Genetics and Teratology

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The key takeaways are that genetics is the study of heredity and variation in organisms, and looks at how traits are passed from parents to offspring. Mendel conducted experiments with pea plants and discovered the laws of inheritance.

The principles of genetics include heredity, which is the transfer of characters from parent to offspring, and variation, which are the differences found between individuals of the same species. Genetics also looks at genes, genetic variations, and traits.

Mendel discovered the laws of inheritance through his experiments with pea plants. He found that traits are passed unchanged from parents to offspring, and that different traits can assort independently of each other during reproduction.

Genetics and Teratology

Genetics is a branch of biology concerned with the study of genes, genetic


variations and hereditary in organisms.
Father of genetics-Gregor Johann Mendel.
The term genetics was coined by Bateson in 1906.
Genetics is the study of principles and mechanisms of hereditary and variations.
Variations are the differences found in morphology, physiology, cytology and
behavioristic traits of an individual belonging to same species and appearing in
progeny.
Variations occur due to
a) Reshuffling of genes
b) Crossing over
c) Combining of chromosomes during gamete formation.
Heredity: it is the study of transfer of characters from parent to offspring from one
generation to the next.
The physical basis of heredity is gene whereas the chemical basis is dealt with
DNA.
*Pre mendalian view
This type of inheritance deals with “theories of blending inheritance”. Which was
proposed by kolruter and Nuclin.
In this there will blending of the characters and not the sex and the colour the
children i.e. blending of characters of two parents.
In most of the cases the progeny will be resembling the grand parents.
Mendalian inheritance:
Mendel was the first one to reveal the mystery of heredity by his interest in
breeding of garden peas.
Though his experiment results were read out in ‘natural history society of brunn’
he did not got any recognition throughout his life
After Mendel scientist T H MORGAN put forward the concept of genes in heredity
during 2nd world war later many scientists with their experiments lead their
pathway to the origin of molecular genetics.
Mendel was the 1st person to propose the transfer of characters from one generation
to the next i.e. Inheritance.
He was a son of farmer cultivating peas
Mendel was an Austrian monk worked on peas
Mendel considered 7 traits
Colour of flower
Flower position
Seed colour
Seed texture
Height
Pod colour
Pod appearance

Mendel conducted crossing experiment between true breeding plants for these 7
traits by emasculations and reciprocal crosses.
A cross between 2 parents differing in single trait is monohybrid cross.
A cross between 2 parents differing in 2 traits is di hybrid cross.
Based on his experiment Mendel proposed universal laws of inheritance.
Human genetics deals with the variations between humans. These variations are, in
part, reflections of differences that exist at the DNAlevel.

Chromosome features:
(a) Chromatids. Metaphase chromosomes are divided longitudinally into two sister
chromatids
(b) Centromere. The chromatids are held together at the centromere, or primary
constriction, which delineates the chromosome into a short arm (p) and a long arm
(q).
(c) Centromere position. Chromosomes are divided into three groups based on
centromere location.
1) Metacentric chromosomes: (such as chromosome 1), have a central centromere.
2) Sub metacentric chromosomes: (such as chromosome 6), have a centromere that
is displaced from the center.
3) Acrocentric chromosomes: (such as chromosome 13), have a
Centromere near one end.
It consists of 23 pairs of chromosomes: 22 homologous pairs of autosomes and one
pair of sex chromosomes.

The autosomes, by convention, are divided into seven groups:


A (chromosomes I to 3),
B (chromosomes 4 and 5),
C (chromosomes 6 to 12),
D (chromosomes 13 to 15),
E (chromosomes 16 to 18),
F (chromosomes 19 and 20),
G (chromosomes 21 and 22).
The sex chromosomes are XX or XY.
Diagnostic cytogenetic analysis can be performed with metaphase or prometaphase
chromosomes obtained from rapidly dividing cells in tissue culture, or, in some
cases, directly from tissues with high mitotic activity.

