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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).
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
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
Critical period of Development-prenatal
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
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
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
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
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)
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
Principles – 7



     Even the most potent teratogenic agent
          cannot produce every malformations
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
In Animal : study



Important

• New teratogenic drugs : Predicted

• Light on teratogenic mechanisms
In Animal : study


    Useless

•Interspecies variability

•   No animal is metabolically and

        physiologically identical to human
Safety and risk of drugs in pregnancy
In human :
   post marketing surveillance
  •   Case report
        rare exposure/ rare malformation

  •   Case-control study
        less costly, recall bias

  •   Prospective cohort study
  •   Meta-analysis
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)
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
Graphical representation of risk of
       drugs in pregnancy




                        Nava-Ocampo AA et al 2007
III. Teratology Information Services
Korean Motherisk Program
Inadvertently drug exposure
       in Pregnancy
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
Perceived teratogenic risk after
 inadvertently drug exposure




                            한정렬 등 대한산부회지 2002
IV. Practical counselling of
     major teratogens :


   Misoprostol /
       Isotretinoin/
             Methotrexate
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
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 :
<마더리스크라운드>Practical counselling of major human teratogens
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,
Isotretinoin 증례


G2P1L1

얼굴의 피지 조절 위해

3년전 부터 이소트레티노인 간헐적으로 복용함.

마지막 복용: 임신 3주, 이소트레티노인 1T
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

 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)
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
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]
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%)
&lt;마더리스크라운드>Practical counselling of major human teratogens
Methotrexate 증례



G2P1L1

류마티스관절염으로 2009년부터 엠티엑스정 복용

마지막 복용 : 임신 4+2주, MTX 4T/week(2.5mg/T)
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
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

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&lt;마더리스크라운드>Practical counselling of major human teratogens

  • 1. Practical Counselling of major teratogens 한국마더세이프전문상담센터 한정열 MD, PhD
  • 2. I. Principles of Teratology
  • 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
  • 7. Critical period of Development-prenatal
  • 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
  • 16. II. Safety and risk of drugs in pregnancy
  • 17. System of evaluation for safety and risk on drug exposure in pregnancy VS FDA TERIS
  • 18. In Animal : study Important • New teratogenic drugs : Predicted • Light on teratogenic mechanisms
  • 19. In Animal : study Useless •Interspecies variability • No animal is metabolically and physiologically identical to human
  • 20. Safety and risk of drugs in pregnancy
  • 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)
  • 23. Criteria for Proof of Human Teratogenicity (Modified from Shepard 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
  • 27. Graphical representation of risk of drugs in pregnancy Nava-Ocampo AA et al 2007
  • 31. 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
  • 32. Perceived teratogenic risk after inadvertently drug exposure 한정렬 등 대한산부회지 2002
  • 33. IV. Practical counselling of major teratogens : Misoprostol / Isotretinoin/ Methotrexate
  • 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,
  • 41. Isotretinoin 증례 G2P1L1 얼굴의 피지 조절 위해 3년전 부터 이소트레티노인 간헐적으로 복용함. 마지막 복용: 임신 3주, 이소트레티노인 1T
  • 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%)
  • 50. Methotrexate 증례 G2P1L1 류마티스관절염으로 2009년부터 엠티엑스정 복용 마지막 복용 : 임신 4+2주, MTX 4T/week(2.5mg/T)
  • 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