TERATOLOGYTERATOLOGY20102010

TeratologyTeratology

Teratology is the science that studies the Teratology is the science that studies the causes, mechanisms, and patterns of causes, mechanisms, and patterns of abnormal development.abnormal development.

Developmental disorders present at birth Developmental disorders present at birth are called congenital anomalies, birth are called congenital anomalies, birth defect or congenital malformation.defect or congenital malformation.

Congenital anomalies are of four clinically Congenital anomalies are of four clinically significant types: malformation, disruption, significant types: malformation, disruption, deformation and dysplasia.deformation and dysplasia.

Malformation - definitionMalformation - definition

Congenital malformation are structural defects Congenital malformation are structural defects present at birth. They may be gross or present at birth. They may be gross or microscopic, on the surface of the body or within microscopic, on the surface of the body or within it, familiar or sporadic, hereditary or it, familiar or sporadic, hereditary or nonhereditary, single or multiple. (Warkany nonhereditary, single or multiple. (Warkany 1947)1947)

A major congenital anomaly is one that is A major congenital anomaly is one that is incompatible with survival, is life-threatening, or incompatible with survival, is life-threatening, or seriously compromises an individual´s capacity seriously compromises an individual´s capacity to function normally in society (Otake et al.1990)to function normally in society (Otake et al.1990)

Teratology - termsTeratology - terms MalformationMalformation is a primary structural defect is a primary structural defect

resulting from a localized error of resulting from a localized error of morphogenesismorphogenesis

DisruptionDisruption is specific abnormality that results is specific abnormality that results from disruption of normal developmental from disruption of normal developmental processes It depends on time not on agentprocesses It depends on time not on agent

DeformationDeformation is an alteration in shape / structure is an alteration in shape / structure of previously normally formed partof previously normally formed part

SyndromeSyndrome is a recognized pattern of is a recognized pattern of malformations with a given etiology.malformations with a given etiology.

Birth defectsBirth defects

3% of all live-born infants have an major 3% of all live-born infants have an major anomalyanomaly

Additional anomalies are detected during Additional anomalies are detected during postnatal live – about 6% at 2 year-olds, postnatal live – about 6% at 2 year-olds, 8% in 5year-olds, other 2% later8% in 5year-olds, other 2% later

Single minor anomalies are present in Single minor anomalies are present in about 14% of newbornsabout 14% of newborns

Birth defects Birth defects

Major anomalies are more common in Major anomalies are more common in early embryos (up to 15%) than they are in early embryos (up to 15%) than they are in newborns (3%). Most severely malformed newborns (3%). Most severely malformed embryos are spontaneously aborted embryos are spontaneously aborted during first 6 to 8 weeks.during first 6 to 8 weeks.

Causes of congenital anomaliesCauses of congenital anomalies

Anomalies caused by genetic Anomalies caused by genetic factorsfactors

Chromosomal aberrations are common and are Chromosomal aberrations are common and are present in 6 to 7% of zygotes – (result =abort)present in 6 to 7% of zygotes – (result =abort)

Numerical chromosomal abnormalitiesNumerical chromosomal abnormalities – – usually non-disjunction- error in cell divisionusually non-disjunction- error in cell division

Down syndrome (21) Edwards (18) Patau (13) Down syndrome (21) Edwards (18) Patau (13) Turner (X0), Klinenfelter (XXY)Turner (X0), Klinenfelter (XXY)

Structural chromosomal abnormalitiesStructural chromosomal abnormalities – – chromosome breaks = translocation, deletion (cri chromosome breaks = translocation, deletion (cri du chat syndrome), duplication, inversion.du chat syndrome), duplication, inversion.

Mutant genesMutant genes – achondroplasia, fragile-X – achondroplasia, fragile-X syndromesyndrome

Down syndromeDown syndrome

TeratogenTeratogen Teratogenesis is process with threshold-level effect.Teratogenesis is process with threshold-level effect. Every chemical substance may be teratogen. This effect Every chemical substance may be teratogen. This effect

depends on quantity. In small amount is without any depends on quantity. In small amount is without any effect.effect.

