SELAMAT

SIANG
 EFFECTS OF POSSIBLE
TERATOGENS SUCH AS
DRUGS, VIRUSES,
RADIATION, AND OTHER
ENVIRONMENT AGENTS

A. A. Gd. Putra Wiradnyana

INTRODUCTION

United States  3 percent of infants have a major

structural malformation that is detectable at birth.
Age 5  3 percent have been diagnosed with a
malformation.
Age 18  another 8 to 10 percent are discovered to
have one or more functional or developmental
abnormalities.
TERATOLOGY

A teratogen  any agent chemicals, viruses,

environmental agents, physical factors, and drugs 
acts during embryonic or fetal development to
produce a permanent alteration of form or function.
Evaluation of potential teratogens :
- The defect must be completely characterized.
- The agent must cross the placenta.
- Exposure must occur during a critical
developmental period  those within the first 8
weeks result in an embryopathy, and after 8 weeks a

fetopathy :
- The preimplantation period.
- The embryonic period .
- Maturation and functional development.
- There must be a biologically plausible association.
- Epidemiological findings must be consistent.
- The suspected teratogen causes a defect in an
animal.
Criteria for proof of human teratogenicity :

- Careful delineation of clinical cases.

- Rare environmental exposure associated with rare
defect, with at least three reported cases  easiest if
defect is severe.
- Proof that the agent acts on the embryo or fetus,
directly or indirectly.
- Proven exposure to agent at critical time(s) in
prenatal development.
- The association must be biologically plausible.
- Consistent findings by two or more
epidemiological studies of high quality:
(a) Control of confounding factors
(b) Sufficient numbers
(c) Exclusion of positive and negative
bias factors
(d) Prospective studies, if possible
(e) Relative risk of three or more
- Teratogenicity in experimental animals,
especially primates
Food and drug administration categories for drugs and
medications :

- Category A  studies in pregnant women have not

shown an increased risk for fetal abnormalities if
administered during the first (second, third, or all)
trimester(s) of pregnancy.
- Category B  animal studies have shown an
adverse effect, but adequate and well controlled
studies in pregnant women have failed to
demonstrate a risk to the fetus during the first
trimester of pregnancy, and there is no evidence of
a risk in later trimesters.
- Category C  animal reproduction studies have
shown that this medication is teratogenic
( embryocidal or has other adverse effect), and there
are no adequate and well controlled studies in
pregnant women.
- Category D  this medication can cause fetal
harm when administered to a pregnant
woman.

- Category X  this medication is

contraindicated in women who are or may
become pregnant.
GENETIC AND PHYSIOLOGYCAL
MECHANISM OF TERATOGENICITY

Teratogens  act by disturbing specific physiological

processes, which leads to cell death, altered tissue
growth, or abnormal cellular differentiation.
Disruption of Folic Acid Metabolism

Several congenital anomalies  from disturbance of

folic acid metabolic pathways  folic acid is
essential for the production of methionine, which is
required for methylation reactions and thus
production of proteins, lipids, and myelin.
Hydantoin, carbamazepine, valproic acid, and
phenobarbital  impair folate absorption or act as
antagonists  they can lead to decreased
periconceptional folate levels in women with epilepsy
and  two to threefold increased risk for fetal
malformations  women with epilepsy should be
given the fewest number of drugs possible during
pregnancy as well as folic acid supplementation .
Fetal Genetic Composition

It is believed that many multifactorial anomalies 

caused by the interaction of environment and certain
altered genes.
Mutation of the gene for methylene tetrahydrofolate
reductase - MTHFR 677C T  neural-tube defects
and other malformations  only when the mother
has inadequate folic acid intake.
Hydantoin, carbamazepine, and phenobarbital are
metabolized by microsomes to arene oxides or
epoxides  these oxidative intermediates normally
are detoxified by cytoplasmic epoxide hydrolase, but
because fetal epoxide hydrolase activity is weak 
oxidative intermediates accumulate in fetal tissue
these free oxide radicals have carcinogenic,
mutagenic, and other toxic effects.
Homeobox Genes

