Transcript A “teratogen”, from the Greek root teras, meaning monster or marvel

Teratogenesis
 A “teratogen”, from the Greek root teras, meaning
monster or marvel, is any environmental factor that
causes a structural or functional abnormality in the
developing fetus or embryo. These environmental
agents include
 infections, medications, drugs, chemicals, maternal
metabolites, such as phenylalanine or mechanical
forces.(1-2)
Effects of drugs on the fetus (2)
 the first week after fertilization is the “period of the
zygote”. During this time the most common adverse
effect of drugs is the termination of pregnancy ,
which may occur before the woman even knows
that she is pregnant.
 The second to the eighth week of gestation is
“period of the embryo”. It is mainly during this
period of organogenesis that drugs produce
dramatic and catastrophic structural
malformations.
terminology
Malformation(3)
A primary structural defect arising from a localized error in
morphogenesis. (cardiac septal defects)
Deformation
An alteration in shape or structure of a part that has differentiated
normally. (mostly involving musculoskeletal system and are probably
caused by intrauterine molding, like various forms of clubfoot and
congenital hip dislocation)
Disruption
A structural defect resulting from destruction of a previously normally
formed part. two mechanisms are involved:
1-entanglement followed by tearing apart or amputation (like amniotic
bands)
2-interruptioin of blood supply to a developing part, leading to
infarction, necrosis or resorption of structure distal to the insult.
(like jejunoileal atresia and gastroschisis)
Dysplasia
An abnormal organization of cells and the structural consequences.
( localized like hemangioma, generalized like connective tissue
disorders)
drug
Effect on fetus and neonate
Accutane ) isotretinoin )
Facial-ear anomaly, heart defect, CNS
anomaly
alcohol
Congenital cardiac, CNS, limb
anomalies
carbamazepine
Spina bifida
Carbon monoxide
Cerebral atrophy, microcephaly, seizure
Cocaine/crack
Microcephaly, LBW, IUGR
misoprostol
Arthrogryposis, cranial neuropathies,
equinovarus
phenytoin
neuroblastoma
Warfarin (coumadin)
Fetal bleeding and death, hypoplastic
nasal structures
penicillamine
Cutis laxa syndrome
MATERNAL MEDICATION AND TOXIN EXPOSURE
AND THE FETUS(3)
The effects of drugs taken by the mother vary
considerably, especially in relation to the time
in pregnancy when they are taken and the fetal
genotype for drug metabolizing enzymes.
Miscarriage or congenital malformations result
from the maternal ingestion of teratogenic
drugs during the period of organogenesis.
Maternal medications taken later, particularly
during the last few weeks of gestation or during
labor, tend to affect the function of specific
organs or enzyme systems, and they adversely
affect the neonate rather than the fetus .
Diagnosis time
The effects of drugs may be evident immediately in the
delivery room or later in the neonatal period, or they may
be delayed even longer.
The administration of diethylstilbestrol during
pregnancy has resulted in vaginal adenosis and vaginal
adenocarcinoma in females in the 2nd or 3rd decade. In
addition to in utero carcinogenesis, various reproductive
problems have been reported in these women, including
cervical anomalies and premature births, ectopic
pregnancies, and spontaneous pregnancy loss.
Impact of genetic
Evidence has confirmed an interaction between genetic factors and
susceptibility to certain drugs or environmental toxins.
•Phenytoin teratogenesis may be mediated by genetic
differences in the enzymatic production of epoxide
metabolites; specific genes may influence the adverse
effects of benzene exposure during pregnancy.
•Growth-restricting effects of smoking on the fetus is
influenced by
polymorphisms of genes encoding enzymes that
metabolize the polycyclic aromatic hydrocarbons in
cigarette smoke .
Drug use in pregnancy
Often the risk of controlling maternal disease must be balanced
with the risk of possible complications in the fetus.
The majority of women with epilepsy have normal fetuses.
Nonetheless, several commonly used antiepileptic drugs (AEDs) are
associated with congenital malformations.