Genetic Defects and Mode of Inheritance


The genetic diseases may range from loss or gain of entire
Chromosomes or large chromosome segments (Chromosomal
Abnormalities) to just change of a single base pair within a gene
(Single gene mutations).
a third type of genetic diseases is a process in which a disorder results of
interaction between one or more abnormal genes and environmental factors
(Multifactorial inheritance). I - Single Mutant Gene:
Each single mutant gene will exhibit one of 4 patterns of Mendelian inheritance:
Autosomal recessive X - linked recessive
Autosomal dominant X - linked dominant
Disease is said to be autosomal or X-linked depending on whether the mutant gene
is located on an autosome or X chromosome.
Also, it is classified as recessive when the one mutant gene cannot express the
disease, while dominant when only one mutant gene is sufficient to express the
disease.
I - Autosomal recessive inheritance:

It has the following characteristics:


The parents: Phenotype: usually normal.
Genotype: It is always heterozygous for this abnormal gene i.e.,carrier for the
disease. They usually related to each other (high incidence of consanguinity).
The risk of occurrence and recurrence: The child of 2 heterozygous parents has a
25% chance of being homozygous. Males and females are affected with equal
frequency.
The pedigree: It usually "horizontal" i.e. affected individual are in the same
generations.
The most common diseases: Thalassemia, sickle cell disease, and glycogen storage
disease.

2 - Autosomal Dominant Inheritance:

It has the following characteristics:


The parents: One only (paternal or maternal) has a one dominant mutant gene i.e.
genotype abnormal and also phenotype express the disease. The other is normal as
regard to genotype and phenotype.
There is no relation between consanguinity and this disease.
The risk of occurrence and recurrence: The child of one affected parent has a 50%
chance of being affected.
Males and females are affected with equal frequency.
The pedigree: It tends to be "vertical" i.e. there are affected individuals in several
generations.
The most common diseases are: Hereditary spherocytosis,
Huntington chorea, and achondroplasia.
3 – Sex- linked recessive inheritance

It has the following characteristics:


The parents: The mother is genotypic carrier and phenotypic normal.
The father is genotypic and phenotypic normal. There is no relation between
consanguinity and this disease.
The risk of occurrence and recurrence:Fifty % of a carrier mother's sons will be
diseased and 50% of a carrier mother's daughters will be carriers.
The pedigree: It tends to be "oblique" i.e. the affected individuals usually are
carrier mother's brothers and carrier mother's sons.
The most common diseases are: Glucose - 6 - phosphate
dehydrogenase deficiency, hemophilia A and B, and Duchenne
muscular dystrophy. 4 - Sex - Linked Dominant Inheritance:
It is a rare pattern of inheritance. The example of this mode is vitamin D-resistant
rickets.
II - Multifactorial Inheritance: The points that characterize this pattern are:
There is a similar rate of recurrence (2-10%) among all 1st degree relatives. The
risk of recurrence is related to the incidence of the disease.
Some disorders have a sex predilection.
The likelihood that both identical twins will be affected is less than 100%.
The risk of recurrence is increased when multiple family members are affected.
The risk of recurrence may be greater when the disorder is more severe.
The most common diseases are: allergic diseases, pyloric stenosis, and
developmental dislocation of the hips. Ill - Chromosomal Abnormalities:
These disorders are an important cause of mental retardation and congenital
anomalies. They include abnormalities of either chromosome number or structure.
1 - Abnormalities of chromosome number
Human cell, in which number of chromosomes is 23, is called haploid cell.
When the number of chromosomes is multiple of haploid (i.e. 46), the cell is called
euploid.
Cell deviation from these is called aneuploid i.e. it has either extra chromosome
(trisomies i.e., 47 chromosomes) or loss of chromosome (monosomies i.e., 45
chromosomes).
The most common example of abnormalities of chromosomal number
is:
Trisomy 21, Down syndrome (47 +21)
Monosomy, Turner syndrome (45, X.)

2 - Abnormalities of chromosome structure


When a piece of a chromosome is missing, this is called "deletion", while
"translocation" means transfer of chromosomal material from one chromosome to
another.
The most common example of chromosomal structure abnormalities is:
o Translocation, Down syndrome {46+ t (14q –21q)}.
o Deletion, Cri du chat {46, (5p-)}.

Birth defects

Birth defects are typically classified as structural or functional and developmental.

Structural defects are when a specific body part is missing or malformed. The most
common structural defects are:

 heart defects
 cleft lip or palate, when there’s an opening or split in the lip or roof of the
mouth
 spina bifida, when the spinal cord doesn’t develop properly
 clubfoot, when the foot points inward instead of forward

Functional or developmental birth defects cause a body part or system not to work
properly. These often cause disabilities of intelligence or development. Functional
or developmental birth defects include metabolic defects, sensory problems, and
nervous system problems. Metabolic defects cause problems with the baby’s body
chemistry.

