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TERATOLOGY TERATOLOGY

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Page 1: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

TERATOLOGYTERATOLOGY

Page 2: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

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 anomalCongenital anomaliesies are of four clinically are of four clinically significant types: malformation, disruption, significant types: malformation, disruption, deformation and dysplasiadeformation and dysplasia..

Page 3: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

Malformation - definitionMalformation - definition

Congenital malformation are structural defects Congenital malformation are structural defects present at birth.present at birth. They may be gross or They may be gross or microscopicmicroscopic, , on the surface of the body or within 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)

Page 4: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

Birth defectsBirth defects

3% of all live3% of all live--born infants have an major 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

Page 5: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

Birth defectsBirth 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.

Page 6: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

Course of lossesCourse of losses

Page 7: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

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.

Page 8: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

Causes of congenital anomaliesCauses of congenital anomalies

Page 9: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

Anomalies caused by genetic Anomalies caused by genetic factorsfactors

Chromosomal aberrationChromosomal aberrationss are common and are 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 nonusually non--disjunction- error in cell divisiondisjunction- error in cell division

Down syndrom (21) Edwards (18) Patau (13) Down syndrom (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

Page 10: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

Anomalies caused by Anomalies caused by environmental factorsenvironmental factors

TeratogensTeratogens are e are exogeneousxogeneous agents that may cause agents that may cause developmental developmental defectsdefects::

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, toxoplasma, (rubella, cytomegalovirus, herpes, toxoplasma,

syphilis)syphilis) IonizinIonizingg radiation radiation (RTG) (RTG) Maternal factorsMaternal factors (diabetes mellitus, (diabetes mellitus, hyperthermia, hyperthermia,

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

Page 11: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

Basic principles in teratogenesisBasic principles in teratogenesis

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

embryoembryo and mother and mother

Page 12: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

Critical and sensitive periods of Critical and sensitive periods of developmentdevelopment

Page 13: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders
Page 14: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

TeratogenTeratogen

Teratogenesis is process with threshold-level effect.Teratogenesis is process with threshold-level effect. Every chemical substance may be teratogenEvery chemical substance may be teratogenicic. This . This

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

Page 15: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

Dose-response relation in teratologyDose-response relation in teratology

A - afflictA - afflicteded B - malformedB - malformed

Page 16: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

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).

Page 17: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

About 80% pregnant women use prescribed About 80% pregnant women use prescribed or over-the-counter drugsor over-the-counter drugs

The drugs should only be taken when The drugs should only be taken when essential thereby avoiding unnecessary essential thereby avoiding unnecessary and unknown risks and 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

Page 18: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

PPREGNANCY RISK CATEGORIESREGNANCY 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'sfive 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 Because of labeling revisions, many products products now use 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.

Page 19: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

US FDA Pregnancy Category US FDA Pregnancy Category DefinitionsDefinitions

A - A - Adequate, well-controlled studies in pregnant women fail toAdequate, well-controlled studies in pregnant women fail to demonstrate a risk to the fetus in demonstrate a risk to the fetus in the first (second, third, or all) the first (second, third, or all) trimester(s), and the possibility of trimester(s), and the possibility of ffetal harm appears etal 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 no adequate, well-controlled studies in pregnant women. OR Animal Animal studies studies have shown an adverse effect on the fetus but adequate, have shown an adverse effect on the fetus but adequate, wellwell--controlled controlled studies in pregnant women have failed to studies in pregnant women have failed to demonstrate a risk to the fetus. demonstrate a risk to the fetus. Despite the animal findings, the Despite the animal findings, the possibility of fetal harm appears remote, if possibility of fetal harm appears remote, if used during pregnancy. 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 studies in pregnant women, OR No studies are available in either in pregnant women, OR No studies are available in either animals or animals or pregnant women. 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 safer drugs cannot be used or are drugs cannot be used or are ineffective) may make use of the ineffective) may make use of the drug drug acceptable despite its risks. 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, or both, and the risk clearly outweighs any possible benefit. The drug and the risk clearly outweighs any possible benefit. The drug is contraindicated is contraindicated in women who are or may become in women who are or may become pregnant. pregnant.