Infants exposed to valproic acid may have multiple anomalies
including neural tube defects, hypospadias, facial anomalies,
cardiac anomalies, and limb defects. In addition, they have lower
developmental index scores compared to those unexposed infants
or those exposed to other commonly used AED.
Radiation(3)
Accidental exposure of pregnant women to radiation is a
common cause for anxiety about whether the fetus will
have birth defects or genetic abnormalities. It is unlikely
that exposure to diagnostic radiation will cause gene
mutations; no increase in genetic abnormalities has been
identified in the offspring exposed as unborn fetuses to
the atomic bomb explosions in Japan in 1945.
Maximum safe dose of radiation in
pregnancy
The recommended occupational limit of maternal exposure to
radiation from all sources is 500 mrad for the entire 40 wk of a
pregnancy.
The limited data on human fetuses show that large doses of
radiation (20,000-50,000 mrad) are harmful to the central
nervous system, as evidenced by microcephaly, mental
retardation, and IUGR. Leukemia is another risk.
Therapeutic abortion is often recommended when exposure
exceeds 10,000 mrad.
It is more likely that a human fetus will be exposed to 1,0003,000 mrad, an amount not shown to cause malformations.
Whether this level of fetal exposure is associated with an
increased risk for childhood cancer or leukemia is
controversial.
Maternal PKU
Mental retardation, hypertonia, low birth weight,
microcephaly, cardiac defects, spontaneous abortion.
Multiple malformation vs sequence
The pattern of multiple anomalies that occurs when a single
primary defect in early morphogenesis produces multiple
abnormalities through
a cascading process of secondary and tertiary errors in
morphogenesis
is called a sequence.
When evaluating a child with multiple anomalies, the physician must
differentiate multiple anomalies secondary to a single localized
error in morphogenesis (a sequence) from a multiple malformation
syndrome. In the former, recurrence risk counseling for the
multiple anomalies depends entirely on the risk of recurrence for
the single localized malformation.
The Robin malformation sequence is a pattern of multiple anomalies
produced by mandibular hypoplasia. Because the tongue is
relatively large for the oral cavity, it drops back (glossoptosis),
blocks closure of the posterior palatal shelves, and causes a V-shaped
cleft palate. There are numerous causes of mandibular hypoplasia, all
of which result in characteristic features of Robin sequence.
Fetal alcohol syndrome
1.
2.
3.
4.
5.
Prenatal onset and persistence of growth
deficiency for weight, length, and head
circumference.
Facial abnormalities including short palpebral
fissure, epicanthal folds, maxillary hypoplasia,
micrognathia, and thin upper lips.
Cardiac defects, primarily septal defects.
Minor joint and limb abnormalities including
some restriction in movements and altered
palmar crease pattern.
Delayed development and mental deficiency
varying from borderline to severe.
Cigarette smoking
Low birth weight
danazole
virilization
hyperthermia
Spina bifida
lithium
Ebstein’s anomaly, macrosomia
methyltestosterone
Masculinization of female fetus
Methyl mercury
Minamata disease
Prednisolone
Cleft palate and lip
progesterone
Masculinization of female fetus
Vitamin D
Supravalvular aortic stenosis,
hypercalcemia
misoprostol
Arthrogryposis, cranial neuropathies
amiodarone
Bradycardia, hypothyroidism
Anesthetic agents (volatile)
CNS depression
Aspirin
Neonatal bleeding
Captopril
Transient anuric renal failure,
oligohydramnios
Dexamethasone
Periventricular leukomalacia
fluoxetine
Transient neonatal withdrawal,
hypertonicity
Oxytocin
Hyperbilirubinemia, hyponatremia
isoxsuprine
Ileus, hypoglycemia, hypocalcemia,
hypotension
Pyridoxine
seizure
sulfonylurea
Refractory hypoglycemia
References
1. Avery 2005
2. Fanarof 2006
3. Nelson 2004