The most common types of functional or developmental birth defects include:

 Down syndrome, which causes delay in physical and mental development


 sickle cell disease, which occurs when the red blood cells become misshapen
 cystic fibrosis, which damages the lungs and digestive system
Genetic Counseling
 Genetic counseling (G.C.) is defined as " an educational process that seeks to
assist affected and/or at risk individuals to understand the nature of a genetic
disorder, its transmission and the options available to them in management and
family planning.
G. C is an important form of preventive medicine. It is expensive but it is an
effective way of diminishing society burden of chronic disease, which is far more
expensive. I - Premarital G.C.
1 - General advice
The chance of both parents carrying the same rare recessive gene is greater if they
are related. The likelihood of the patient's disease being recessively inherited is
thus increased in the presence of consanguinity.
2 - Specific advice:
Premarital screening carrier cases of some common recessive disorder e.g.
thalassemia, is an important task. A premarital advice for those carriers may lead to
prevention of such incurable diseases.

II - Preconception G.C.
1 - General advice:
The increasing risk of trisomy with increasing parental age must be put in mind. 2 -
Specific advice:
Parents with previous baby with definite genetic disorder must be informed
about the nature of this disease, the risk of recurrence and the available options,
e.g. family planning if already have children (in the case of autosomal
recessive disorder). Ill – Post conception G.C.
1 - General advice:
Avoidance of any teratogens e.g., radiation, drugs and infections during
pregnancy. 2 - Special advice:
Pregnancy at risk of genetic disorder gets benefit of prenatal diagnosis.
This may include ultrasound, amniocentesis and chorionic villus
sampling and fetal blood sampling.
After a definite diagnosis of a genetic disorder, some disease may get benefit from
intrauterine treatment e.g. hydrocephalus.
 On the other hand genetic indication for interrupting pregnancy is still
controversial (for religious causes) e.g. trisomy. IV - Neonatal Screening
1 - General advice
Universal neonatal screening is helpful for detection of common genetic
disorder in which early detection is mandatory e.g. hypothyroidism.
2 - Specific advice
The high-risk newborn infant for specific genetic disease must be screened early
for this disease, e.g. developmental dislocation of the hip. Prenatal Diagnosis
Definition
1. Prenatal diagnosis is the process that aims at reaching a diagnosis regarding the
presence or absence as well as the nature of a possible genetic or dysmorphic
disorder present in a fetus.
2. Prenatal diagnosis allows the detection of birth defects and genetic disorders
before delivery giving the parents the option of pregnancy termination or
additional time for emotional adjustment. Indications
1. Prenatal diagnosis is indicated in cases with increased risk of birth defect or
genetic disease such as:
1. Women >35 years (risk of Down syndrome)
2. Elevated maternal serum alpha fetoprotein (risk of open defect, e.g. neural tube
defects)
3. Low maternal serum alpha fetoprotein (risk of Down syndrome)
4. Prior history of autosomal trisomy (risk of trisomy)
5. Parents with balanced chromosomal translocation (risk of unbalanced
karyotype). Balanced translocation means translocation of a part of a chromosome
to another chromosome within the same cell so that the genetic material of the
whole cell is not changed.
6. Family history of genetic disorder or carrier parent (risk of specific disorder in
family)
7. Family history of isolated structural defect (risk of same structural defect).
Techniques used in prenatal diagnosis
1-Maternal serum alpha fetoprotein (AFP)
2-Fetal ultrasound
3-Amniocentesis
4-Chorionic villus sampling (CVS)
5-Percutaneous umbilical blood sampling (PUBS)
6-Fetoscopy Trisomy 21
(Down syndrome)
Down syndrome (DS), has a consistent and specific phenotype (mental retardation
and mongoloid facies) and constant genotype (presence of three copies of
chromosome 21). Incidence:
Down syndrome occurs in approximately 1 in 600 births but the chance of
occurrence varies with the mother's age.
The sex ratio at birth is 1.24 males to 1.0 female. Genotypes of Down syndrome:
1 - Meiotic non-disjunction Trisomy 21:
All the cells show an additional No. 21 chromosome, i.e. 47, XX, +21. This type is
resulting frommeiotic non-disjunction.
Approximately 95% of all Down syndrome are of this type.
About 70% of trisomy 21 is born to mothers over 30 years.
However, both parents are usually normal as regards to phenotypes as well as
genotypes.
2 - Translocation Trisomy 21:
All cells show normal number of chromosomes (46), however an extra-
chromosome 21 is attached to another one (13,14, 15 or 21) i.e. 46, XX, +t (14q
