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TERATOGENIC DRUGS

Setyo Purwono
Bagian Farmakologi & Terapi
Fakultas Kedokteran - UGM

Teratolog
y
Teratology
is the science that studies

the causes, mechanisms, and


patterns of abnormal development.
Developmental disorders present at
birth are called congenital anomalies,
birth defect or congenital
malformation.
Congenital anomalies are of four
clinically significant types:
malformation, disruption,
deformation and dysplasia.

Teratology - terms
Malformation is a primary structural
defect resulting from a localized error of
morphogenesis
Disruption is specific abnormality that
results from disruption of normal
developmental processes. It depends on
time not on agent
Deformation is an alteration in shape /
structure of previously normally formed part
Syndrome is a recognized pattern of
malformati ons with a given etiology.

Anomalies caused by genetic


factors
Chromosomal aberrations are common and
are present in 6 to 7% of zygotes (result
=abort)
Numerical chromosomal
abnormalities usually non-disjunctionerror in cell division
Down syndrom (21) Edwards (18) Patau
(13) Turner (X0), Klinenfelter (XXY)
Structural chromosomal
abnormalities chromosome breaks =
translocation, deletion (cri du chat
syndrome), duplication, inversion.
Mutant genes achondroplasia, fragile-X
syndrome

Anomalies caused by environmental


factors
Teratogens are exogenous agents that may

cause developmental defects.


Drugs ( warfarin, valproic acid, phenytoin,
vitamin A, thalidomide, cytostatic drugs
cyclophosphamide, lithium carbonate)
Chemicals (PCBs : polychlorynated biphenyls,
methyl mercury, alcohols)
Infections (rubella, cytomegalovirus, herpes,
toxoplas ma, syphilis)
Ionizing radiation (RTG: radioisotope
thermoelectric generator)
Maternal factors (diabetes mellitus,
hyperthermia, phenylketonuria, hyper-/hypothyrosis)

Basic principles in
teratogenesis
Critical periods of development
Dosage of the drug or chemical
Genotype (genetic constitution) of
the embryo and mother

Sensitive Period- That broad period of


time when, if an insult occurs, there are
likely to be consequences.

insults may occur over a broad period of time


or in a number of ways

e.g., the neurobehavioral effects due to exposure of


alcohol during last trimester)

Critical Period- A specific period of time


during which, if an insult occurs, a
particular consequ ence will happen
Malformation of ears due to thalidomide
exposure on days 34-38 of PND.

Critical and sensitive periods of


development

Characteristics and Effects of Teratogens

Time of exposure

Worst effects= period when a body part or


organ system is developing.
When is this?

Susceptibility to harm varies

Not all embryos or fetuses are affected in the


same way by the same exposure.

Characteristics of the fetus influence the effects


Studies with identical twins frequently show that one
twin has impairment from a teratogen while the
other doesnt.
Research on FAS shows that ounce/day can cause
neurobehavioral problems in some children, while
some children born to alcoholic mothers dont get
FAS

Characteristics and Effects of


Teratogens

Different teratogens can cause the


same defect (equifinality)

For example: ADHD (attention deficit


hyperactivity disorder) may be caused
by

chronic stress experienced by the mother


during pregnancy
exposure to drugs during pregnancy
exposure to alcohol during pregnancy

Characteristics and Effects of


Teratogens

Single teratogen may cause more


than 1 defect (multifinality)

Rubella may cause blindness,


deafness, and mental impairments
Exposure to alcohol may cause
physical malformations, growth
retardation, and mental retardation.

Characteristics and Effects of


Teratogens

Dose Response (more is worse than less)

FAS- Fetal Alcohol Syndrome

Associated with heavy drinking throughout


pregnancy
physical malformations
may have major mental retardation

FAE- Fetal Alcohol Effects

Associated with binge drinking, or occasional


drinking- Not as heavy, not as often
Behavioral effects- ADHD, less ability to control
emotions

Characteristics and Effects of


Teratogens

Fathers exposure to teratogens also


increases risk
WHY??????

Because sperm take 72 hours to mature and


during this period the sperm are susceptible
to malformations due to environmental
exposures
Tetracycline (discolors the enamel of the
infants teeth).

Typically associated with mom, but it is also true if


dad takes it.

Characteristics and Effects of


Teratogens

Long-term outcomes can be


mediated by postnatal experience

Initial effects seem to be more severe


Effect may be a susceptibility
Long term high quality care and
enriched environment helps
OVERCOME or minimize bad start
HIV Babies with parents who were drug
and alcohol users did better than non.
WHY??

Environmental Teratogens

What are they?


Methyl mercury- Pollutant found in
fish (very high quantities in some
areas of Japan)

Increased birth weight C-Sections


Neurobehavioral effects (ADD, ADHD,
Learning disorder)

Environmental Teratogens

Lead Poisoning- found in old paint


and water pipes

Anemia- treatable
Encephalopathy- abnormal
development of the brain & MR
Young children and infants who are
lead poisoned can get MR- Eating the
paint off the walls

Social Drugs

Alcohol- 43% of alcoholic mothers have FAS


kids (other 57% have FAE)

Full blown FAS:

early exposure (specifically days 19-23)- results in facial


dysmorphology- Diagnostic criteria

repeated exposure, throughout pregnancy (early/late)

wide set eyes (small eyes)


thin upper lip
flat filtrum

microencephaly
mental retardation (mild to severe)
growth retardation (<10% on growth charts)

Late exposure (last trimester)

Decreased birth weight


Hyperactivity
Emotional lability (inability to control emotions/lots of
emotional outbursts)

Social Drugs- Alcohol

MECHANISM- How does it work?

