기형학의 원칙

한국마더세이프전문상담센터

한정열 MD, PhD

2015. 3 .3

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 toxicology)

임신 전(양친) , 임신 중, 출산 후부터 sexual

maturation까지 노출에 기인한 developing

organism에 미치는 adverse effects의 과학

들어가기 전…

I. Principles of Teratology

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

Principles – 1

JG Wilson, 1977

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

Principles – 2

Critical period of Development-prenatal

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

Principles – 3

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

Principles – 4

- Types of effect depend on susceptibility,

timing of exposure, interrelationship

among effects

Four manifestations of deviant

development : death, malformation,

growth retardation, and functional deficit

Principles – 5

Period of developmental susceptibility

to pre-and postnatal exposures

Germ cell Development

Organogenesis Fetal period Neonatal period Adolescence

Fertilization Birth Sexual Maturity

Prenatal/Neonatal death

Structural abnormalities

Functional deficits

Altered growth

Carcinogenesis

Manifestations of deviant development

increase in frequency and degree 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 effects.

Determination of the no observed adverse effect

level(NOAEL) or benchmark dose(BMD)

Teratogenesis follows

a toxicological dose response curve

% o

f survivo

rs with

Rdpro

ductive

toxicity

Dose of Teratogen or mutagen

Background incidence of Human reproductive toxicity

Teratogenesis

Mutagenesis

R.L. Brent 2001

0

30

100

Even the most potent teratogenic agent

cannot produce every malformations

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 secondary

epiphysis, IUGR

• Alcohol: Fetal alcohol syndrome

• DES : Clear cell adenocarcinoma, adenosis, genital abnomalities

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

『구족화가앨리슨래퍼와그녀의아들패리스』

Justice delayed is justice denied <영국 선데이타임즈>

THALIDOMIDE APOLOGY

BendectinHistorical case II.

1983.06.10 경향신문 4면 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 surveillance

• 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 Determining Human Teratogenicity

(Modified from Shepard 1994, 2002)

Human Teratogen

Human Teratogen

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

임부금기 등급 분류

(식품의약품안전처 2008)

III. Teratology Information Services

: teratogen counselling

Korean MotheriskProgram

Inadvertently drug exposure in Pregnancy

태아동산 (충북 음성)

Unintended pregnancy

0

1

2

3

알코올 흡연 방사선 약물

노출 빈도 (OR)

Han JY et al. Birth Defects Res A Clin Mol Teratol. 2005

Unintended pregnancy : 48%

한정렬 등 대한산부회지 2002

Perceived teratogenic risk after

inadvertently drug exposure

[상담사례 - 1]

32세 G2 P0

생리 연장 위해서 임신 5주경까지

마이보라를 복용하였음.

아기만 괜찮다면 낳고 싶습니다.

경구용 피임약 (Oral contraceptives)

FDA : X

경구용 피임약 (Oral contraceptives)

헌혈에의한Acitretin노출태아에문제없나요?

[상담사례 - 2]

Acitretin 노출

AbstractWe 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 not contaminated 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 at delivery (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 in either group. In conclusion, inadvertent exposure to acitretin-contaminated blood products was not associated with adverse pregnancy outcomes, probably because of the removal of acitretin and etretinate during the manufacturing process of blood products.

한국마더세이프전문상담센터

☎1588-7309

서울 및 지역거점센터의 네트워크 구축 및 활성화

서울 및 지역거점센터의 스텝 및 상담원

상담 사례들종류 횟수 Percent 사 례

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, 12~16주사이염색,펌을했어요괜찮을까요?

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

상담종류별 상담건수 추이

임신 중 상담

66.4%

계획임신

8.5%

모유수유 상담

25.1%

임신

계획임신

모유 수유

N=7,341 (2011년)

Calls at MotherSafe Center

2014년 서울 및 거점센터 상담건수

2,686건

마더세이프 DB 구축 및 활용

마더세이프 DB 시스템 구축 : 상담과 동시에 DB 구축 및 1년 후 임신결과 추적

마더세이프 DB 구축 및 활용

마더세이프 DB 시스템 구축 :

DB 활용 :

1. 상담자료로 활용 (예, 바라크루드 복용 임신부)

2. 상담의 evidence를 위한 논문출간(출산 후 아기의 기형여부 및 모유수유 시 부작용 여부)

예, Pregnancy outcomes and factors associated with voluntary pregnancy termination in women who had

been treated for acne with isotretinoin.

3. KIMS(대한민국의약정보센터)와 협업하여 임신부 다빈도 노출약물정보구축

콜센터(2010-2014) : 35,000건 클리닉(2001-2014) : 6,000건

마더세이프 콜의 인지 경로

2012.03.14 ~ 2012.04.19 N=384

Symposium for Teratology

Training Course for Teratogen Counseling

마더세이프 프로그램 홍보

페르노리카와 임신부 금주 캠페인

국내 및 국제 보건소 요원 교육

모자보건사업과정

-한국보건인력개발원-

보건소요원

-서울 중구보건소-

동남아시아 보건요원

- KOICA-

감사합니다 !!!