1) The document discusses principles of teratology and developmental toxicology, including that susceptibility to teratogens depends on factors like developmental stage, dosage, and genetics.
2) It provides an overview of evaluating drug safety and risk in pregnancy, including limitations of animal and human studies. The FDA classification system for risk is discussed.
3) Examples of counseling for inadvertent exposures to misoprostol, isotretinoin, and methotrexate during pregnancy are presented, including potential risks and outcomes.
3. 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
4. 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).
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
8. Period of developmental susceptibility
to pre-and postnatal exposures
Carcinogenesis
Altered growth
Functional deficits
Structural abnormalities
Prenatal/Neonatal death
Germ cell Organogenesis Fetal period Neonatal period Adolescence
Development
Fertilization Birth Sexual Maturity
9. Principles – 3
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
10. 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
11. 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
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
Teratogenesis
Rdproductive toxicity
% of survivors with
Mutagenesis
30
Background incidence of
Human reproductive toxicity
0
Dose of Teratogens 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
21. In human :
post marketing surveillance
• Case report
rare exposure/ rare malformation
• Case-control study
less costly, recall bias
• Prospective cohort study
• Meta-analysis
22. 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)
24. Drugs or Substances Suspected or Proven
to Be Human Teratogen
Williams Obstetrics 23rd ed. 2010
25. 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
26. 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
34. Misoprostol 증례 :
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
35. 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.
37. 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.
40. 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,
42. 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.
44. 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
45. 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)
46. 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
47. Isotretinoin 노출 후 임신 경과 39.73±1.05주
분맊주수:
(37.50-41.50주)
출생체중:3,251±322gm
임신결과 빈도 (%)
(2,600-3,960gm)
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]
48. 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)
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%)
51. Methotrexate
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
53. 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.
57. 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.
58. 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