Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.
기형학의 원칙
한국마더세이프전문상담센터
한정열 MD, PhD
Contents
I. Principles of Teratology
II. Safety and risk of drugs in Pregnancy
III. Teratology Information Services
: Tera...
들어가기 전…

 기형학 (Teratology) :
배아기나 태아기에 구조나 기능의 발달 이상의
원인과 기전 그리고 징후를 다루는 과학

 발달 독성학 (Developmental toxicology)
임신 전(양친)...
I. Principles of Teratology
Principles – 1

Susceptibility to teratogenesis/developmental

toxicity depends on the genotype of the
conceptus and the m...
Principles – 2

Susceptibility to teratogenesis/developmetal

toxicity varies with the developmental stage
at the time of ...
Critical period of Development-prenatal
Principles – 3

Teratogenic agents act in specific
mechanism on developing cells and
tissues to initiate sequences of
abno...
Principles – 4

The access of adverse influences to
developing tissues depends on the
nature of the influence(agent)
- Che...
Principles – 5

Four manifestations of deviant

development : death, malformation,
growth retardation, and functional defi...
Period of developmental susceptibility
to pre-and postnatal exposures
Carcinogenesis
Altered growth
Functional deficits
St...
Principles – 6

Manifestations of deviant development
increase in frequency and degree as
dosage increases, from the no-ef...
Teratogenesis follows
a toxicological dose response curve
100
% of survivors with
Rdproductive toxicity

Teratogenesis

Mu...
Principles – 7

Even the most potent teratogenic agent
cannot produce every malformations
Most teratogens have a confined group
of congenital malformations
• MTX: growth retardation, microsephaly, meningomyelocel...
II. Safety and risk of drugs
in pregnancy
Historical case I.

THALIDOMIDE
1960’s Anxiolytic and sedative drug

Malformations : 20 percent
Specific time window :
34 ...
THALIDOMIDE VICTIMS

『구족화가 앨리슨래퍼와 그녀의 아들 패리스』
THALIDOMIDE APOLOGY

Justice delayed is justice denied

<영국 선데이타임즈>
Historical case II.

Bendectin

1987.07.16 경향신문 4면 사회 기사(뉴스)

1983.06.10 경향신문 4면 사회 기사(뉴스)
Historical case II.

Bendectin
U.S.A. Temporal Trends for Limb Reduction Deformities,
Bendectin Sales, and Hospitalization...
Historical case III.

Diethylstilbestrol (DES)
1940-1971, 10milion pregnant women to “support” high risk pregnancies.
But ...
임신 중 약물의 안전성 평가 체계

VS

FDA

TERIS
In Animal : study

Important
• New teratogenic drugs : Predicted

• Light on teratogenic mechanisms
In Animal : study

Useless
•Interspecies variability
•

No animal is metabolically and
physiologically identical to human
Safety and risk of drugs in pregnancy
In human :

post marketing surveillance

•

Case report
rare exposure/ rare malformation

•

Case-control study
less costl...
Case report
Meta-analysis

BMJ 2014
Safety and risk of drugs in pregnancy
Limitations
• Is there association between safety and long term usage?
Thalidomide :...
Criteria for Proof of Human Teratogenicity

(Modified from Shepard 2001)
Drugs or Substances Suspected or Proven
to Be Human Teratogen

Williams Obstetrics 23rd ed. 2010
FDA classification
A

Controlled Studies show no risk

B

No evidence of risk in humans

C

Risk cannot be ruled out

D

P...
FDA system is not ideal:
• Onus on the clinician to interpret category information
• Drugs in categores D & X, and a certa...
Graphical representation of risk of
drugs in pregnancy

Nava-Ocampo AA et al 2007
III. Teratology Information Services
: teratogen counselling
Korean Motherisk
Program
Inadvertently drug exposure
in Pregnancy
Unintended pregnancy
 Unintended pregnancy : 48%

3
2

노출 빈도 (OR)
1
0
알코올

흡연

방사선

약물
Han JY et al. Birth Defects Res A ...
Perceived teratogenic risk after
inadvertently drug exposure

한정렬 등 대한산부회지 2002
[상담사례]

경구용 피임약 (Oral contraceptives)
32세 G2 P0
생리 연장 위해서 임신 5주경까지
마이보라를 복용하였음.
아기만 괜찮다면 낳고 싶습니다.
경구용 피임약 (Oral contraceptives)
FDA : X
한국마더세이프전문상담센터

☎1588-7309
서울 및 지역거점센터의 네트워크 구축 및 활성화
상담 사례들
종류

횟수

Percent

사례

약물

476

85%

가슴확대술, 간수치상승, 간질, 감기, 구충제, 갑상선항진증, 게실염, 결핵, 고혈압,
골반염, 공황장애, 구충제, 근육통, 다이어트, 기관지염...
상담종류별 상담건수 추이

N=8,129

2013.12
지역별 마데세이프 콜 분포 (중앙 콜센터)

