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1 임산부의예방접종과 항생제사용 Tip 가톨릭대학교의정부성모병원 산부인과김연희

2 내용순서 임신중면역력과감염 임신중예방접종 백일해예방접종 인플루엔자접종 B 형간염접종 임신중항생제사용 증례별항생제정리

3 balance in maternal immune response to infection Cellular immunity The Lancet 1998,

4 Ab placenta transfer to baby Placenta integrity 모체 IgG 총량 HIV or malaria IgG subtype 임신주수

Ab transfer through placenta 임신주수 : 17-22 주부터태반을통해항체이동, 28-32 주 : 태아혈청내농도는모체수준의 50% 정도.

5 Ab transfer through placenta 임신주수 : 주부터태반을통해항체이동, 주 : 태아혈청내농도는모체수준의 50% 정도. Ig G subtypes IgG subtype 분만시임신주수 => 항체전달력 Clinical and Developmental Immunology, 2012

6 백신의종류 생백신 사백신 약독화생백신 전세포사백신 성분백신 유전자재조합 Toxoid 백신 접합백신 병원성약독항원성유지강한면역반응유발병원성보유 균체의불활성화 면역에기여하는일분성분 유전자재조합기술로제조 임신중가능한백신 균체의외독소를무독화 병원성다당질에단백을결합시켜면역증강 바이러스 MMR, 수두로타바이러스 박테리아 BCG, 경구장티푸스 불화화소아마비주사인플루엔자 HAV Rabies Pertussis Typhoid Cholera 인플루엔자 B 형간염비세포성백일해 Hib HBV HPV Td (DPT) 디프테리아, 파상풍 Hib ( 뇌수막염 ) PCV ( 페렴구균 )

7 What Is New in Maternal Immunization?

8 Pertussis, 백일해 ( 百日咳 ) Whooping cough Agents: Bordetella pertussis 전염력이강한세균성감염, 심한기침, 호흡부전 5 세이하소아매년약 63,000 명사망 (WHO 2013). 생후 2 달신생아 : 입원 (82%), 폐렴 (25%), 경련 (4%), 뇌증 (1%), 사망 (1%)

9 미국내백일해감염역학 MMWR 51(4): 75, 2005

10 UK

11 한국 - KOSIS ( 국가통계포털 )

12 Tdap 후면역력의유지 임신부 : 최근 2년이내접종력 (+), 임신전 (n = 86), 임신중. (n = 19, 대부분임신초기, 3명만 20주이후접종 ) 임신부와신생아혈액내 Pertussis-specific IgG 를측정. 신생아 anti PT IgG 값 : 영아가첫접종을시행하는생후 2 달에 IgG 농도는예방에유효한수치인 5EU 미만임. 질환특이항체의짧은반감기 Clin Inf Dis 2013:56

13 Tdap 구성 : Reduced diphtheria toxoid, tetanus toxoid, acellular pertussis * 성인백신스케줄 성인은 Td 스케줄 (3 회 ) 또는매 10 년마다시행하는접종중한번은 Tdap 으로접종 ( 최초 1 회 ) 12 개월이하유아와밀접한접촉이예상 부모, 조부모, 의료인 임신계획여성 임신중여성 출산직후

14 효과적인접종시기 Tdap 임신중접종군과비접종군사이제대혈항체값농도비교, 분만시기별백일해특이항체양측정 임신중접종군은평균 3.6 배항체값이높음 시기별 27 주이후로증가하여 30 주접종시가장높고이후로감소함. JAMA 2018

15 접종은언제가가장좋은가? Tdap 접종시기 임신 27 ~ 30+6 주접종시 : 신생아혈청내 IgG 항체값이출생 108 일까지유지됨. Vaccine 32 (2014), 5787

16 접종시기와분만시기간격 Times btw tdap and delivery Cord sera of IgG to PT IgG to FHA IgG to PRN 1-28(N=15) ( N=22) (N=18) p <0.03 <0.001 >0.73 PT, pertussis toxin; FHA, filamentous hemagglutin; PRN, pertactin - Tdap 접종후분만시기까지 8-12 주 : 분만시가장높은신생아제대혈내항체값 Vaccine 32 (2014) 5787

17 접종범위 국내소아백일해전염경로 - 약 80 % 가가정내전염이의심됨 원인이밝혀진 264 건중 - 부모 50 % - 가족구성원 75 % others 25% sibling 20% grandpar ents 8% mother 32% father 15%

18 Evaluation of Two Vaccine Education Interventions to Improve Pertussis Vaccination Among African American Women: A Randomized Controlled Trial This small, prospective randomized controlled trial -Tdap education intervention : video group or ibooks or control. Vaccine 2017

19 임신부예방접종 35 세여자, 현재임신 8 주 오늘뉴스에서인플루엔자유행주의보발령이보도됨 임신중인플루엔자는어떻게예방하는지문의차병원방문함 임신중백신접종이가능한가?

