BIRTH DEFECT AND

TERATOGENESIS
dr. Stefani Harum Sari, Msi.Med
 PENYEBAB PENYAKIT
A. Lingkungan: biologis, fisik, dan kimia
B. Genetik
C. Psikologis dan perilaku
D. Nutrisi
E. Degeneratif
 PATOMEKANISME PENYAKIT
A. Trauma
B. Inflamasi
C. Infeksi
D. Respons imun
E. Gangguan hemodinamik (iskemik, infark, thrombosis,
syok)
F. Proses penyembuhan (tissue repair and healing)
G. Neoplasia
H. Pencegahan secara aspek biomedik
I. Kelainan genetik
J. Nutrisi, lingkungan, dan gaya hidup
 REFERENCES
1. Langman’s Medical Embryology 12th Edition
2. A Textbook of Modern Toxicology 3th Edition
 BIRTH DEFECT
• Birth Defect = Congenital Malformation =
Congenital Anomaly
• Definition : a terminology which describe
structural, behavioral, functional and
metabolic disorders present at birth.
 BIRTH DEFECT

Genetics:
chromosome and
mutant genes
Unknown (40- (28%)
45%)

Environment (3-
Combination 4%)
genetic and
environment (20-
25%)

Twinning (0,5-1%)
TYPES OF ABNORMALITIES

1. Malformation
2. Disruption
3. Deformation
4. Dysplasia
 MALFORMATION
• occur during formation of structures, for example: during
organogenesis
• intrinsically abnormal developmental process in early
pregnancy
• Examples :
polydactyly, cleft lip, heart defects, anal atresia, spina bifida
 DISRUPTION
• Result in morphological alterations of already formed
structures and are caused by destructive processes
• Extrinsically abnormal developmental process, initially normal
• Example : amniotic bands
 DEFORMATION
• Result from mechanical
process that mold apart of
the fetus over a prolonged
period
• Normal reaction on an
abnormal mechanical
force
• Examples : Club foot
 DISPLASIA
• Abnormal cellular
organization
• Examples
local: nevus flammeus,
haemangioma
systemic: ectodermal
dysplasia, osteogenesis
imperfecta
 HISTORY
• I.G. de Saint-Hillaire (1805–1861) - was first
to introduce the term “teratology”,
• Early 1940: congenital defects were caused
primarily by hereditary factors
• W. Lenz (1961): observed linked limb defects to
Thalidomide (sedative drug).
 TERATOGENESIS
• Teratology = Teratos + Logos
teratos , which means “ monster”
• Teratology is the study of abnormal development includes the
causes, mechanisms, and patterns

How
about this ?
Is he scary?
 TERATOGENESIS
• Teratogenesis is the production of an
abnormal organism includes the chemical,
biochemical, and molecular events that lead
to deleterious effects on development
 TERATOGEN
• Agent that increases the occurrence of
structural or functional abnormalities in
offspring when given to either parent before
conception, to the mother during pregnancy, or
to the developing embryo or fetus.
 TERATOGEN
• Affect the developing embryo or fetus
without significant toxicity in the mother

• These agents may include chemicals,

environmental factors, viruses, radiation,
toxic plants, and metabolite deficiencies or
excesses
 PRINCIPLES
Wilson ’ s Principles of Teratogenesis (1959):
1. Susceptibility to teratogenesis depends on the genotype of the
conceptus and the manner in which it interacts with environmental
factors  (G + E Factors)
2. Susceptibility to teratogens varies with the developmental stage at
the time of exposure.
3. Teratogenic agents act in specific ways on developing cells and
tissues to initiate abnormal developmental processes.
4. The access of adverse environmental influences to developing tissues
depends on the nature of the influences.
5. The final manifestations of altered development are death,
malformation, growth retardation, and functional disorder.
6. Manifestations of altered development increase in frequency and in
degree as dosage increases from no effect to 100% lethality.
CRITICAL PERIODS
CRITICAL PERIODS
TERATOGEN