21q).
Approximately 4% of Down syndrome is of this type.
The 2 underlying mechanisms of translocation are:
a) Sporadic type: half of translocated Down syndrome arise de
novo in the affected individual. Both parents are usually normal.
b) Inherited type: another half inherited the disease from a
translocation carrier parents i.e. 46, XX, t (14q 21q). 3 - Mosiacism:
The incidence of this is about 1% of Down syndrome. They have various
proportions of trisomy 21 (47, XX, + 21) and normal cells (46, XX) resulting from
mitotic non-disjunction. This group may be of normal intelligence, depending on
the number of trisomic cells present.
The parents are usually normal, however, parental mosiacism had been discovered
in some cases.
Clinical Manifestations:
1 - Early presentations:
There is an increased frequency of prematurity, and birth weight is usually
somewhat decreased.
Prolonged physiological jaundice may be present. 2 - General manifestations:
The head: It tends to be brachycephalic (occipital flattening). Head circumference
is likewise smaller than average. The fontanels may be late in closing. The hair is
often fine and soft and may be sparse. The face is usually rounded with a flat
profile.
The eyes: They have many characteristic signs. The palpebral fissures slant
upward and outward, and epicanthic folds are often present. The epicanthic folds
and flat nasal bridge may give the appearance of hypertelorism, but interorbital
distance is usually not increased. Small white spots, referred to as Brushfield spots,
may be visible on the iris.
Ears: They tend to be small and ear canals may be atretic.
Mouth cavity: High arched palate may be present. In older children the tongue is
often protuberant due to narrow oral cavity. Eruption of the teeth is frequently
delayed and the positioning irregular. The neck short, and the nuchal skin
excessive.
Hands are short, and there is often a single transverse palmar crease (simian
crease) and incurved fifth finger (clinodactyly). A single fifth finger crease is
common. There is often a wide gap between the first and second fingers and toes.
The dermal ridge patterns provide valuable diagnostic evidence.
3 - CNS manifestations:
During the first years of life profound hypotonia and laxity of joints are often
evident but lessen, as the child grows older.
The most significant feature of Down syndrome is varying degrees of mental
retardation. The milestones including speech, locomotion and social behavior are
all decayed. The intelligent quotient (I.Q.) ranges from 20 to 75 with a mean of 50.
Complications of Down syndrome:
1 - Congenital heart diseases (CHD): At least 40% have CHD, of which the most
characteristic are endocardial cushion defects, followed by ventricular or atrial
septal defects.
2 - Gastrointestinal malformation: These include duodenal stenosis or atresia,
esophageal atresia, anal atresia, and megacolon.
3 - Intercurrent infection: Frequent respiratory, eyes and skin infections. Serous
otitis media may end by hearing loss. Down syndrome has a decreased immune
defense mechanism.
4 - Oncology: There is a 10 to 30 fold increased risk of acute lymphoblastic
leukemia compared with the general population.
5 - Sexual development: Males may be infertile owing to interstitial fibrosis of the
testes and hypoplasia of semeniferous tubules.
6 - Neurological complications: In about 10 - 15% of Down syndrome has unstable
atlanto-axial joint with subsequent dislocation and neurological complications.
7 - Congenital hypothyroidism may coexist and requires thyroid replacement.
8 - Ophthalmic complications: refractive errors and keratoconus.

Investigations:
1 - Cytogenetic studies:
Although the clinical picture of DS is often straight forward, cytogenetic analysis
should always be obtained.
This test provides confirmation of the diagnosis as well as determine the genotypes
of DS for accurate genetic counseling.
Chromosomal study can be obtained from any dividing nucleated cell.
Because blood is easy to obtain, cytogenetic studies are usually done on
lymphocytes. If there is a suspicion of mosiacism, fibroblast cytogenetic studies
must be considered.
Karyotyping must be done for diseased infant and for parents. 2 - Laboratory
findings:
Polycythemia in the first days of life has been noted, as well as
transient congenital leukemoid reaction that resolves by age 5 months.
Complete blood pictures and bone marrow examinations are
mandatory when leukemia is suspected. 3 - Imaging studies:
Pelvis X-ray may reveal flattening of the inner edges of the ileum and widening of
the iliac wings.
The second phalanx of the little finger is often small or absent.
Screening lateral cervical radiograph has been recommended at about age 6 years
to diagnose unstable atlanto-axial joint.
Echo-Doppler evaluation is mandatory for all cases even if there are no clinical
cardiac abnormalities

