3. Historical case I.
THALIDOMIDE
Anxiolytic and sedative drug
Malformations : 20 percent
Specific time window :
34 to 50 days menstrual age
Upper limb more seriously affected.
Phocomelia formed limb
4. Instructive of teratological principles
1. Placenta has been believed to be a perfect barrier
that was impenetrable to toxic substance
2. 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 day
New 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 perfusion
Exposed men in utero : normal sexual function, fertility
but, epididymal cysts, microphallus,
cryptorchidism, testicular hypoplasias
Sons 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
13. In human : post marketing surveillance
• Case report
rare exposure/ rare malformation
• Case-control study
less costly, recall bias
• Prospective cohort study
• Meta-analysis
14. 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)
20. 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
21. System of evaluation for safety and risk
on drug exposure in pregnancy
VS
FDA TERIS
22. 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
23. 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
24. 증례
32세 G2 P0
생리 연장 위해서 임신 5주경까지
마이보라를 복용하였음.
아기만 괜찮다면 낳고 싶습니다.
28. 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 2011년
상담 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)
29. Isotretinoin 노출 시기별 분포(n=79)
45.6%
50
40
29.1%
30 22.8%
20
10
0
conception>1Mo conception<1Mo conception during
after isotretinoin after isotretinoin isotretinoin
discontinuation discontinuation treatment
30. 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%)
32. 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
33. 임싞 유지 여부에 따른 분석
임싞중절(n=20) 임싞유지(n=52) 평균± P-value
표준편차
약물 노출 없는 경우
기본적 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 0.393
자가 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
35. Acitretin 노출
Abstract
We 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.
36. 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
47. PER maintenance
PER
PER Development
Daegu
MotherSafe Project
Gwangju
Counseling
Clinic
Seoul
Daejon
Call center
Pusan
PER: pregnancy exposure registry
Chanwon
Public information
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