(2011.1.1~2011.06.30)
Calls at MotherSafe Center
Total 27,610

Month

Year
Cases

4
2010

2011

2012

2013

3,547

7,341

8,326

8,129
Database of KMC
Clinic : 6,500
Call center : 23,00건
마더세이프 콜의 인지 경로

2012.03.14 ~ 2012.04.19

N=384
Symposium for Teratology
Training Course for Teratogen Counseling
감사합니다 !!!
기형학의 원칙
기형학의 원칙
기형학의 원칙
기형학의 원칙
기형학의 원칙
기형학의 원칙
Upcoming SlideShare
Loading in …5
×

기형학의 원칙

1,846 views

Published on

Published in: Health & Medicine
  • Be the first to comment

  • Be the first to like this

기형학의 원칙

  1. 1. 기형학의 원칙 한국마더세이프전문상담센터 한정열 MD, PhD
  2. 2. Contents I. Principles of Teratology II. Safety and risk of drugs in Pregnancy III. Teratology Information Services : Teratogenic risk counselling
  3. 3. 들어가기 전…  기형학 (Teratology) : 배아기나 태아기에 구조나 기능의 발달 이상의 원인과 기전 그리고 징후를 다루는 과학  발달 독성학 (Developmental toxicology) 임신 전(양친) , 임신 중, 출산 후부터 sexual maturation까지 노출에 기인한 developing organism에 미치는 adverse effects의 과학
  4. 4. I. Principles of Teratology
  5. 5. Principles – 1 Susceptibility to teratogenesis/developmental toxicity depends on the genotype of the conceptus and the manner in which this interacts with adverse environmental factors  Maternal/paternal genetic influences  Genetic polymorphism  Genomic imprinting  Gene-environmental interactions JG Wilson, 1977
  6. 6. Principles – 2 Susceptibility to teratogenesis/developmetal toxicity varies with the developmental stage at the time of exposure to an adverse influence Stage specificity has been defined for several developing organs and for exposures at several different developmental stages
  7. 7. Critical period of Development-prenatal
  8. 8. Principles – 3 Teratogenic agents act in specific mechanism on developing cells and tissues to initiate sequences of abnormal developments(pathogenesis) - Pathogenesis is a process – early effects may be repaired / compensated - Mechanistic studies, especially related to alterations in gene expression, are helping to understand how agents acts/interact ex) valproic acid
  9. 9. Principles – 4 The access of adverse influences to developing tissues depends on the nature of the influence(agent) - Chemical characteristics- size, charge, lipid solubility, ionization, protein binding, concentration gradients - Placental barrier, BBB - Metabolic capability- maternal, placental, embryo/fetal, neonatal
  10. 10. Principles – 5 Four manifestations of deviant development : death, malformation, growth retardation, and functional deficit - Types of effect depend on susceptibility, timing of exposure, interrelationship among effects
  11. 11. Period of developmental susceptibility to pre-and postnatal exposures Carcinogenesis Altered growth Functional deficits Structural abnormalities Prenatal/Neonatal death Germ cell Development Organogenesis Fertilization Fetal period Neonatal period Birth Adolescence Sexual Maturity
  12. 12. Principles – 6 Manifestations of deviant development increase in frequency and degree as dosage increases, from the no-effects to the totally lethal level.  High dose may result in fewer malformations due to increased death  Dose-response relationship for different types of effects.  Determination of the no observed adverse effect level(NOAEL) or benchmark dose(BMD)
  13. 13. Teratogenesis follows a toxicological dose response curve 100 % of survivors with Rdproductive toxicity Teratogenesis Mutagenesis 30 Background incidence of Human reproductive toxicity 0 Dose of Teratogen or mutagen R.L. Brent 2001
  14. 14. Principles – 7 Even the most potent teratogenic agent cannot produce every malformations
  15. 15. Most teratogens have a confined group of congenital malformations • MTX: growth retardation, microsephaly, meningomyelocele, mental retardation, hydrocephalus • Coumarine derivatives: nasal hypoplasia, stippling of secondary epiphysis, IUGR • Alcohol: Fetal alcohol syndrome • DES : Clear cell adenocarcinoma, adenosis, genital abnomalities