They are regulatory and encode nuclear proteins that

act as transcription factors to control the expression
of other developmentally important genes  they are
essential for establishing positional identity of
various structures along the body axis from the
branchial area to the coccyx.
An example of homeobox gene teratogenicity 
retinoic acid  during embryogenesis  retinoids
such as vitamin A activate genes essential for normal
growth and tissue differentiation retinoic acid is a
potent teratogen that can activate these genes
prematurely  abnormalities in the hindbrain and
limb buds.
Paternal Exposures

Several mechanisms are postulated:

- One is the induction of a gene mutation or
chromosomal abnormality in sperm drug
exposure at any time during the 2 months prior
to conception could result in a mutation.
- A second possibility is that during intercourse a
drug in seminal fluid could directly contact the
fetus.
- And a third is that paternal germ cell exposure
to drugs or environmental agents may alter gene
expression.
EXAMPLES OF KNOWN AND SUSPECTED
TERATOGENS

Alcohol

Lemoine and associates categorized the wide

spectrum ofalcohol related fetal defects  fetal
alcohol syndrome.
Prevalence  0.6 to 3 per 1000 births.
Fetal alcohol syndrome diagnostic criteria :

I. Dysmorphic facial features

a. Small palpebral fissures
b. Thin vermilion border
c. Smooth philtrum
II. Prenatal and/or postnatal growth impairment
III. Central nervous system abnormalities
a. Structural: Head size < 10th percentile,
significant brain abnormality on imaging
b. Neurological
c. Functional: Global cognitive or intellectual
deficits, functional deficits in at least three
domains.
Alcohol related birth defects :

I. Cardiac  atrial or ventricular septal

defect, aberrant great vessels, conotruncal
heart defects.
II. Skeletal  radioulnar synostosis, vertebral
segmentation defects, joint contractures,
scoliosis.
III. Renal  aplastic or hypoplastic kidneys,
dysplastic kidneys, horseshoe kidney, ureteral
duplication.
IV. Eyes  strabismus, ptosis, retinal vascular
abnormalities, optic nerve hypoplasia.
V. Ears  conductive or neurosensory hearing
loss.
VI. Minor  hypoplastic nails, clinodactyly, pectus
carinatum or excavatum, camptodactyly,
"hockey stick" palmar creases, refractive
errors, "railroad track" ears
Dose Effect

Binge drinking  increased risk of stillbirth

If the mothers drank an average of 8 ounces of
alcohol per day  23 percent had a frontal cortex
measurement below the 10th percentile compared
with only 4 percent of nonexposed fetuses.
Anticonvulsant Medications

Valproate  1 – 2 % with monotherapy, 9–12 % with

polytherapy  D.
Phenytoin  5 – 11 %  D.
Carbamazepine  1 – 2 %  D.
Phenobarbital  10 – 20 %  D.
Lamotrigine  4 fold with monotherapy, 10 fold with
polytherapy C.
Topiramate  2%  C.
Levetiracetam  skeletal abnormalities and
impaired growth in animals at doses similar to
or greater than human therapeutic doses.
The abnormalities  fetal hydantoin syndrome
( craniofacial anomalies, fingernail hypoplasia,
growth deficiency, developmental delay, cardiac
defects, clefts ), spina bifida, urinary tract
malformations , neural tube defects, skeletal
abnormalities.
Angiotensin Converting Enzyme ( ACE )
Inhibitors and Angiotensin Receptor Blockers

ACE inhibitors  enalapril, captopril, and

lisinopril  fetotoxic and embryotoxicity  disrupt
the fetal renin-angiotensin system  they may
provoke
prolonged fetal hypotension and hypoperfusion,
thus initiating a sequence of events leading to renal
ischemia, renal tubular dysgenesis, and anuria.
Oligohydramnios  prevent normal lung
development and lead to limb contractures .

Reduced perfusion  growth restriction, relative

limb shortening, and maldevelopment of the
calvarium.