4. Genetic counseling:
i – Preconception:
Advise the mother not to be pregnant in advanced ages to prevent the occurrence
of DS and other genetic disorders. ii - Prenatal:
Pregnant women with the risk of having DS (old age, translocated carrier) may get
benefit from prenatal diagnosis. This procedure can be achieved by:
a. Screening tests: decreased maternal serum alpha - fetoprotein
and unconjugated estriol while increased human chorionic
gonadotropin.
b. Confirmation test: amniocentesis or chorionic - villus sampling for chromosomal
analysis.
c. After definite prenatal diagnosis medical abortion may be indicated in some
countries. iii - Postnatal:
Family with DS must be aware of the nature of the disease and recurrence risk
(RR), which depends upon cytogenetic analysis of infant and parents.
Recurrence risk of Down syndrome due to various cytogenetic patterns:
Infant Parents Recurrence risk
Trisomy 21:
Normal Mosiac (M or F)
1-2% Depends upon degree of mosiacism
Translocation: 14/21 14/21 14/21 21/21
Normal Carrier (mother) Carrier (father) Carrier (M or F)
Slightly increased 10- 15% 3-5 % 100%
Mosiac: Normal Mosiac (M or F)
Slightly increased Depends upon degree of mosiacism
Teratogenesis and Mutagenesis
HISTORY
Teratology, the study of environment-induced malformations, began as a modern
science in the 1930s, with the publication of a set of experiments in which pregnant
pigs were fed a diet deficient in vitamin A.
1 The resulting abnormalities in the offspring demonstrated that mammalian
development, by its residence within the mother, was not as protected as was
previously believed. In fact, the results of these experiments showed that relatively
simple alterations in the environment could have devastating effects on the
embryo. The susceptibility of mammalian embryos to toxicity from xenobiotic
agents was demonstrated in a series of studies in experimental animals with
congeners of biologically important molecules, such as the amino acid mimic
azaserine.
2 A human counterpart to these experiments was reported in the 1950s, when
aminopterin was used in some human pregnancies to produce abortion. Several
malformed children were born after the drug failed to terminate the pregnancies.
3 The thalidomide episode of the early 1960s increased our understanding of
developmental toxicology by providing an example of an agent that produced
minimal toxicity to adults but a high degree of toxicity for the embryo.
Such selective embryotoxicity remains the key element of many experiments
evaluating the toxic potential of drugs used during pregnancy.
It was during the 1960s that regulatory agencies, including the Food and Drug
Administration in the United States, developed requirements for testing drugs in
animals before approval for marketing. Drug studies were required to use doses
high enough to cause maternal toxicity in order to add confidence that a
biologically relevant dose for that
Modern developmental toxicity studies in animals are performed with an
understanding of how each species handles the drug. With the use of current
animal testing protocols, drugs that could produce birth defects in human beings
should be able to be identified.
Both teratogens and mutagens can cause alterations in the structure and
functioning of the body, but the mechanisms differ.
Teratogens cause damage by altering embryonic or fetal development directly.
Mutagens cause changes within the genetic material that may lead to inherited
disease if the germ cells are affected or to cancer if somatic cells are involved.

PRINCIPLES OF TERATOLOGY
Principle 1: Susceptibility to teratogenesis depends on the genotype of the
conceptus and the manner in which it interacts with the environment
Principle 2: Susceptibility to a teratogenic agent varies with the developmental
stage at which the exposure occurs
Principle 3: Teratogenic agents act in specific ways (mechanisms) on developing
cells and tissues to initiate abnormal embryogenesis (pathogenesis)
Principle 4: The final manifestations of abnormal development are death,
malformation, growth retardation, and functional disorder
Principle 5: Access of an adverse environmental agent to developing tissues
depends on the nature of the agent (influences)
Principle 6: The manifestations of deviant development increase in degree as
dosage increases from the no-effect to the lethal level