20 Influenza vaccination 효과 임신중인플루엔자백신효과연구 ( 다국적다기관 ): 임산부임신중입원치료에대하여 40 % 예방효과 HIV 감염군과비감염산모인플루엔자백신효과를비교 인플루엔자감염율 모체약 57.7 % 예방 아기 48.8 % 예방 NEJM 2014 Clin Inf Dis 2018

21 Influenza 백신대대조군연구 백신효과 : 63% 열과호흡기질환 아기 29% / 모체측 36% NEJM 2008

22 maternal immunization recommendation 백신 임신중권장 고위험군에서임 신중접종 임신중금기 인플루엔자 O O Tdap O O 폐렴구균백신 O O 뇌수막구균 Men ACWY/ serogroup B O A 형간염 O* O B 형간염 O** O HPV MMR O O Varicella O O 분만후수유중접종 O O

23 ** 간염백신에대한고위험군 가 ) A 형간염위험군 만성간질환자, 어린이들을돌보는시설에근무하는사람, A 형간염바이러스에노출될위험이있는의료진및실험실종사자, 음식물을다루는요식업체종사자, A 형간염유행지역으로여행또는근무예정인경우, 혈액제재를자주투여받는경우, 남성동성애자, 주사약물남용자, 최근 2 주이내에 A 형간염환자와접촉한경우 나 ) B 형간염위험군 남성동성애자, 성관계자가여러명인사람, HIV 감염인, 주사약물남용자, HBV 소유자의배우자나가족등친밀한접촉을갖는사람, 만성신부전환자, 만성간질환환자, 직업적으로 HBV 노출위험이많은사람, 단체생활을하는지체장애인과이들을보호하는직원

24 B 형간염백신접종권장대상 접종권장대상 모든신생아 ( 출생후 12 시간이내 ) 성인 : B 형간염항체가없는 *, 미접종일반성인 총 3 회 : 2 차 ( 일차주사후최소 1 달 ). 3 차 ( 일차주사에서 6 개월후혹은 2 차주사후최소 2 개월후 ) B 형간염고위험군 B 형간염감염위험이높은의료종사자, B 형간염환자배우자 HBs 항원양성인산모에서태어난신생아 만성간질환자, 만성신질환자 ( 혈액투석환자 ), HIV 감염인 남성동성애자, 성파트너가여럿인경우

25 B 형간염백신접종권장대상 B 형감염항체검사 건강성인 : 백신접종후항체검사불필요 고위험군 : 항체검사시행 음성시백신재시행 백신무반응자 : 백신 3회접종후항체역가 <10mIU/mL인경우 + 고위험군 : 3회추가접종고려 총 6회접종후에도항체역가낮은경우추가접종불필요

26 Major Birth Defects after Vaccination Reported to the Vaccine Adverse Event Reporting System (VAERS), 1990 to 2014 Vaccine Adverse Event Reporting System: the CDC and the Food and Drug Administration to monitor the safety to detect potential safety issues with licensed vaccines during pregnancy (3.2%) : major birth defects 보고됨 년동안백신과관련하여같은패턴의특이적선천성결함이나이상은없었음. Vaccines, 2016

27 임신중항생제치료 안전성 질환별항생제치료

28 Antibiotics in Pregnancy: Are They Safe? Cons: streptomycin, kanamycin (-hearing loss), tetracycline (- weakening, hypoplasia, and discoloration of long bones and teeth) Pros: PPROM 에서 latency period 증가, 신생아예후호전과 childhood disability 감소 (ORACLE study ) Rev Obstet Gynecol Summer; 2(3):

29 임신중항생제치료, 안전한가? 자궁내항생제노출과소아의비만과관련성? => conflict. International Journal of Obesity 2015 Obes Rev. 2018

30 임신중항생제노출과신생아천식 Ann Epidemiol, 2018 Trimester-specific association between antibiotics exposure during pregnancy and childhood asthma or wheeze: the role of confounding 임신부의감염여부를 adjustment 하면위험도관련성없어짐.