Page 20: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

DrugsDrugs

QUALITY OF DATA

0

0,05

0,1

0,15

0,2

0,25

0,3

Pro

por

tion

90% 1%

n=2240

Page 21: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

Process of assessing reproductive Process of assessing reproductive or embryo/fetotoxic effect of drugor embryo/fetotoxic effect of drug

A sudden increase in the prevalence of a specific malformation is A sudden increase in the prevalence of a specific malformation is observedobserved

An association is established between the introduction or an An association is established between the introduction or an increased usage of a drug and an increased prevalence of a increased usage of a drug and an increased prevalence of a specific malformationspecific malformation

Drug use must be taken place in the sensitive period for the Drug use must be taken place in the sensitive period for the introduction of that specific malformationintroduction of that specific malformation

Drug or its metabolite suspected of causing malformation has to be Drug or its metabolite suspected of causing malformation has to be proved capable of reaching the embryo or fetusproved capable of reaching the embryo or fetus

It must be established that the drug and not condition (disease) It must be established that the drug and not condition (disease) causes the specific malformationcauses the specific malformation

The finding have to be confirmed by another independent studyThe finding have to be confirmed by another independent study The result of specific laboratory animal studies mightThe result of specific laboratory animal studies might support the support the

epidemiological findings epidemiological findings

Page 22: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

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)

Page 23: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

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

Page 24: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

ENTISENTIS

Page 25: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

Teratology Information Services (TIS) provide information on the possible risks of exposure to

drugs and other exogenous agents during pregnancy and lactation.

Teratology Information Services are consulted by the medical profession and other health care

professionals, some of them counsel lay people as well. Answers provided are specifically oriented

towards individual patients. Detailed knowledge of dose, time of exposure, adverse effects on the

mother related to the exposure, diseases, previous pregnancies, family history of the patient and the

pharmacological and toxicological properties of the agents have to be taken into account to make a

specific risk assessment.A TIS deals with the following types of

inquiries:

TISTIS

Page 26: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

Before pregnancyBefore pregnancy- A couple is planning a pregnancy and is being exposed to drugs/chemicals.- A couple is planning a pregnancy and is being exposed to drugs/chemicals.What is the risk?What is the risk? Should this exposure be changed or stopped?Should this exposure be changed or stopped?Does this exposure decrease fertility?Does this exposure decrease fertility?

During pregnancyDuring pregnancy- A pregnant woman has taken a drug before she realises that she is pregnant.- A pregnant woman has taken a drug before she realises that she is pregnant.What is the risk?What is the risk? Would recommending termination of pregnancy be justified?Would recommending termination of pregnancy be justified?What prenatal diagnostic procedures can be offered?What prenatal diagnostic procedures can be offered?- A drug has to be prescribed to a pregnant woman.- A drug has to be prescribed to a pregnant woman.Is it safe?Is it safe? Is there a less toxic/teratogenic drug with comparable therapeutic Is there a less toxic/teratogenic drug with comparable therapeutic efficacy to which the woman should be transferred?efficacy to which the woman should be transferred?Is the risk of taking a drug greater than the risk of the disease for which the Is the risk of taking a drug greater than the risk of the disease for which the drug is taken?drug is taken? Are there risks acceptable to the patient when compared with Are there risks acceptable to the patient when compared with the spontaneous risk of developmental disorders?the spontaneous risk of developmental disorders?- A pregnant woman has attempted to commit suicide by taking an overdose of - A pregnant woman has attempted to commit suicide by taking an overdose of a drug.a drug.What information should be given to the physician at the emergency What information should be given to the physician at the emergency department?department? Can the appropriate antidote be given to her?Can the appropriate antidote be given to her?- A pregnant woman is addicted to drugs/alcohol.- A pregnant woman is addicted to drugs/alcohol.Do they have an adverse effect on the course of pregnancy?Do they have an adverse effect on the course of pregnancy? What are the What are the effects on fetal development?effects on fetal development? Can neonatal problems be expected or are there Can neonatal problems be expected or are there any long-term consequences for the child?any long-term consequences for the child?