Teratogen is factor that is present in environment in so Teratogen is factor that is present in environment in so high amount that it can increase occurrence of high amount that it can increase occurrence of embryotoxicity manifestation up to basic frequency in embryotoxicity manifestation up to basic frequency in non-exposed population non-exposed population

Teratogenicity is a manifestation of developmental Teratogenicity is a manifestation of developmental toxicity representing a particular case of toxicity representing a particular case of embryo/fetotoxicity, by the induction or the increase of embryo/fetotoxicity, by the induction or the increase of frequency of structural disorders in the progeny. frequency of structural disorders in the progeny.

Basic principles in teratogenesisBasic principles in teratogenesis

Critical periods of developmentCritical periods of development Dosage of the drug or chemical Dosage of the drug or chemical Genotype (genetic constitution) of the Genotype (genetic constitution) of the

embryo and motherembryo and mother

Critical and sensitive periods of Critical and sensitive periods of developmentdevelopment

Dose-response relation in teratologyDose-response relation in teratology

A - afflictedA - afflicted B - malformedB - malformed

Course of lossesCourse of losses

Consequences of exposure to Consequences of exposure to teratogensteratogens

Death – abortion or miscarriageDeath – abortion or miscarriage MalformationMalformation IUGR – intrauterine growth retardationIUGR – intrauterine growth retardation Functional defects in the newbornFunctional defects in the newborn Normal newbornNormal newborn

Anomalies caused by Anomalies caused by environmental factorsenvironmental factors

TeratogensTeratogens are exogenous agents that may cause are exogenous agents that may cause developmental defects:developmental defects:

DrugsDrugs (warfarin, valproic acid, phenytoin, vitamin A, (warfarin, valproic acid, phenytoin, vitamin A, thalidomide, cytostatic drugs – cyclophosphamide, thalidomide, cytostatic drugs – cyclophosphamide, lithium carbonate)lithium carbonate)

ChemicalsChemicals (PCBs, methylmercury, alcohols) (PCBs, methylmercury, alcohols) InfectionsInfections (rubella, cytomegalovirus, herpes virus, (rubella, cytomegalovirus, herpes virus,

toxoplasma, syphilis)toxoplasma, syphilis) Ionizing radiationIonizing radiation (X-rays) (X-rays) Maternal factorsMaternal factors (diabetes mellitus, hyperthermia, (diabetes mellitus, hyperthermia,

phenylketonuria, hyper-/hypo-thyreosis)phenylketonuria, hyper-/hypo-thyreosis)

ThalidomideThalidomide Firm Gruenewald brought it on market in 1957 Firm Gruenewald brought it on market in 1957 1958-1961 cases of irreversibile polyneuropathia1958-1961 cases of irreversibile polyneuropathia W.Lenz (1961) reports on accumulation of specific W.Lenz (1961) reports on accumulation of specific

malformations (focomelia) malformations (focomelia) Thalidomide was gone out of marketThalidomide was gone out of market 8000 -12000 malformed newborns8000 -12000 malformed newborns Critical period 38. – 50. day after ovulationCritical period 38. – 50. day after ovulation Risk 1-2:10 if exposed during critical periodRisk 1-2:10 if exposed during critical period ie. 20% risk.ie. 20% risk. It probably blocks the expression of growth factors It probably blocks the expression of growth factors

(IGF1,FG2,integrins) and formation of vessels(IGF1,FG2,integrins) and formation of vessels

Testing for teratogenicityTesting for teratogenicity Standardized procedures for testing drugs for Standardized procedures for testing drugs for

teratogenic potential are usedteratogenic potential are used They use at least two common mammalian laboratory They use at least two common mammalian laboratory

species that are given several different doses of the test species that are given several different doses of the test agent once or several successive days during agent once or several successive days during organogenesis and early fetal periodorganogenesis and early fetal period

Coventionally 3 doses are administered; the highest Coventionally 3 doses are administered; the highest causing maternal toxicitycausing maternal toxicity

Evaluation of human case reports and epidemiological Evaluation of human case reports and epidemiological investigation (retrospective and prospective).investigation (retrospective and prospective).