  16. 16. II. Safety and risk of drugs in pregnancy
  17. 17. Historical case I. THALIDOMIDE 1960’s Anxiolytic and sedative drug Malformations : 20 percent Specific time window : 34 to 50 days menstrual age Upper limb more seriously affected. Phocomelia formed limb
  18. 18. THALIDOMIDE VICTIMS 『구족화가 앨리슨래퍼와 그녀의 아들 패리스』
  19. 19. THALIDOMIDE APOLOGY Justice delayed is justice denied <영국 선데이타임즈>
  20. 20. Historical case II. Bendectin 1987.07.16 경향신문 4면 사회 기사(뉴스) 1983.06.10 경향신문 4면 사회 기사(뉴스)
  21. 21. Historical case II. Bendectin U.S.A. Temporal Trends for Limb Reduction Deformities, Bendectin Sales, and Hospitalizations for NVP
  22. 22. Historical case III. 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)
  23. 23. 임신 중 약물의 안전성 평가 체계 VS FDA TERIS
  24. 24. In Animal : study Important • New teratogenic drugs : Predicted • Light on teratogenic mechanisms
  25. 25. In Animal : study Useless •Interspecies variability • No animal is metabolically and physiologically identical to human
  26. 26. Safety and risk of drugs in pregnancy
  27. 27. In human : post marketing surveillance • Case report rare exposure/ rare malformation • Case-control study less costly, recall bias • Prospective cohort study • Meta-analysis
  28. 28. Case report
  29. 29. Meta-analysis BMJ 2014
  30. 30. 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)
  31. 31. Criteria for Proof of Human Teratogenicity (Modified from Shepard 2001)
  32. 32. Drugs or Substances Suspected or Proven to Be Human Teratogen Williams Obstetrics 23rd ed. 2010
  33. 33. FDA classification A Controlled Studies show no risk B No evidence of risk in humans C Risk cannot be ruled out D Positive evidence of risk X Contraindicated in pregnancy From 1979
  34. 34. FDA system is not ideal: • Onus on the clinician to interpret category information • Drugs in categores D & X, and a certain extent those in C may 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
  35. 35. Graphical representation of risk of drugs in pregnancy Nava-Ocampo AA et al 2007
  36. 36. III. Teratology Information Services : teratogen counselling
  37. 37. Korean Motherisk Program
  38. 38. Inadvertently drug exposure in Pregnancy
  39. 39. Unintended pregnancy  Unintended pregnancy : 48% 3 2 노출 빈도 (OR) 1 0 알코올 흡연 방사선 약물 Han JY et al. Birth Defects Res A Clin Mol Teratol. 2005
  40. 40. Perceived teratogenic risk after inadvertently drug exposure 한정렬 등 대한산부회지 2002
  41. 41. [상담사례] 경구용 피임약 (Oral contraceptives) 32세 G2 P0 생리 연장 위해서 임신 5주경까지 마이보라를 복용하였음. 아기만 괜찮다면 낳고 싶습니다.
  42. 42. 경구용 피임약 (Oral contraceptives) FDA : X
  43. 43. 한국마더세이프전문상담센터 ☎1588-7309
  44. 44. 서울 및 지역거점센터의 네트워크 구축 및 활성화
  45. 45. 상담 사례들 종류 횟수 Percent 사례 약물 476 85% 가슴확대술, 간수치상승, 간질, 감기, 구충제, 갑상선항진증, 게실염, 결핵, 고혈압, 골반염, 공황장애, 구충제, 근육통, 다이어트, 기관지염, 눈다래끼, 두드러기, 두 통, 루푸스, 류마티스관절염, 멀미, 머릿니, 무좀, 방광염, 변비, 부비동염, 불면 증, 사후피임약, 소화불양, 손목통증, 수면내시경, 수면제, 습진, 아토피, 여드름, 우울증, 위내시경, 유선염, 이석증, 입덧, 치과치료, 장염, 중이염, 질염, 천식, 피임, 허리디스크, 화상, 후두염, B형간염, MRI조영제, 헬리코박터균 음주 3 0.5% 음주후 수유 언제부터 가능한지, 모유수유중 맥주 200ml 마심, 임신초반(6주) 하 루 1500cc의 맥주를 주 3~4회 마심 흡연 4 0.7% 흡연 10년전 부터 하루 10개피, 임신중 흡연(하루 1~2개피)이 아이에 영향이 있 는지, 6년동안 하루 10~14개피 흡연, 6주초까지 감염 1 0.1% 중환자실에서 근무하는 간호사- 손에 상처가 있었는데 VDRL환자의 혈액이 팔에 튀었고 며칠후 피부에 뭐가 나기 시작함 유해물질 4 0.7% 파마, 염색, 비듬, 12~16주 사이 염색, 펌을 했어요 괜찮을까요? 산과지식 62 11.1% 모유수유 중단, 방법, 혼합수유, 수유시 영양제, 임신중 영양제, 수유자세, 유두통증, 젖양 늘리는방법, 피임방법 방사선 10 1.8% 계획중 다리골절로 x-ray 촬영하려하는데 괜찮은지, 첫아이 X-ray촬영시 간접촬영, 디스크로 x-ray 촬영, 건강검진으로 방사선노출(X-ray, CT, Mammography), Chest PA 찍을 예정인데 괜찮나요? 계 560 100
  46. 46. 상담종류별 상담건수 추이 N=8,129 2013.12
  47. 47. 지역별 마데세이프 콜 분포 (중앙 콜센터) (2011.1.1~2011.06.30)
  48. 48. Calls at MotherSafe Center Total 27,610 Month Year Cases 4 2010 2011 2012 2013 3,547 7,341 8,326 8,129
  49. 49. Database of KMC Clinic : 6,500 Call center : 23,00건
  50. 50. 마더세이프 콜의 인지 경로 2012.03.14 ~ 2012.04.19 N=384
  51. 51. Symposium for Teratology
  52. 52. Training Course for Teratogen Counseling
  53. 53. 감사합니다 !!!

×