1. Infectious Agents
2. Physical Agents
3. Chemical Agents
4. Hormones
 INFECTIOUS AGENTS
1. CMV (citomegalovirus)
2. Rubella (German Measless)
3. Herpes simplex virus
4. Varicella virus
5. Toxoplasmosis
 CMV
• Mother has no symptoms, but the effects on the fetus can be
devastating
• The infection can cause serious illness at birth and is sometimes
fatal. On the other hand, some infants are asymptomatic at birth,
but develop abnormalities later, including hearing loss, visual
impairment, and intellectual disability.
 RUBELLA
• During trimester 1
• (German Measless) during pregnancy  Congenital Rubella
Syndrome (hearing, eye, cardiovascular and brain defect)
CRS (Congenital Rubella Syndrome)
 PHYSICAL AGENTS
Radiation
• Among women survivors pregnant at the time of the
atomic bomb explosions over Hiroshima and Nagasaki,
28% spontaneously aborted, 25% gave birth to children
who died in their first year of life, and 25% gave birth to
children who had severe birth defects involving the
central nervous system.
• explosion of the nuclear reactor at Chernobyl, which
released up to 400 times the amount of radiation as the
nuclear bombs, has also resulted in an increase in birth
defects throughout the region.
 CHEMICAL AGENTS
1. Thalidomide
2. Phenitoin
3. ACE inhibitors
4. Alcohol
5. Isotretinoin (Vit A)
6. Mercury
DRUGS
CATEROGIES
 THALIDOMIDE
Limb defect
• Meromelia: partial absence of extremities
• Amelia: complete absence of extremities
• Phocomelia: absence of the long bone, rudimentary hand and
feet attached to the trunk
 PHENITOIN
• Anticonvulsant agent
• Cause Foetal Hydantoin Syndrome (FHS) in 10% of
children born to epileptic mothers treated with phenytoin
during pregnancy
• FHS classic (Hanson, 1986):
1) abnormalities of pre- and post-natal growth - this set
includes microcephaly
2) delay in development, and impaired psycho-motor
performance - cases of mental retardation are
common
3) dysmorphic craniofacial features and limb
anomalies
 ACE INHIBITORS
• ACE inhibitors are anti-hypertensive drugs prescribed
to control high blood pressure
• Captopril presents a slight teratogenic risk in the
2nd and 3rd trimesters of human pregnancy; it
causes a high incidence of foetal death in rabbits and
sheep.
• Enalapril also offers a slight teratogenic risk in the
2nd and 3rd trimesters in humans
• Affect the fetal angiotensin renin system which does
not become active until the second trimester
• Fetal hypotension and decreased fetal renal blood
flow cause renal impairment and oligohydramnios
(deficient amniotic fluid)
• Lead to a variety of adverse effects including pulmonary
hypoplasia (incomplete lung tissue development),
hypocalvaria (underdevelopment of the skull), limb
deformities, persistent patent ductus arteriosus
(failure to close fetal bypass duct between descending
aorta and pulmonary artery), and neonatal death
 ALCOHOL
• Induce fetal alcohol spectrum disorder
(FASD): intellectual disability to structural
abnormalities of the brain (microcephaly,
holoprosencephaly), face, and heart.

• Fetal alcohol syndrome (FAS) represents the

severe end of the spectrum and includes
structural defects, growth deficiency, and
intellectual disability
 ALCOHOL
• Alcohol and acetaldehyde can damage developing fetal cells,
impair placental/fetal blood flow, leading to hypoxia
• inhibiting effects on DNA synthesis, placental amino acid
transport, and development of the fetal brain
 ISOTRETINOIN (VIT A)
• Drug for the treatment of cystic acne and other chronic
dermatoses
• Cause isotretinoin embryopathy
• Critical period of exposure is 4 to 10 wk of gestation
• The defects include hydrocephalus, microcephaly,
cerebellar dysgenesis, depressed nasal bridge, microtia or
absent external ears, cleft palate, anomalies of the aortic
arch, cardiac defects (including ventricular septal defect,
atrial septal defect, tetralogy of Fallot), and hypoplastic
adrenal cortex
 HORMONES
1. Androgenic Agents
2. DES
3. Maternal diabetes
4. Maternal obesity
 Androgenic Agents
• Synthetic progestins were frequently used during pregnancy to
prevent abortion
• The progestins ethisterone and norethisterone have
considerable androgenic activity, and many cases of
masculinization of the genitalia in female embryos
• The abnormalities consist: enlarged clitoris associated with
varying degrees of fusion of the labioscrotal folds.
 DES
• Diethylstilbestrol (DES), which was used to
prevent abortion, raised the incidence of
carcinomas of the vagina and cervix in women
exposed to the drug in utero.
 MATERNAL DIABETES
• Disturbances in carbohydrate metabolism during
pregnancy in diabetic mothers cause a high
incidence of stillbirths, neonatal deaths,
abnormally large infants, and congenital
malformations.
 MATERNAL OBESITY
• Prepregnancy obesity, is associated with a
twofold increased risk for having a child with a
neural tube defect.
• Causation has not been determined but may
relate to maternal metabolic disturbances
affecting glucose, insulin, or other factors.
• Prepregnancy obesity also increases the risk for
having a baby with a heart defect, omphalocele,
and multiple congenital anomalies.