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  • 1. 임신 중 약물의 안전성 관동대학교 제일병원 핚정열2011.9.28 조산사협회
  • 2. Contents• Safety and risk for drugs in pregnancy• Korean MotherSafe Program
  • 3. Historical case I. THALIDOMIDEAnxiolytic and sedative drugMalformations : 20 percentSpecific time window : 34 to 50 days menstrual ageUpper limb more seriously affected.Phocomelia formed limb
  • 4. Instructive of teratological principles1. Placenta has been believed to be a perfect barrier that was impenetrable to toxic substance2. The extreme variability in species susceptibility to drugs had not yet been appreciated.3. Demonstrated the close relationship between the timing of exposure and the type of defect. ex. upper limb phocomelia : 27-30 day, lower limb phocomelia : 30-33 dayNew Ix of thalidomide erythema nodosum leprosum, cutaneous lupus erythematosus, chronic graft-versus-host disease, prurigo nodularis, certain malignancies
  • 5. Historical case II. Diethylstilbestrol (DES) 1940-1971, 10milion pregnant women to “support” high risk pregnancies. But no beneficial effects. Herbst(1971) : 8 cases of vaginal clear cell adenocarcinoma Incomplete carcinogen: absolute cancer risk 1 per1000, not related by dose no relationship between location of tumor & timing of exposure. Structural and functional abnormality: ectropion, adenosis – malignant potential (2 fold increase)
  • 6. Continue…Most common reported abnormalities: hypoplastic, T-shaped uterine cavity, cervical collars, hoods, septa, excombs, and “withered” fallopian tubes.Poor pregnancy outcome related to uterine malformations, decreased endometrial thickness and reduced uterine perfusionExposed men in utero : normal sexual function, fertility but, epididymal cysts, microphallus, cryptorchidism, testicular hypoplasiasSons of women exposed in utero: increased risk of hypospadias (prevalence ratio 21.3) [Klip H. Et al. Lancet. 2002]
  • 7. Historical case III. Bendectin U.S.A. Temporal Trends for Limb Reduction Deformities, Bendectin Sales, and Hospitalizations for NVP
  • 8. Safety and risk of drugs in pregnancy
  • 9. In Animal : studyImportant• New teratogenic drugs : Predicted• Light on teratogenic mechanisms
  • 10. In Animal : study Useless•Interspecies variability• No animal is metabolically and physiologically identical to human
  • 11. Safety and risk of drugs in pregnancy
  • 12. In human : post marketing surveillance • Case report rare exposure/ rare malformation • Case-control study less costly, recall bias • Prospective cohort study • Meta-analysis
  • 13. Safety and risk of drugs in pregnancy Limitations• Is there association between safety and long term usage? Thalidomide : in 4 years Phenytoin : in 30 years Valproic acid : in 22 years Carbamazepine : in 31 years• Sample size?• Is there methodology to detect less potent teratogen? (Reproductive Toxicology 2001)
  • 14. Criteria for Proof of Human Teratogenicity (Modified from Shepard 2001)
  • 15. Drugs or Substances Suspected or Proven to Be Human Teratogen Williams Obstetrics 23rd ed. 2010
  • 16. Graphical representation of risk of drugs in pregnancy Nava-Ocampo AA et al 2007
  • 17. Inadvertently drug exposure in Pregnancy
  • 18. Perceived teratogenic risk after inadvertently drug exposure 핚정렬 등 대핚산부회지 2002
  • 19. Unintended pregnancy  Unintended pregnancy : 48%32 노출 빈도 (OR)10 알코올 흡연 방사선 약물 Han JY et al. Birth Defects Res A Clin Mol Teratol. 2005
  • 20. System of evaluation for safety and risk on drug exposure in pregnancy VS FDA TERIS
  • 21. FDA classificationA Controlled Studies show no riskB No evidence of risk in humansC Risk cannot be ruled outD Positive evidence of riskX Contraindicated in pregnancy From 1979
  • 22. To provide therapeutic guidance The system is not ideal: • Many drug ratings are based on animal data, case reports, limited or no human data • Information rarely updated • Onus on the clinician to interpret category information • Drugs in categores D & X, and a certain extent those in C may pose similar risks • Create the impression that drugs within a category pose similar risks FDA new rules : remove the A-X categories a narrative fetal risk summary, clinical considerations and inadvertent exposure including registries available Most current and accurate information : online reproductive toxicity services, Reprotox, TERIS
  • 23. 증례32세 G2 P0생리 연장 위해서 임신 5주경까지마이보라를 복용하였음.아기만 괜찮다면 낳고 싶습니다.
