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기형학의 원칙
한국마더세이프전문상담센터
한정열 MD, PhD
I. Principles of Teratology
II. Safety and risk of drugs in Pregnancy
III. Teratology Information Services
: Teratogenic risk counselling
Contents
기형학 (Teratology) :
배아기나 태아기에 구조나 기능의 발달 이상의
원인과 기전 그리고 징후를 다루는 과학
발달 독성학 (Developmental toxicol-
ogy)
임신 전 ( 양친 ) , 임신 중 , 출산 후부터 sexual
maturation 까지 노출에 기인한 developing
organism 에 미치는 adverse effects 의 과학
들어가기 전…
I. Principles of Teratology
Susceptibility to teratogenesis/develop-
mental 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
Principles – 1
JG Wilson, 1977
Susceptibility to teratogenesis/develop-
metal toxicity varies with the developmen-
tal stage
at the time of exposure to an adverse in-
fluence Stage specificity has been defined
for several developing organs and
for exposures at several different developmental
stages
Principles – 2
Critical period of Development-pre-natal
Teratogenic agents act in specific
mechanism on developing cells and
tissues to initiate sequences of ab-
normal
developments(pathogenesis) - Pathogenesis is a process – early effects may be repaired / com-
pensated
- Mechanistic studies, especially related to alterations in gene ex-
pression,
are helping to understand how agents acts/interact ex) valproic
acid
Principles – 3
The access of adverse influences to
developing tissues depends on the
nature of the influence(agent)
- Chemical characteristics- size, charge, lipid solubility, ion-ization, protein binding, concentration gradi-ents
- Placental barrier, BBB
- Metabolic capability- maternal, placental, embryo/fetal, neonatal
Principles – 4
- Types of effect depend on susceptibil-
ity,
timing of exposure, interrelationship
among effects
Four manifestations of deviant de-
velopment : death, malformation,
growth retardation, and functional deficit
Principles – 5
Period of developmental susceptibil-ity to pre-and postna-
tal exposures
Germ cell Development
Organogenesis Fetal period Neonatal period Adolescence
Fertilization Birth Sexual Matu-rity
Prenatal/Neonatal death
Structural abnormalities
Functional deficits
Altered growth
Carcinogenesis
Manifestations of deviant develop-
ment increase in frequency and de-
gree as dosage increases, from the
no-effects to the totally lethal level.
Principles – 6
High dose may result in fewer malformations due to
increased death
Dose-response relationship for different types of ef-
fects.
Determination of the no observed adverse effect
level(NOAEL) or benchmark dose(BMD)
Teratogenesis follows
a toxicological dose response curve
% o
f surv
ivors w
ith
Rdp
roductiv
e tox
ic-ity
Dose of Teratogen or mutagen
Background incidence of Human reproductive toxic-ity
Teratogenesis
Mutagenesis
R.L. Brent 2001
0
30
100
Even the most potent teratogenic agent
cannot produce every malforma-tions
Principles – 7
Most teratogens have a confined group
of congenital malformations • MTX: growth retardation, microsephaly, meningomyelocele,
mental retardation, hydrocephalus
• Coumarine derivatives: nasal hypoplasia, stippling of sec-ondary
epiphysis, IUGR
• Alcohol: Fetal alcohol syndrome
• DES : Clear cell adenocarcinoma, adenosis, genital abnomali-ties
II. Safety and risk of drugs in pregnancy
Historical case I.
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
THALIDOMIDE
THALIDOMIDE VICTIMS
『구족화가 앨리슨래퍼와 그녀의 아들 패리스』
Justice delayed is justice denied < 영국 선데이타임즈 >
THALIDOMIDE APOLOGY
BendectinHistorical case II.
1983.06.10 경향신문 4 면 사회 기사 ( 뉴스 )
1987.07.16 경향신문 4 면 사회 기사 ( 뉴스 )
U.S.A. Temporal Trends for Limb Reduction Deformities,
Bendectin Sales, and Hospitalizations for NVP
BendectinHistorical case II.
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)
Diethylstilbestrol (DES)
Historical case III.