32 나름의원칙을갖자 Absolutely indicated 된경우쓰자 비뇨기계감염, pyelonephritis, 맹장염, 담낭염, 융모양막염, 상부감염예방 ( 무증상세균뇨 ), GBS sepsis 예방 가능하면임신초기는약물치료를피하자. 안전한약을찾자. 오래된약은상대적으로정보가많다. 가능하면단일제재, 효과적인최소양을사용하자. ( 예외 : preterm PROM) over-the-counter drugs 사용을줄이자.

33 증례별항생제사용 비뇨기계감염 상부감염예방 ( 무증상세균뇨 ) 맹장염 담낭염 융모양막염 Prophylaxis for GBS sepsis 진통전양막파열 (prelabor ROM) 성병감염

34 비뇨기계감염 신우신염 - 원인 : E. coli (m/c), Klebsiella pneumonia, enterobacter species - 치료 Amoxacillin + Gentamicin Or Cephazolin Or Ceftriaxone - 항생제 2 주치료 - 배양검사필수 ( 치료시작시치료종료후 1 달이내 ) 방광염 무증상세균뇨 *: - 예방적목적치료 - nitrofurantoin 100mg / day for 21days

35 Asymptomatic Bacteriuria Single-dose treatment Amoxicillin, 3 g Ampicillin, 2 g Cephalosporin, 2 g Nitrofurantoin, 200 mg Trimethoprim-sulfamethoxazole, 320/1600 mg 3-day course Amoxicillin, 500 mg three times daily Ampicillin, 250 mg four times daily Cephalosporin, 250 mg four times daily Ciprofloxacin, 250 mg twice daily Levofloxacin, 250 or 500 mg daily Nitrofurantoin, 50 to 100 mg four times daily or 100 mg twice daily Trimethoprim-sulfamethoxazole, 160/800 mg twice daily Other Nitrofurantoin, 100 mg four times daily for 10 days Nitrofurantoin, 100 mg twice daily for 5 to 7 days Nitrofurantoin, 100 mg at bedtime for 10 days Treatment failures Nitrofurantoin, 100 mg four times daily for 21 days Suppression for bacterial persistence or recurrence Nitrofurantoin, 100 mg at bedtime for pregnancy remainder

36 Aerobes Others 여성골반감염주요원인균 Gram-positive cocci : group A, B, and D streptococci, enterococcus, Staphylococcus aureus, Staphylococcus epidermidis Gram-negative bacteria Escherichia coli, Klebsiella, Proteus Gram-variable Gardnerella vaginalis Mycoplasma and Chlamydia, Neisseria gonorrhoeae Anaerobes Cocci Peptostreptococcus and Peptococcus species Others Clostridium, Bacteroides, Fusobacterium, Mobiluncus

37 골반감염관련광범위항생제 Clindamycin + gentamicin Clindamycin + aztreonam Extended-spectrum penicillins Cephalosporins Vancomycin Metronidazole + ampicillin + gentamicin Carbapenems Gold standard PLUS Ampicillin added with sepsis syndrome or suspected enterococ cal infection 신기능이상시 Gentamicin substitute Piperacillin, piperacillin tazobactam, ampicillin/sulbactam, tic arcillin/clavulanate Cefotetan, cefoxitin, cefotaxime Added to other regimens for suspected Staphylococcus aureus infections Metronidazole has excellent anaerobic coverage Imipenem/cilastatin, meropenem, ertapenem reserved for spec ial indications

GBS infection streptococcus agalactiae Gastrointestinal and genitourinary tracts (15-30% of healthy adults) No symptomatic 1/100-200 pregnancy with GBS :

38 GBS infection streptococcus agalactiae Gastrointestinal and genitourinary tracts (15-30% of healthy adults) No symptomatic 1/ pregnancy with GBS : neonatal infections including bacteremia and meningitis U.S. CDC recommends universal vaginal AND rectal screening for GBS at 35 to 37 weeks of gestation

39 질과직장내 GBS screening culture 주 ( 모든임산부대상 ) Intrapartum prophylaxis 이전아기가중증 GBS 감염 현임신중 GBS 세균뇨 (+) GBS screening 양성 GBS 감염상태가부정확하거나모르는경우 임신 37 주미만분만예정 양막파열후 18 시간경과 진통중열 진통중 nucleic acid amplication test (NAAT) test 양성 Intrapartum prophylaxis NOT indicated 이전임신중 GBS 검사양성 현재제왕절개분만계획중 ( 진통 없고양막파수없음 ) GBS screening 음성 ACOG / CDC AAP guidelines for GBS prophylaxis