  • 24. 경구용 피임약 (Oral contraceptives)FDA : X
  • 25. 이소트레티노인 노출
  • 26. Isotretinoin 연도 별 상담 건수 25 24 총 상담건수: 79건 20 15 11 10 8 8 7 7 5 5 4 3 1 1 0 2001년 2002년 2003년 2004년 2005년 2006년 2007년 2008년 2009년 2010년 2011년상담 시 Maternal age : 29.7±3.4 yrs(23~41 yrs) Gravidity 2.0± 1.4(1~7)상담 시 Gestational age: 57.5±21.6 days (32~132 days)
  • 27. Isotretinoin 노출 시기별 분포(n=79) 45.6%5040 29.1%30 22.8%20100 conception>1Mo conception<1Mo conception during after isotretinoin after isotretinoin isotretinoin discontinuation discontinuation treatment
  • 28. 수정 후 Isotretinoin 노출굮 특징(n=23) 노출기갂: 23.43±27.51일(1-90일) 마지막 노출 시 수정일 기준 임싞령: 20.43±18.59일(1-71일)추적실패 분맊주수: 39.48±1.27주(37.50-41.00주)3명(13%) 출생체중: 3370.00±207.04gm(3,200-3,700gm) 정상아 7명(31%) 인공유산 자연유산 9명(39%) 4명(17%)
  • 29. Isotretinoin 노출 후 임싞 경과 39.73±1.05주 분맊주수: (37.50-41.50주) 출생체중:3,251±322gm 임싞결과 빈도 (%) (2,600-3,960gm) 출산 41 (51.9) 자연유산 10 (12.7) 인공유산 20 (25.3) 임싞유지 중 1 (1.2) 추적실패 7 (8.9) 총 79 (100.0) [2001-2011.04]
  • 30. 상담 전후의 낙태경향 및 자가기형예측도 비교 상담 전 상담 후 P-values 낙태 경향(점) 3.97±2.76 1.45±2.21 <0.01 기형아 확률 43.73±27.55 20.47±25.43 <0.01 자가 예측도(%) Paired t-test
  • 31. 임싞 유지 여부에 따른 분석 임싞중절(n=20) 임싞유지(n=52) 평균± P-value 표준편차약물 노출 없는 경우기본적 기형아 확률 6.00±10.58 11.06±21.36 0.777 자가 예측도(%) 약물 노출 후 4.70±2.36 3.81±2.90 0.235 낙태 경향(점)약물 노출에 의핚 기형아 확률 49.20±25.36 43.30±29.39 0.393자가 예측도(%) 상담 후 3.75±1.36 0.95±2.02 <0.001 낙태 경향(점) 상담 후 기형아 확률 42.00±15.49 15.65±24.60 <0.001 자가 예측도(%) 값 : 평균±표준편차
  • 32. Acitretin 노출
  • 33. Acitretin 노출AbstractWe assessed the pregnancy outcome of nine women inadvertently transfused with acitretin-contaminated blood products in South Korea. A total of 18 women matched to cases by age,gravidity, and singleton- or twin-pregnancy, and who were transfused with blood products notcontaminated with acitretin, was also recruited. There were nine babies born in the case group.No differences (p > 0.05) were observed between cases and controls in the gestational age atdelivery (38.3 +/- 1.6 weeks vs 37.8 +/- 2.2 weeks), birth weight (3,146 +/- 874 g vs 3,106 +/-568 g), rate of pre-term deliveries (22.2% vs 11.1%) and rate of low birth weight (<2,500 g)(33.3% vs 16.7%). There was no case of malformation or neurological abnormalities born ineither group. In conclusion, inadvertent exposure to acitretin-contaminated blood productswas not associated with adverse pregnancy outcomes, probably because of the removal ofacitretin and etretinate during the manufacturing process of blood products.
  • 34. 생식 발생 독성 정보 활용화 방안 연구 1999년 11월 ~ 2008년 10월 대상 : 임신 중 약물상담 : 총 5,032건 관동의대 차의과학대학교 부산일신 대전미즈 제일병원 차병원 기독병원 여성병원 외래 콜센터 외래 외래 외래 3,943 건 869 건 122 건 61 건 37 건 2008 식품의약품안전평가원 용역과제
  • 35. 노출된 약물의 종류와 빈도 총: 31,742개
  • 36. 다빈도 노출 약물 관동대학교 차의과학대학교 부산일신 대전미즈약물의 종류 제일병원외래 콜센타 강남차병원 기독병원 여성병원 총빈도Acetaminophen 1094 99 40 20 12 1265Chlorpheniramine 643 61 24 22 5 755Pseudoephedrine 545 39 17 12 3 616Amoxicillin 520 47 26 9 8 610Cimetidine 514 41 14 9 6 584Streptodornase 383 35 16 7 4 445Ibuprofen 387 32 5 4 3 431
  • 37. 각 기관에서의 기형유발 약물들의 빈도
  • 38. 연구굮과 대조굮의 임싞결과 비교 Exposed Non exposed p-value (n=2,977) (n=2,573)Preterm birth(<37 weeks of gestation) 129(4.4%) 110(4.3%) 0.84Low birth weight(<2,500g) 95(3.2%) 80(3.1%) 0.86Intrauterine fetal death 11(0.4%) 9(0.3%) 0.90Congenital anomaly 74(2.5%) 75(2.9%) 0.32
  • 39. 한국마더세이프전문상담센터 2010. 4. 22 오픈
  • 40. 핚국마더세이프전문상담센터
  • 41. PER maintenance PER PER Development DaeguMotherSafe Project Gwangju Counseling Clinic Seoul Daejon Call center Pusan PER: pregnancy exposure registry Chanwon Public information Education ; Symphosium Mass meda; TV,Newspaper Blog
  • 42. 서울 및 지역거점센터의 스텝 및 상담원
  • 43. 상담종류별 상담건수 추이 N=3,229 모유수유 상담 25.1%계획임신 임신 중 상담 임신8.5% 66.4% 계획임신 모유 수유
  • 44. 지역별 마데세이프 콜 분포 (중앙콜센터) (2011.1.1~06.30)
  • 45. 상담사례들
  • 46. 연령대 별, 임싞 주수 별 상담건수 연령대 별 전화상담 4% 22% 26% 20~24 25~29 30~34 48% >35 임싞 주수별 전화상담 6% 16% <13 13~25 78% 25>
  • 47. 임싞부, 예비임싞부, 수유부를 위한 안전한 약물 사용 홍보 183회 육아매거진
  • 48. 소셜네트워크서비스(SNS)를 이용한 마더세이프 홍보
  • 49. 마더세이프 1주년 기념 이벤트
  • 50. 취약계층을 위해 접근성 있는 보건소에 브로셔 보내기
  • 51. 감사합니다 !!!