Moms ability to metabolize alcohol is


reduced during pregnancy- decreases as
pregnancy advances
breakdown of alcohol uses extra oxygenreduces the amount that is available to the
developing organism- Occurs by collapsing
the umbilical cord
Alcohol can cross the placenta which impairs
embryonic and fetal development
Fetuss ability to metabolize alcohol is 50% of
moms (so alcohol remains longer at the end
of pregnancy)

Social Drugs

Smoking (nicotine)

Effects

Decreased birthweight
Decreased heart rate
Increased carbon monoxide in moms system,
impairs oxygen exchange and crosses the placentaBook study
increased spontaneous abortions
increased perinatal mortality
increased hyperactivity, ADHD, ADD

Mechanism

reduced oxygen available to the developing fetus

Decreased heart rate and blood pressure

Social Drugs

Caffeine- Not as much known.


Studies have conflicting results.

Increases heart rate


Increases blood pressure
Constricts blood vessels
Dehydrates, so probably reduces the
oxygen supply

Illegal Drugs

Marijuana- small numbers of studiesWHY?????

Moms who smoke during pregnancy

Attention may be impaired


babies are smaller

Moms who smoke during pregnancy:

have better parent-infant relationship at 1 month of


age
have calmer babies
Have better social interactions with the infant

Problem with the internal validity. Why??

Self-selected group may have more relaxed view


of the world, so therefore have more lax
relationship with the child

Illegal Drugs

Cocaine

Effects:

Decreased gestational age


Pre-term, low birth weight
Placental abruption
Increased rates of birth defects- Malformations of
the heart, CNS, gastrointestinal tract
Increased hyperactivity, ADD at school age.

Mechanism: reduced oxygen supply


Recent study with 300 exposed & 300 nonexposed, controlling for SES found that Low
SES had a greater effect on the infant
development than cocaine.

Low B-W and Gest Age

Low birth weight and pre-term birth

Low birth weight= < 2500g or 5.5 lbs


Pre-term birth = < 35 weeks- Not
necessarily bad
Influences on the size of the infant

Mothers ht, wt
Mothers age
Mothers weight at birth
Environmental variables
Nutrition
Birth order

Birth weight

Babies BW

14
40
Maternal Age (in years)

<14 or >40, increased risk

Gestational weight, Birth weight,


and Survival
Low Birth weight & survival
Weight at birth
% survival
1 1 lbs
33%
1 - 2 lbs
67%
2 - 3 lbs
84%
3 3 lbs
91%
>5 lbs
98%
Pre-term birth & survival to 1 year
Gestational age @ birth
<24 weeks
35%
24-25 weeks
63%
26-29 weeks
86%
30-32 weeks
93%
33-36 weeks
98%
37-40 weeks
99.3%
41+ weeks
99.4 %

Course of losses

Testing for teratogenicity


Standardized procedures for testing drugs for
teratogenic potential are used
- They use at least two common mammalian
laboratory
species that are given several different doses of
the
test agent once or several successive days
during
organogenesis and early fetal period
- Coventionally 3 doses are administered; the
highest
causing maternal toxicity
Evaluation of human case reports and
epidemiological investigation (retrospective and

PREGNANCY RISK CATEGORIES RESPONSE:

Labeling of some prescription drugs


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

US FDA Pregnancy Category


Definitions

Adequate, well-controlled studies


in pregnant women fail to
demonstrate a risk to the fetus in
the first (second, third, or all)
trimester(s), and the possibility
of fetal harm appears.

Animal studies do not indicate a risk


to the fetus; however, there are no
adequate, well-controlled studies in
pregnant women. OR
Animal
studies have shown an
adverse effect on the fetus
but
adequate, well-controlled studies in
pregnant women
have failed to
demonstrate a risk to the fetus.
Despite the animal findings, the
possibility of fetal harm appears
remote, if used during pregnancy.

C
Animal studies have shown that the drug
exerts teratogenic or embryocidal effects,
and there are no adequate, well-controlled
studies in pregnant women,
OR No studies are available in either
animals or pregnant women.
D
Positive evidence of human fetal risk
exists, but benefits in certain situations
(eg, life-threatening situations or serious
diseases for which safer drugs cannot be
used or are ineffective) may make use of
the drug acceptable despite its risks.

Studies in animals or humans


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

Recommendation
Disease have to be treated in all cases!
Disease without treatment is more risky
than appropriate treatment.
We should use drugs with well-known
effect on pregnancy without signs of
embryotoxicity. It is not recommended to
change quickly a lot of drugs.
It is not recommended to use
combinations of various drugs.
Undesirable effects may be multiplayed.
Any woman in reproductive age may
be pregnant !!