The first trimester  8 percent had major congenital

anomalies predominantly cardiovascular and central
nervous system malformations.
Antifungals

Fluconazole and itraconazole  exposed newborns

had skull abnormalities, cleft palate, humeral-radial
fusion, and other arm abnormalities, limb defects and
other adverse outcomes.
Anti Inflammatory Agents

Nonsteroidal Anti Inflammatory Drugs

( NSAIDs )

The third trimester  decrease fetal urine output and

reduce amnionic fluid volume, presumably by
increasing vasopressin levels and responsiveness to it
 when the drug is taken for longer than 72 hours.
Leflunomide

This is a pyrimidine-synthesis inhibitor used to treat

rheumatoid arthritis  contraindicated in pregnancy
 in animal studies with multiple species,
hydrocephalus, eye anomalies, skeletal abnormalities,
and embryo death have been reported with amounts
given at or below human equivalent exposure.
Antimalarials

Second- or third-trimester use of mefloquine for

asymptomatic malaria treatment  a fivefold
increased risk of stillbirth.
Antimicrobials

Aminoglycosides  gentamicin or streptomycintoxic

 nephrotoxicity and ototoxicity  but this can be
avoided by using lower divided doses.

Chloramphenicol  when given to the preterm

neonate  the gray baby syndrome  cyanosis,
vascular collapse, and death.
Sulfonamides  do not appear to pose any
significant teratogenic risk  hey displace bilirubin
from protein binding sites, raising theoretical
concerns about hyperbilirubinemia in the preterm
neonate if used near delivery.

Tetracycline  yellow-brown discoloration of

deciduous teeth or be deposited in fetal long bones
when used after 25 weeks.
Antineoplastic Agents

Cyclophosphamide  In the first trimester

resulting in cell death and heritable DNA alterations
in surviving cells  the most common fetal
anomalies are missing and hypoplastic digits,
necrosis of limb buds, cleft palate, single coronary
artery, imperforate anus, and fetal growth restriction
with microcephaly.
Methotrexate  methotrexate - aminopterin
syndrome  growth restriction, failure of
calvarial ossification, craniosynostosis,
hypoplastic supraorbital ridges, small posteriorly
rotated ears, micrognathia, and severe limb
abnormalities.
Antivirals

Amantadine  used in pregnancy to treat influenza

infections  the first trimester  cardiac defects.

Ribavirin  treat respiratory syncytial virus

infections in infants and young children  the drug is
highly teratogenic in all animal  category X 
contraindicated for use in pregnancy.

Efavirenz  birth defects  anencephaly, cleft

palate, and microphthalmia.
Bosentan

This is an endothelin receptor antagonist  to treat

pulmonary hypertension  teratogenic in rats,
causing abnormalities of the head, face, and large
blood vessels, and it is also carcinogenic in rats and
mice  category X.
Hormones

The first 9 weeks  the primordial structures that will

become the external genitalia are bipotential .

Between 9 and 14 weeks, the testis secretes androgen

and the male fetus develops a male perineal phenotype.

Because the ovaries do not secrete androgens, the

female fetus continues to develop a female phenotype,
which is completed by 20 weeks.
Exposure to exogenous sex hormones before 7
completed weeks generally  has no effect on
external structures.

Between 7 and 12 weeks  female genital tissue is

responsive to exogenous androgens and exposure 
full masculinization.
Androgens

Fetal effects from early exposure to androgens  is autosomal

recessive congenital adrenal hyperplasia.

Testosterone and anabolic steroids  In adult women 

cause extreme and irreversible virilization, liver
dysfunction, and mood and libido disorders.

Exposure of a female fetus results in varying degrees of

virilization  including labioscrotal fusion after first
trimester exposure and phallic enlargement from later fetal
exposure.
Androgenic Progestins  antenatal exposure to
medroxyprogesterone acetate  virilization of female
fetuses and feminization of male fetuses.

Norethindrone  cause female fetus masculinization

in 1 percent of exposures.

Danazol exposed female fetuses  virilized,

clitoromegaly, fused labia, and urogenital sinus
malformation.
Estrogens

Diethylstilbestrol (DES)  hypoplastic, T-shaped

uterine cavity ( cervical collars, hoods, septa, and
coxcomb ) and "withered" fallopian tubes.

Women  increased risk for poor pregnancy outcomes

related to uterine malformations, decreased endometrial
thickness, and reduced uterine perfusion.

Men  increased risk for epididymal cysts,

microphallus, cryptorchidism, and testicular hypoplasia.
Immunosuppressants

Corticosteroids  hydrocortisone, prednisone, and

other corticosteroids  in animal studies cleft
palate.

