는상부및하부요로감염의위험인자이며조기검진과치료를통해증상성요로감염으로의진행을막을수있다. 무증상세균뇨가적절히치료되지않을경우 20 40% 에서급성신우신염으로진행하며조기분만, 일시적신부전, 급성호흡부전증후군및폐혈증등의합병증이발생할수있다. 요로감염의치료후 3분의 1 가량의산모가재발하기때문에추적관찰이중요할것으로생각한다. REFERENCES 1. Patterson TF, Andriole VT. Detection, significance, and therapy of bacteriuria in pregnancy. Update in the managed health care era. Infect Dis Clin North Am 1997;11 (3): Gilstrap LC 3rd, Ramin SM. Urinary tract infections during pregnancy. Obstet Gynecol Clin North Am 2001;28 (3): Schaeffer AJ. Infections of the urinary tract. In: Walsh PC, Retik AB, Vaughan ED, Wein AJ, editors. Campbell s Urology. 8th edition. Philadelphia: WB Saunders; 2002; Millar LK, Cox SM. Urinary tract infections complicating pregnancy. Infect Dis Clin North Am 1997;11 (1): Gilbert GL, Garland SM, Fairley KF, McDowall DM. Bacteriuria due to ureaplasmas and other fastidious organisms during pregnancy: prevalence and significance. Pediatr Infect Dis 1986;5 (6 Suppl):S Cohen I, Veille JC, Calkins BM. Improved pregnancy outcome following successful treatment of chlamydial infection. JAMA 1990;263 (23): Sweet RL. Bacteriuria and pyelonephritis during pregnancy. Semin Perinatol 1977;1 (1): Krieger JN. Complications and treatment of urinary tract infections during pregnancy. Urol Clin North Am 1986;13 (4): Waltzer WC. The urinary tract in pregnancy. J Urol 1981;125 (3): Christensen B. Which antibiotics are appropriate for treating bacteriuria in pregnancy? J Antimicrob Chemother 2000;46 (Suppl 1):29-34 [discussion 63-5] 11. Dashe JS, Gilstrap LC 3rd. Antibiotic use in pregnancy. Obstet Gynecol Clin North Am 1997;24 (3): Philipson A. Pharmacokinetics of ampicillin during pregnancy. J Infect Dis 977;136 (3): Stratton CW, Quinn J, Peterson L. Emerging resistance in uropathogens: its impact on management of acute cystitis in women [special issue]. Postgrad Med S 1994;31: Hooton TM, Stamm WE. Diagnosis and treatment of uncomplicated urinary tract infection. Infect Dis Clin North Am 1997;11 (3): McFadyen IR, Campbell-Brown M, Stephenson M, et al. Single-dose treatment of bacteriuria in pregnancy. Eur Urol 1987;13 (Suppl 1): Dinsmoor MJ, Gibbs RS. The role of the newer antimicrobial agents in obstetrics and gynecology. Clin Obstet Gynecol 1988;31 (2): Reeves DS. A perspective on the safety of antibacterials used to treat urinary tract infections. J Antimicrob Chemother 1994;33 (Suppl A): Keenan C. Prevention of neonatal group B streptococcal infection. Am Fam Physician 1998;57 (11): Weiser ACSA. The use and misuse of antimicrobial agents in urology. AUA Update Series 2002;21: MacLean AB. Urinary tract infection in pregnancy. Int J Antimicrob Agents 2001;17 (4):273-6 [discussion 6-7] 21. Porter PJ, Sweeney EA, Golan H, et al. Controlled study of the effect of prenatal tetracycline on primary dentition. Antimicrobial Agents Chemother (Bethesda) 1965;5: Whalley PJ, Adams RH, Combes B. Tetracycline toxicity in pregnancy. Liver and pancreatic dysfunction. JAMA 1964;189: Rubin RH, Shapiro ED, Andriole VT, Davis RJ, Stamm WE. Evaluation of new anti-infective drugs for the treatment of urinary tract infection. Infectious Diseases Society of America and the Food and Drug Administration. Clin Infect Dis 1992;15 (Suppl 1): S McLaughlin SP, Carson CC. Urinary tract infection in women. Med Clin North Am 2004;88 (2): Turck M, Goffe BS, Petersdorf RG. Bacteriuria of pregnancy. Relation to socioeconomic factors. N Engl

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페링야간뇨소책자-내지-16

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