PREGNANCY RISK CATEGORIESPREGNANCY RISK CATEGORIES RESPONSE: RESPONSE:

Labeling of some prescription drugs includes information Labeling of some prescription drugs includes information about the level of risk for the fetus and the extent of about the level of risk for the fetus and the extent of caution necessary in their use. The FDA has established caution necessary in their use. The FDA has established five categories (A, B, C, D, and X) to indicate a drug's five categories (A, B, C, D, and X) to indicate a drug's potential for causing teratogenicity. This format was first potential for causing teratogenicity. This format was first announced in the September 1979 FDA Drug Bulletin. announced in the September 1979 FDA Drug Bulletin. Because of labeling revisions, many products now use Because of labeling revisions, many products now use this format.this format.

A similar, but somewhat expanded, classification system A similar, but somewhat expanded, classification system was adopted by the Australian Drug Evaluation was adopted by the Australian Drug Evaluation Committee (ADEC) in 1989. Germany set forth its own Committee (ADEC) in 1989. Germany set forth its own classification system. classification system.

US FDA Pregnancy Category US FDA Pregnancy Category DefinitionsDefinitions

A - A - Adequate, well-controlled studies in pregnant women fail to Adequate, well-controlled studies in pregnant women fail to demonstrate a risk to the fetus in the first (second, third, or all) demonstrate a risk to the fetus in the first (second, third, or all) trimester(s), and the possibility of fetal harm appears trimester(s), and the possibility of fetal harm appears remote. remote.

B - B - Animal studies do not indicate a risk to the fetus; however, there are Animal studies do not indicate a risk to the fetus; however, there are no adequate, well-controlled studies in pregnant women. OR Animal no adequate, well-controlled studies in pregnant women. OR Animal studies studies have shown an adverse effect on the fetus but adequate, have shown an adverse effect on the fetus but adequate, well-controlled well-controlled studies in pregnant women have failed to studies in pregnant women have failed to

demonstrate a risk to the fetus. Despite the animal findings, the demonstrate a risk to the fetus. Despite the animal findings, the possibility of fetal harm appears remote, if used during pregnancy. possibility of fetal harm appears remote, if used during pregnancy.

C - C - Animal studies have shown that the drug exerts teratogenic or Animal studies have shown that the drug exerts teratogenic or embryocidal effects, and embryocidal effects, and there are no adequate, well-controlled there are no adequate, well-controlled

studies in pregnant women, OR No studies are available in either studies in pregnant women, OR No studies are available in either animals or pregnant women. animals or pregnant women.

D - D - Positive evidence of human fetal risk exists, but benefits in certain Positive evidence of human fetal risk exists, but benefits in certain situations (eg, life-threatening situations or serious diseases for which situations (eg, life-threatening situations or serious diseases for which safer drugs cannot be used or are ineffective) may make use of the safer drugs cannot be used or are ineffective) may make use of the drug acceptable despite its risks. drug acceptable despite its risks.

X - X - Studies in animals or humans have demonstrated fetal abnormalities Studies in animals or humans have demonstrated fetal abnormalities or there is positive evidence of fetal risk based on human experience, or there is positive evidence of fetal risk based on human experience, or both, and the risk clearly outweighs any possible benefit. The drug or both, and the risk clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become is contraindicated in women who are or may become pregnant. pregnant.