Page 27: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

- A pregnant woman is exposed at work to certain chemicals.What is the risk?Should she continue this work?- A pregnant woman is exposed to an infectious agent.What are the risks of a maternal infection for the fetus?Are techniques available for the diagnosis of a fetal infection and what are the management options?Similar questions are made for non-infectious maternal diseases.- A pregnant woman has been exposed to...What are the risks of certain physical exposures such as heat and radiation (especially x-rays and radioactive materials), vaccinations or environmental pollution?- A man has been exposed to chemicals or has been treated with drugs.Are there any paternally mediated risks for the fetus or baby?

Page 28: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

• After PregnancyA baby is born with a birth defect or a neonatal disorder.Can this be attributed to a drug or chemical to which the mother was exposed before or during pregnancy?

  A drug has to be prescribed to a mother while she is breastfeeding. A A drug has to be prescribed to a mother while she is breastfeeding. A mother uses a prescription drug or is exposed to an other exogenous mother uses a prescription drug or is exposed to an other exogenous agent, while breastfeeding.agent, while breastfeeding.What is the (relative) dose the neonate (infant) is exposed to?What is the (relative) dose the neonate (infant) is exposed to?Is this acceptable for its age?Is this acceptable for its age?What is the treatment of choice during breastfeeding?What is the treatment of choice during breastfeeding?

When you have a specific question. Please check the When you have a specific question. Please check the MembersMembers section for section for the TIS in your area.the TIS in your area.

Page 29: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

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

Page 30: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

QUESTION

REGISTRATION

processing DATABASE actual research

Reprotox Micromedex Shepard TERIS Medline CC

MONOGRAPHS PAPERS ENTIS CZTIS REGISTER

history RISK ASSESMENT status praesens

INTERACTIONS Conclusion

do not follow up follow up

written record ANSWERto 24 hours

Question 1month after birth

ENTIS

Page 31: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

CZTIS - Počet faktorů

0

0,1

0,2

0,3

0,4

0,5

0,6

1 2 3 4 5 6 >6

Počet faktorů

Pro

po

rce

Number of negative factorsNumber of negative factors

Page 32: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

Drugs according to ATC groupsDrugs according to ATC groups

0

0,05

0,1

0,15

0,2

0,25

0,3

A B C D G H J L M N P R V

ATC

Pro

po

rce

Page 33: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

Question to CZTIS in 2003: 125Question to CZTIS in 2003: 125 Psychiatric drugs 23Psychiatric drugs 23 Antibiotics 20Antibiotics 20 Fungicides 3Fungicides 3 Antiviral drugs 4Antiviral drugs 4 Viral diseases with fever 6Viral diseases with fever 6 Antihypertensives 11Antihypertensives 11 AnticoagulantAnticoagulant drugdrug 55 Hyper-/hypothyrHyper-/hypothyroidismoidism 7 7 Epilepsy 5Epilepsy 5 Hormones 9Hormones 9

Vitamines (retinoids) 10Vitamines (retinoids) 10

Vaccination and profylaxy 8Vaccination and profylaxy 8 Tumors 8Tumors 8 Allergy, immunosupression 3Allergy, immunosupression 3 Crohn disease, ulcerative Crohn disease, ulcerative

colitis 4 colitis 4

Clofibrate, statinClofibrate, statinees 4s 4 Breastfeeding 3Breastfeeding 3 Occupational exposition 4Occupational exposition 4 Alcohol and poisoning 4Alcohol and poisoning 4 Alternative drugs 4Alternative drugs 4 Other 6Other 6

Page 34: TERATOLOGY. Teratology  Teratology is the science that studies the causes, mechanisms, and patterns of abnormal development.  Developmental disorders

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 not pregnancy without signs of embryotoxicity. It is not recommended to change quickly a lot of drugs.recommended to change quickly a lot of 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.

AnyAny woman woman in reproductive age in reproductive age may be may be pregnantpregnant !! !!