practical counselling of major human teratogens
Post on 03-Jun-2015
829 Views
Preview:
TRANSCRIPT
Practical Counselling of
major teratogens
한국마더세이프전문상담센터
한정열 MD, PhD
I. Principles of Teratology
정 의
기형학 (Teratology) :
배아나 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
Malformations : alterations in normal development
that occur as a result of an intrinsic abnormality in
the developmental process.
Deformations : result from an abnormal mechanical
force on an otherwise normal fetus (eg, clubbed
foot in the setting of oligohydramnios).
Disruptions : due to the disruption of an otherwise
normal developmental process (eg, gastroschisis,
which is thought to result from a vascular disruption
in the fetal anterior abdominal wall).
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
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
Teratogenic agents act in specific ways
(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
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 Teratogens 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
System of evaluation for safety and risk on drug exposure in pregnancy
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 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
Korean Motherisk Program
Inadvertently drug exposure in Pregnancy
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
IV. Practical counselling of major teratogens :
Misoprostol /
Isotretinoin/
Methotrexate
G1P0 임신 8주에 약물상담외래 방문 : Fetal pole : 1.9cm Good FHB 미국의 한 OBGyn clinic에서 임신 5주에 vaginal bleeding과 G-sac 모양 좋지 않아 임신 중절 위해 싸이토텍 2T 복용함. 임신 중절되지 않고 출혈 있어 제일병원 방문
Misoprostol 증례 :
Misoprostol
Misoprostol is a drug that is used for the prevention of non steroidal
anti inflammatory drug (NSAID) induced gastric ulcers, for early
abortion, to treat missed miscarriage, and to induce labor. The latter
use is controversial in the United states. Misoprostol was invented and
marketed by Pfizer under the trade name Cytotec (often misspelled
Cyotec).
Pharmacologically, misoprostol is a synthetic prostaglandin E1(PGE1)
analogue.
Misoprostol
Reprotox® Quick take: Misoprostol use during early pregnancy has been associated with abortion and with congenital malformations in surviving infants.
A meta-analysis concluded that misoprostol use in early pregnancy increases the risk of Moebius sequence and transverse terminal limb defects.
Misoprostol 증례 :
Dear Han:
While there is no doubt that misoprostol is a cause of Mebius sequence, the
absolute risk is very minimal, and in our prospective series-not a single case
was found. There is however one case described in the literature.
I believe the advice should mention a very small risk. Some of the features
may be detected by detailed ultrasound.
All the best
gidi Gideon Koren MD, FRCPC, FACMT Director, The Motherisk Program The Hospital for Sick Children, Professor of Pediatrics,Pharmacology, Pharmacy and Medical Genetics The University of Toronto,
G2P1L1 얼굴의 피지 조절 위해 3년전 부터 이소트레티노인 간헐적으로 복용함. 마지막 복용: 임신 3주, 이소트레티노인 1T
Isotretinoin 증례
Isotretinoin
Isotretinoin is a medication used mostly for cystic acne.
It was first developed for brain, pancreatic and other cancers.
It is used to treat harlequin-type ichthyosis, a usually lethal skin
disease, and lamellar ichthyosis.
Its effects are systemic and nonselective.
It is a retinoid, meaning it is related to vitamin A,
and is found in small quantities naturally in the body.
Isotretinoin
Quick take: Isotretinoin use during pregnancy increases the
incidence of congenital anomalies.
Vitamin A and many retinoids produce congenital anomalies in
different species; defects produced involve the central nervous
system, the head, limbs, and cardiovascular system
Isotretinoin 연도 별 상담 건수
상담 시 Maternal age : 29.7±3.4 yrs(23~41 yrs) Gravidity 2.0± 1.4(1~7)
1 1
7
3
8 8
5
11
7
24
4
0
5
10
15
20
25
2001년 2002년 2003년 2004년 2005년 2006년 2007년 2008년 2009년 2010년 2011년
총 상담건수: 79건
Isotretinoin 노출 시기별 분포(n=79)
0
10
20
30
40
50
conception>1Mo
after isotretinoin
discontinuation
conception<1Mo
after isotretinoin
discontinuation
conception during
isotretinoin
treatment
45.6%
22.8%
29.1%
Isotretinoin 노출 후 임신 경과
임신결과 빈도 (%)
출산 41 (51.9)
자연유산 10 (12.7)
인공유산 20 (25.3)
임신유지 중 1 (1.2)
추적실패 7 (8.9)
총 79 (100.0)
[2001-2011.04]
분맊주수: 39.73±1.05주
(37.50-41.50주)
출생체중:3,251±322gm
(2,600-3,960gm)
수정 후 Isotretinoin 노출군 (n=23)
노출기간: 23.43±27.51일(1-90일)
마지막 노출 시 수정일 기준 임신령: 20.43±18.59일(1-71일)
정상아
7명(31%)
자연유산
4명(17%)
인공유산
9명(39%)
추적실패
3명(13%)
분맊주수: 39.48±1.27주(37.50-41.00주)
출생체중: 3370.00±207.04gm(3,200-3,700gm)
G2P1L1 류마티스관절염으로 2009년부터 엠티엑스정 복용 마지막 복용 : 임신 4+2주, MTX 4T/week(2.5mg/T)
Methotrexate 증례
Methotrexate , abbreviated MTX and formerly known as
amethopterin, is an antimetabolite and antifolate drug.
It is used in treatment of cancer, autoimmune diseases,
ectopic pregnancy, and for the induction of medical
abortions. It acts by inhibiting the metabolism of folic
acid. Methotrexate began to replace the more toxic
antifolate aminopterin starting in the 1950s
Methotrexate
Methotrexate
Quick take: Methotrexate increases the incidence of congenital
anomalies in experimental animals and appears to do so in humans
as well.
A critical period for exposure of 6-8 weeks after fertilization and a
critical dose of 10 mg/week have been described, although not
universally accepted.
Teratology 1992
Teratology 1992
Teratology 1992
Hello,
This is a great question, we have looked at case reports and case series
in the literature to try and answer this. We evaluated whether a
malformation or closely related group of malformations occurred more
often in case reports and case series than would be expected by
chance. We compared the proportion of all malformations represented
by each specific malformation with the same proportion derived from
the Metropolitan Atlanta Congenital Defects Program (MACDP).
Our disproportionality analysis supported pulmonary atresia,
craniosynostosis, and limb deficiencies as possibly associated with
methotrexate exposure.
Please note that our study (Hyoun et al. in press) included both
mothers inadvertently exposed to MTX for presumed ectopic
pregnancy as well as those being treated for Rheumatoid arthritis.
To help you I have included a portion of a table from our study that
lists the cases in the literature that may be most similar to your
patient. There is a limited reference list as well which I hope can help
you. I was hoping to answer you more succinctly than this, but I just
don't think we have that information yet.
Let me know if you have any other questions. Sarah Obican
Sarah Obican
Sarah Obican
Sarah Obican
Sarah Obican
Sarah Obican
한국마더세이프전문상담센터
top related