임신 중 약물의 안전성 평가 체계
VS
FDA TERIS
Important
• New teratogenic drugs : Predicted
• Light on teratogenic mechanisms
In Animal : study
Useless
•Interspecies variability
• No animal is metabolically and
physiologically identical to human
In Animal : study
Safety and risk of drugs in pregnancy
• Case report rare exposure/ rare malformation
• Case-control study less costly, recall bias
• Prospective cohort study
• Meta-analysis
In human :
post marketing surveil-lance
Case report
BMJ 2014
Meta-analysis
• 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?
Safety and risk of drugs in pregnancy
Limitations
(Reproductive Toxicology 2001)
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 Positive evidence of risk
X Contraindicated in pregnancy
From 1979
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
Nava-Ocampo AA et al 2007
Graphical representation of risk of drugs in pregnancy
III. Teratology Information
Services
: teratogen counselling
Korean Motherisk Program
Inadvertently drug exposure in Pregnancy
Unintended pregnancy
알코올 흡연 방사선 약물0
0.5
1
1.5
2
2.5
3
노출 빈도 (OR)
Han JY et al. Birth Defects Res A Clin Mol Teratol. 2005
Unintended pregnancy : 48% Unintended pregnancy : 48%
한정렬 등 대한산부회지 2002
Perceived teratogenic risk after inadvertently drug exposure
[ 상담사례 ]
32 세 G2 P0
생리 연장 위해서 임신 5 주경까지
마이보라를 복용하였음 .
아기만 괜찮다면 낳고 싶습니다 .
경구용 피임약 (Oral contracep-tives)
FDA : X
경구용 피임약 (Oral contracep-tives)
한국마더세이프전문상담센터
☎1588-7309
서울 및 지역거점센터의 네트워크 구축 및 활성화
상담 사례들 종류 횟수 Percent 사 례
약물 476 85% 가슴확대술 , 간수치상승 , 간질 , 감기 , 구충제 , 갑상선항진증 , 게실염 ,
결핵 , 고혈압 , 골반염 , 공황장애 , 구충제 , 근육통 , 다이어트 , 기관지염 ,
눈다래끼 , 두드러기 , 두통 , 루푸스 , 류마티스관절염 , 멀미 , 머릿니 ,
무좀 , 방광염 , 변비 , 부비동염 , 불면증 , 사후피임약 , 소화불양 , 손목통
증 , 수면내시경 , 수면제 , 습진 , 아토피 , 여드름 , 우울증 , 위내시경 , 유선
염 , 이석증 , 입덧 , 치과치료 , 장염 , 중이염 , 질염 , 천식 , 피임 ,
허리디스크 , 화상 , 후두염 , B 형간염 , MRI 조영제 , 헬리코박터균
음주 3 0.5% 음주후 수유 언제부터 가능한지 , 모유수유중 맥주 200ml 마심 , 임신초반 (6
주 ) 하루 1500cc 의 맥주를 주 3~4 회 마심
흡연 4 0.7% 흡연 10 년전 부터 하루 10 개피 , 임신중 흡연 ( 하루 1~2 개피 ) 이 아이에
영향이 있는지 , 6 년동안 하루 10~14 개피 흡연 , 6 주초까지
감염 1 0.1% 중환자실에서 근무하는 간호사 - 손에 상처가 있었는데 VDRL 환자의 혈액이
팔에 튀었고 며칠후 피부에 뭐가 나기 시작함
유해물질 4 0.7% 파마 , 염색 , 비듬 , 12~16 주 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-ray 촬영시
간접촬영 , 디스크로 x-ray 촬영 , 건강검진으로 방사선노출 (X-ray, CT, Mam-
mography), Chest PA 찍을 예정인데 괜찮나요 ?
계 560 100
상담종류별 상담건수 추이
2013.12
N=8,129
지역별 마데세이프 콜 분포 ( 중앙 콜센터 )
(2011.1.1~2011.06.30)
2010 2011 2012
4Month
Year
Calls at MotherSafe Center
8,3267,3413,547
Total 27,610
Cases
8,129
2013
Clinic : 6,500Call center : 23,00 건
Database of KMC
MotherSafe.exe
마더세이프 콜의 인지 경로
2012.03.14 ~ 2012.04.19 N=384
Symposium for Teratology
Training Course for Teratogen Counsel-ing
감사합니다 !!!