40 Intrapartum regimen for GBS Regimen Recommended Alternative Penicillin allergic not at high risk for anaphylaxis at high risk for anaphylaxis and with GBS susceptible to clindamycin at high risk for anaphylaxis and with GBS resistant to clindamycin or susceptibility unknown Treatment Penicillin G, 5 million units IV initial dose, then 2.5 to 3.0 million units IV every 4 hours until delivery Ampicillin, 2 g IV initial dose, then 1 g IV every 4 hours or 2 g every 6 hours until delivery Cefazolin, 2 g IV initial dose, then 1 g IV every 8 hours until deliver Clindamycin, 900 mg IV every 8 hours until delivery Vancomycin, 1 g IV every 12 hours until delivery

41 Preterm PROM 항생제투여목적 to prolong the pregnancy to prevent infection and inflammation-related neonatal morbidity as a result of (sub)clinical infection of the fetus to protect the mother from uterine/ pelvic infection.

42 진통전양막파수관리 Term : 임신 37 0/ 7 주이상 분만진행 GBS prophylaxis as indicated Late Preterm 임신 34 0/7 36 6/7 Same as for early term and term Preterm ( 임신 24 0/7 33 6/7 주 ) Expectant management Antibiotics recommended to prolong latency if there are no contraindications Single-course corticosteroids GBS prophylaxis as indicated ACOG committee opinion. 2016

43 Regimen : unclear! PROM antibiotics ACOG opinion GBS prophylaxis Ampicillin 2g IV Q6 h + Erythromicin 250mg Q 6 h (48 h ) Oral amoxicillin(250mg Q 8h )+ erythromycin base 333g Q 8 h (5days) Other regimens for preterm PROM Azithromycin 500 mg PO (1day), then 250 mg PO daily 6 days, + penicillin 5MU then 2.5MU Q4 h for 48 h Azithromycin 1 g PO 1, ampicillin 2 g IV Q6 h 48 h, amoxicillin 250 mg PO Q8 h 5 d Azithromycin 1 g PO 1, ampicillin 2 g IV Q6 h 48 h, amoxicillin 500 mg PO Q8 h 5 d

Gentamicin Same above Recommended antibiotics (sever penicillin allergy) Clindamycin or 900 mg IV every 8 hours

44 분만전융모양막염의심시 Recommended Dosage Ampicillin + 2g iv every 6hours Gentamicin 2mg/kg IV load followed by 1.5mg/kg every 8hrs or 5mg /kg / iv Recommended antibiotics (mild penicillin allergy) Cefazolin 2g IV every 8 hours Gentamicin Same above Recommended antibiotics (sever penicillin allergy) Clindamycin or 900 mg IV every 8 hours Vancomycin and 1g IV every 12hours Gentamicin Same above Alternative regimens Ampicillin sulbactam 3g IV every 6 hours 분만후기존투약하던항생제에대하여재평가필수!

45 Sexual assault Prophylaxis Against Neisseria gonorrhoeae Chlamydia trachomatis Bacterial vaginosis Trichomonas vaginalis Hepatitis B (HBV) HIV Regimen Ceftriaxone 250 mg IM single dose + Azithromycin 1 g or ally single dose Azithromycin 1 g orally single dose or Amoxicillin 500 mg orally three times daily for 7 days Metronidazole 500 mg orally twice daily for 7 days or Metronidazole gel 0.75%, one full applicator (5 g) intrava ginally once daily for 5 days Or Clindamycin cream 2%, one full applicator (5 g) intravaginally at bedtime for 7 days Metronidazole 2 g orally single dose or Tinidazole 2 g orally single dose If not previously vaccinated, give first dose HBV vaccine, repeat at 1 2 and 4 6 months Consider retroviral prophylaxis if risk for HIV exposure i s high

46 Tip for vaccination and antibiotics in pregnancy 적절한정보공유와교육 위험요소와장점을상담하기 의무기록남기기 - 임신 24 주임신성당뇨 screening 과함께예방접종교육하기 - 28 주내원시임신부예방접종여부결정및기록남기기

47 Thank you for your attention

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