Systemic corticosteroids  category D  used in

the first trimester  they are not considered to
represent a major teratogenic risk.
Mycophenolate Mofetil  inosine monophosphate
dehydrogenase inhibitor  to prevent rejection in
recipients of kidney, liver, or heart transplantation,
and autoimmune disease  malformations have
involved the ear and include bilateral microtia, anotia,
and/or atresia of the external auditory canals 
category D.
Iodine Preparations

Contraindicated during pregnancy  it readily

crosses the placenta and is avidly concentrated in the
fetal thyroid by the end of the first trimester.

High doses of radiation  ablate the fetal thyroid as

well as increase the future risk for childhood thyroid
cancer.
Methyl Mercury

Prenatal exposure  disturbances in neuronal cell

division and migration  resulting in a range of
defects from developmental delay and mild
neurological abnormalities to microcephaly and
severe brain damage.
Psychiatric Medications

Lithium  this drug is used for manic depressive

illness  Ebstein anomaly  characterized by a
downward or apical displacement of the tricuspid
valve that leads to atrialization of the right ventricle,
and transient neonatal toxicity ( hypothyroidism,
diabetes insipidus, cardiomegaly, bradycardia,
electrocardiogram abnormalities, cyanosis, and
hypotonia ).
Selective Serotonin Reuptake Inhibitors (SSRIs) 
citalopram, escitalopram, fluoxetine, fluvoxamine,
paroxetine, and sertraline  there are two types of
neonatal effects  first syndrome ( jitteriness or
shivering, increased muscle tone, feeding or digestive
disturbances, irritability or agitation, and respiratory
distress )  second syndrome ( persistent pulmonary
hypertension in the newborn ).
Retinoids

Vitamin A  to avoid doses higher than the

recommended daily allowance of 5000 IU  these
women had ingested from 10,000 to 300,000 IU of
vitamin A daily during the first 9 weeks of pregnancy
 only three exposed newborns had birth defects 
there was no relationship between vitamin dose and
outcome.
Bexarotene  used to treat refractory T-cell
lymphoma  eye and ear abnormalities, cleft palate,
and incomplete ossification resulted  contraindicated
during pregnancy.

Isotretinoin  one of the most potent teratogens in

common use  a high rate of fetal loss, and the 26
fold increased malformation rate.
Etretinate  to treat psoriasis  associated with
severe anomalies similar to those with isotretinoin .

Tretinoin  used as a gel preparation for topical

treatment of acne vulgaris and as a antineoplastic
therapy for acute promyelocytic leukemia at doses
9000 to 14,000 times greater than those used topically
 this form is likely to be highly teratogenic,
although no affected fetuses have been reported to
date.
Thalidomide

This anxiolytic and sedative drug  most notorious

human teratogen  malformations in approximately
20 percent of fetuses exposed  defects primarily
are limited to structures derived from the
mesodermal layer, such as limbs, ears, cardiovascular
system, and bowel musculature.
Warfarin ( coumadin derivatives )

These anticoagulants  warfarin and dicumarol, are

low molecular weight  readily cross the placenta,
and can cause  significant adverse teratogenic and
fetal effects.

If exposed between the sixth and ninth weeks  the

fetus is at risk for warfarin embryopathy.
During the second and third trimesters  hemorrhage
leading to disharmonic growth and deformation from
scarring in any of several organs.

Defects may be regionally  dorsal midline central

nervous system dysplasia  agenesis of the corpus
callosum, Dandy-Walker malformation, and midline
cerebellar atrophy; ventral midline dysplasia such as
microphthalmia, optic atrophy, and blindness; and
developmental delay and mental retardation.
Recreational Drugs

Amphetamines  in cohort studies the frequencies

of major and minor congenital anomalies were no
greater than those for controls.

Methamphetamines  to treat obesity and narcolepsy

in adults and hyperkinetic children  symmetrical
fetal growth restriction but does not appear to
increase the frequency of congenital anomalies.
Cocaine  topical anesthetic and local
vasoconstrictor  skull defects, cutis aplasia,
porencephaly, subependymal and periventricular
cysts, ileal atresia, cardiac anomalies, and visceral
infarcts.
Heroin  fetal growth restriction, perinatal death,
and several perinatal complications, are common in
the offspring of narcotic addicted mothers.