Drug classification by risk factorsDrug classification by risk factors

The rating according to FDA classification The rating according to FDA classification does not provide sufficient useful does not provide sufficient useful therapeutic guidancetherapeutic guidance

The characterization of different categories The characterization of different categories of drugs are ambiguous and difficult to of drugs are ambiguous and difficult to evaluate whether reader is physicianevaluate whether reader is physician

The anxiety may even lead to The anxiety may even lead to unnecessary termination of pregnancyunnecessary termination of pregnancy

DrugsDrugs

QUALITY OF DATA

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About 80% pregnant women use prescribed About 80% pregnant women use prescribed or over-the-counter drugsor over-the-counter drugsThe drugs should only be taken when The drugs should only be taken when essential thereby avoiding unnecessary and essential thereby avoiding unnecessary and unknown risks unknown risks The same is obviously applied to social The same is obviously applied to social drugs like tobacco, alcohol and additive drugs like tobacco, alcohol and additive drugsdrugs

Surveillance and monitoringSurveillance and monitoring

International Clearinghouse of Birth Defect International Clearinghouse of Birth Defect Monitoring Systems (1974)Monitoring Systems (1974)

EUROCAT ( European Concerted Action EUROCAT ( European Concerted Action on Congenital Abnormalities and Multiple on Congenital Abnormalities and Multiple Births – 1979)Births – 1979)

ENTISENTIS

In 1990, two networks of Teratology In 1990, two networks of Teratology Information Services were established, Information Services were established, OTIS (USA and Canada) and ENTIS OTIS (USA and Canada) and ENTIS (Europe).(Europe).

They provide information relating to the They provide information relating to the pertinent situation of the person involvedpertinent situation of the person involved

They carry out follow-up studies to learn They carry out follow-up studies to learn about what happened during the course of about what happened during the course of pregnancy and health of the newbornpregnancy and health of the newborn

RecommendationRecommendation Disease have to be treated in all cases! Disease Disease have to be treated in all cases! Disease

without treatment is more risky than appropriate without treatment is more risky than appropriate treatment.treatment.

We should use drugs with well-known effect on We should use drugs with well-known effect on pregnancy without signs of embryotoxicity. It is pregnancy without signs of embryotoxicity. It is not recommended to change quickly a lot of not recommended to change quickly a lot of drugs.drugs.

It is not recommended to use combinations of It is not recommended to use combinations of various drugs. Undesirable effects may be various drugs. Undesirable effects may be multiplayed. multiplayed.

Any woman in reproductive age may be Any woman in reproductive age may be pregnant !!pregnant !!

Drugs classified X according to FDA:Drugs classified X according to FDA:

ThalidomideThalidomide CytostaticsCytostatics Warfarin and other coumarin derivativesWarfarin and other coumarin derivatives Anti-epileptic drugsAnti-epileptic drugs Retinoids Retinoids AlcoholAlcohol AndrogensAndrogens ACE inhibitorsACE inhibitors DiethistilbestrolDiethistilbestrol

Fetal valproate syndromeFetal valproate syndrome

Fetal alcoholic syndromeFetal alcoholic syndrome

Embryopatia caused by retinoid Embryopatia caused by retinoid acid acid

Fetal warfarin syndromeFetal warfarin syndrome

ThalidomideThalidomide

Thalidomide is currently used in France and I Thalidomide is currently used in France and I suppose in other European countries for asuppose in other European countries for alarge number of indications in severe aphtosis, large number of indications in severe aphtosis, leprosy, Behçet and Jessner-Kanoff diseases,leprosy, Behçet and Jessner-Kanoff diseases,cutaneous lupus, multiple myeloma, graft versus cutaneous lupus, multiple myeloma, graft versus host disease. In France, the prescription is limited host disease. In France, the prescription is limited to a restricted panel of hospital physicans under to a restricted panel of hospital physicans under very specific administrative conditions.very specific administrative conditions.

Sirenomelia and caudal Sirenomelia and caudal regression syndromeregression syndrome• It occurs in diabetic It occurs in diabetic

women more oftenwomen more often

CZTISCZTIS