The document summarizes the principles of teratology and developmental toxicology. It discusses seven principles: 1) Genetic and environmental factors influence susceptibility, 2) Susceptibility varies by developmental stage, 3) Teratogens act through specific mechanisms, 4) Access of influences depends on agent characteristics, 5) Effects can include death, malformations, growth issues, or functional deficits, 6) Risk increases with dose, 7) Not all malformations can be caused. It also discusses evaluating drug safety in pregnancy through animal studies, human data, and limitations. Teratology information services provide counseling based on these principles.

1. 기형학의 원칙
한국마더세이프전문상담센터
한정열 MD, PhD

2. Contents
I. Principles of Teratology
II. Safety and risk of drugs in Pregnancy
III. Teratology Information Services
: Teratogenic risk counselling

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. I. Principles of Teratology

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. 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. Critical period of Development-prenatal

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. 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. 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. 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. 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. 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. Principles – 7
Even the most potent teratogenic agent
cannot produce every malformations

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. II. Safety and risk of drugs
in pregnancy

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. THALIDOMIDE VICTIMS
『구족화가 앨리슨래퍼와 그녀의 아들 패리스』

19. THALIDOMIDE APOLOGY
Justice delayed is justice denied
<영국 선데이타임즈>

20. Historical case II.
Bendectin
1987.07.16 경향신문 4면 사회 기사(뉴스)
1983.06.10 경향신문 4면 사회 기사(뉴스)

21. Historical case II.
Bendectin
U.S.A. Temporal Trends for Limb Reduction Deformities,
Bendectin Sales, and Hospitalizations for NVP

23. 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)

24. 임신 중 약물의 안전성 평가 체계
VS
FDA
TERIS

25. In Animal : study
Important
• New teratogenic drugs : Predicted
• Light on teratogenic mechanisms

26. In Animal : study
Useless
•Interspecies variability
•
No animal is metabolically and
physiologically identical to human

27. Safety and risk of drugs in pregnancy

28. In human :
post marketing surveillance
•
Case report
rare exposure/ rare malformation
•
Case-control study
less costly, recall bias
•
Prospective cohort study
•
Meta-analysis

29. Case report

30. Meta-analysis
BMJ 2014

32. 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)

33. Criteria for Proof of Human Teratogenicity
(Modified from Shepard 2001)

34. Drugs or Substances Suspected or Proven
to Be Human Teratogen
Williams Obstetrics 23rd ed. 2010

35. 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

37. 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

38. Graphical representation of risk of
drugs in pregnancy
Nava-Ocampo AA et al 2007

39. III. Teratology Information Services
: teratogen counselling

40. Korean Motherisk
Program

41. Inadvertently drug exposure
in Pregnancy

42. 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

43. Perceived teratogenic risk after
inadvertently drug exposure
한정렬 등 대한산부회지 2002

44. [상담사례]
경구용 피임약 (Oral contraceptives)
32세 G2 P0
생리 연장 위해서 임신 5주경까지
마이보라를 복용하였음.
아기만 괜찮다면 낳고 싶습니다.

45. 경구용 피임약 (Oral contraceptives)
FDA : X

46. 한국마더세이프전문상담센터
☎1588-7309

47. 서울 및 지역거점센터의 네트워크 구축 및 활성화

48. 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

49. 상담종류별 상담건수 추이
N=8,129
2013.12

50. 지역별 마데세이프 콜 분포 (중앙 콜센터)
(2011.1.1~2011.06.30)

51. Calls at MotherSafe Center
Total 27,610
Month
Year
Cases
4
2010
2011
2012
2013
3,547
7,341
8,326
8,129

52. Database of KMC
Clinic : 6,500
Call center : 23,00건

53. 마더세이프 콜의 인지 경로
2012.03.14 ~ 2012.04.19
N=384

54. Symposium for Teratology

55. Training Course for Teratogen Counseling

59. 감사합니다 !!!