TERATOGENESIS

A teratogen is an agent that can produce a permanent alteration of structure or


function in an organism after exposure during embryonic or fetal life.
Teratogens include environmental factors, medications, drugs of abuse, and
occupational chemicals. Clinical teratology is concerned with the following:
1. The relationship between the anomalies in a child and teratogenic exposure.
2. The risk of anomalies for a child of a woman who has been exposed to a
teratogen.
3. The risks to a pregnant woman of treatment or exposure to a given agent.
Principles of clinical teratology:
Teratogens act at vulnerable periods of embryogenesis and fetal development.
a. In general, the embryo is most sensitive to damage between 2 and 10 weeks after
conception (4 to 12 weeks after the beginning of the last menstrual period). During
this time, most structures and organs are differentiating and forming. Each
structure has its own period of greatest sensitivity within this time.
b. The first 2 weeks after conception is generally considered to be a period that is
resistant to the induction of malformations by teratogens.
At this point, the embryo consists of few cells, and damage is usually either
repaired completely or results in death of the embryo.
c. By 10 weeks after conception, most structures in the embryo have been formed,
so malformations are unlikely to be produced by subsequent exposures.
Teratogenic factors are thought to be responsible for about 10% of all congenital
anomalies. These factors fall into several groups:
1) Maternal metabolic imbalance: as children of women with
insulin-dependent diabetes mellitus have a risk of congenital
anomalies that is two to three times greater than that of the general
population.
2) Infectious agents can involve the embryo or fetus transplacentally. For
example:
Congenital toxoplasmosis (may be asymptornatic or present
with a variety of abnormalities. Severely affected infants may
exhibit chorioretinitis, hydrocephaly or microcephaly, intracranial calcification,
and mental retardation.
Rubella (German measles) embryopathy produces fetal growth
retardation, hepatosplenomegaly, purpura, jaundice,
microcephaly, cataracts, deafness, congenital heart disease,
and mental retardation.
Congenital cytornegalovirus (CMV) infection may produce fetal growth
retardation, hepatosplenornegaly, hemolytic anemia,
purpura, jaundice, intracranial calcification, and microcephaly.
3) Ionizing radiation causes DNA damage and can injure the
developing embryo.
4) Environmental agents and occupational chemicals:
1. Hyperthermia, regardless of cause, that produces sustained
elevation of maternal body temperature to levels substantially
above normal (e.g., 40 ºC)
2. Lead
5) Drugs of abuse
(1) Alcohol: Classic fetal alcohol syndrome occurs among the
children of women with chronic, severe alcoholism during
pregnancy.
(2) Cocaine: Maternal use of cocaine during pregnancy has been
associated with placental abruption and the occurrence of
vascular disruptions such as encephaloclastic lesions in the fetus.
(3) Medications:
1. Thalidomide exposure in the first trimester of gestation may
produce limb reduction defects, facial malformations, and
other congenital anomalies.
2. Aminopterin and other cytotoxic drugs kill rapidly growing
cells in the fetus and cause growth deficiency and a variety
of other anomalies.
3. An increased rate of congenital anomalies is observed
among the children of epileptic women treated with
anticonvulsant medications during pregnancy.

MUTAGENESIS
A mutagen is an agent that can alter the DNA or chromosomes.

1. While teratogens act only during embryonic or fetal development, mutagens


may act at any time of life. Thus, mutations may occur in the gamete, zygote,
embryo, fetus, child, or adult.
2. Teratogens affect the development of a tissue, organ, or structure. In contrast, a
mutation always affects a single cell.
a) If this single cell is a germ cell, the mutation may be transmitted to subsequent
generations.
b) If a single cell in a very early embryo sustains a mutation, many tissues of the
embryo (including the germ cells) may be affected as embryogenesis progresses.
c) If a single cell in an embryo, fetus, child, or adult sustains a
mutation; only cells derived from the mutated cell will carry the
mutation. Most cells in the individual will not contain the mutation.

SUMMARY:
A teratogen is any plant, food, nutritional state, or physical agent that can
compromise normal fetal development and result in the production of a congenital
mal-formation. Teratogenesis, in its simplest terms, is the destruction of a critical
number of cells in excess of which the fetus is able to restore by later proliferation.
In considering the effects of drugs on pregnancy, it is important to remember the 6
principles of teratology: genetic susceptibility, development stage, mechanisms,
end points, access, and dose response. Keeping these principles in mind will
facilitate critical review of the literature that is relevant to pregnancy management.

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