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