Methadone  synthetic opioid narcotic structurally

resembles propoxyphene  used primarily as
maintenance therapy for narcotic addiction 
congenital anomalies were not increased above
background in cohort studies.
Marijuana  there is no evidence, however, that
marijuana is associated with human anomalies  the
birthweight of exposed fetuses has been reported to
be lower in some studies but not others.
Miscellaneous Drugs

Toluene  prenatal abuse is associated with toluene

embryopathy, growth deficiency, microcephaly, and
characteristic facial and hand findings, midface
hypoplasia, short palpebral fissures, wide nasal
bridge, and abnormal palmar creases.
Tobacco

Cigarette smoke  smoking doubles the risk of low

birthweight and increases the risk of fetal growth
restriction two to threefold, hydrocephaly,
microcephaly, omphalocele, gastroschisis, cleft lip
and palate, and hand abnormalities.
VIRAL INFECTION

Fetal Varicella Infection

The fetus may develop congenital varicella syndrome

 chorioretinitis, microphthalmia, cerebral cortical
atrophy, growth restriction, hydronephrosis, and skin
or bone defects
Infection before 13 weeks  0.4 % had neonates
with congenital varicella.

The highest risk was between 13 and 20 weeks  2

% had evidence of congenital varicella.

After 20 weeks gestation  they found no clinical

evidence of congenital infection.
Fetal Effects Mumps Infection

The first trimester  increased risk of spontaneous

abortion.

Infection in pregnancy is not associated with

congenital malformations, and fetal infection is rare.
Fetal Rubeola ( Measles ) Infection

The virus  not appear to be teratogenic  increased

frequency of abortion, preterm delivery, and low-
birthweight neonates with maternal measles.

If a woman develops measles shortly before birth,

there is considerable risk of serious infection
developing in the neonate, especially in a preterm
neonate.
Congenital Rubella Syndrome

Rubella is teratogenic agents known  sequela of

fetal infection being worst during organogenesis.

The first 12 weeks  80 % of pregnant women with

congenital infection.

At 13 to 14 weeks  54 percent, and by the end of

the second trimester  25 %.
Congenital rubella syndrome includes one or more of the
following :

Eye defects  cataracts and congenital glaucoma.

Heart disease  patent ductus arteriosus and
pulmonary artery stenosis.
Sensorineural deafness  the most common single
defect Central nervous system defects  microcephaly,
developmental delay, mental retardation, and
meningoencephalitis.
Pigmentary retinopathy.
Neonatal purpura.
Hepatosplenomegaly and jaundice.
Radiolucent bone disease.
Fetal Respiratory Viruses Infection

Teratogenic effects are controversial  women with a

common cold had a four to fivefold increased risk of
fetal anencephaly.
Adenoviral infection is a common cause of childhood
myocarditis.
Parvovirus Infection

Fetal infection  abortion, nonimmune hydrops, and

stillbirth.

80 % of hydrops  second trimester  22 to 23 weeks.

The critical period for maternal infection leading to fetal

hydrops  13 to 16 weeks.
Congenital Cytomegalovirus Infection

Congenital CMV infection is a syndrome 

growth restriction, microcephaly, intracranial
calcifications, chorioretinitis, mental and motor
retardation, sensorineural deficits, hepato-
splenomegaly, jaundice, hemolytic anemia, and
thrombocytopenic purpura.
Most infected infants are asymptomatic at birth, but
some develop late onset sequelae  hearing loss,
neurological deficits, chorioretinitis, psychomotor
retardation, and learning disabilities.
RADIATION

National Council on Radiation Protection

and Measurement ( NCRP )  it is better do in 14
days before next period for unpregnan woman and
avoid for pregnan woman  10 or 14 day rule.

After radiotherapy  avoid pregnan for 1 – 2 years

 because increase risk recurren cancer after
radiotherapy, and need further therapy.
FETAL RADIATION EFFECTS

Save range dose for the fetal  0,05 Gy.

Dose > 0,5 Gy  radiation during organogenesis

period  abortion, IUGR, congenital malformation,
microcephaly, and mental retardation.
TERIMA KASIH