When an embryo is most vulnerable to be attacked
by a teratogens?? Risk of teratogenscity Mother is far away : This is the time
there is no savior to young kid(blastocyst) and blastocyst is vulnerable / prone to be
attacked by drugs/ bad environment . When blastocyst is vulnerable to any attack by drug?? Dose and duration of drug counts!! How early
at what dose of drug?? : When mother is
far away!!!! During
the first 3 days after ovulation development takes place in the fallopian tube(
I call it mother is away!!-not nearby to protect) . At the time of fertilization a pronuclear
stage exists during which the nuclei from the egg and the sperm retain their
integrity within the egg cytoplasm. After the pronuclear fuse the fertilized
egg begins a series of mitotic cell divisions. The two cell stage is reached
about 30 hours after fertilization. With continued division the cells develop
into a solid ball of cells, which reaches the endometrial cavity about 3 days
after fertilization. Thereafter a fluid filled cavity forms within the cell ass
at which time the conceptus is called a blastocyst , The number of cells
increases from about 12 to 32 by the end of the third day to 250 by the sixth
day.
Until about
3 days after conception any cell is to potential that is capable of initiating
development of any organ system. For this reason separation of cells during
this period gives rise to monozygotic twins usually each normal . At the
blastocyst stage cells first begin to differentiate. By this stage o
development the embryo is located in the uterus where implantation occurs 6 to
7 days after conception.
One group of cells forms the inner
cell mass that will ultimately develop into the fetus. Different tissues arise
from each of the three cell layers. Brain nerves and skin develop from the
ectoderm the lining of the digestive tract, respiratory tract and part of the
bladder as well as the liver and pancreas from the endoderm and connective
tissue cartilage muscle blood vessels the heart kidneys and gonads develop from
the mesoderm . The group of cells
forming the periphery of the blastocyst is termed the trophoblast. The placenta
and the fetal membranes develop from this outer cell layer.
Drug 12:-
More information about Alcohol : Each year between 1,000 and 6,000 babies in the United
States are born with fetal alcohol syndrome (FAS) . This is pattern of mental
and physical birth defects that is common in babies of mothers who drink heavily
during pregnancy. Even moderate or
light drinking during pregnancy may harm the baby Anticoagulants Drug
13:- Low –molecular weight heparins may have substantial benefits over
standard unfractionated heparin. The molecules are still relatively large and
do not cross the placenta . The half life is longer allowing for once daily
administration. However enoxaparin is cleared more rapidly during pregnancy so
twice daily dosing is a advised. Low molecular weight heparins have a much more
predictable dose response relationship obviating the need for monitoring of
partial thromboplastin time . There is less risk for heparin induced
thrombocytopenia and clinical bleeding at delivery but studies suggesting less
risk for osteoporosis are preliminary.
The risk of
heparin during pregnancy may not be justified in patients with only a single
remote episode of thrombosis in the past. Certainly conservative measures
should be recommended such as elastic stockings and avoidance of prolonged
sitting or standings.
Drug 14
: Warfarin L: heparin have been discus cussed : Warfarin has been associated with
chondrodysplasia punctata. Which is
similar t the genetically determined conradi-Hunermann syndrome. Warfarin embryopathy occurs in about 5% of
exposed pregnancies and includes nasalhypoplasia bone stippling seen on radiologic examination ophthalmologic abnormalities
including bilateral optic atrophy and mental retardation . Ophthalmologic
abnormalities and mental retardation may occurs even with use only beyond the
first trimester. The risk for pregnancy complications is higher when the mean
daily dose of warfarin is more than 5 mg. Women with mechanical heart valves
especially the first generation valves require warfarin anticoagulation because
heparin is not safe or effective, Heparin treatment is associated with more
thromboembolic complications and more bleeding complications than warfarin
therapy.
Drugs:
15:-Thyroid and Antithyroid Drugs :Prophylthiouracil and methimazole both cross the placenta and may cause some
degree of fetal goiter. In contrast the thyroid hormones triiodothyronine and
thyroxine cross the placenta poorly so fetal hypothyroidism produced by
antithyroid drugs cannot be corrected satisfactorily by administration of
thyroid hormone to the mother. Thus the goal of such therapy during pregnancy
is to keep the mother slightly hyperthyroid to minimize fetal drug exposure. By
the third trimester 3.0% of women no longer need antithyroid medication.
However in
2009 the FDA released a black box warning highlighting serious liver injury
with PTU treatment to a greater extent than methimazole. Some authors are now
advocating treatment with PTU only during the first trimester and switching to
methimazole for the remainder of the pregnancy.
The need for
thyroxin increases in many women with primary hypothyroidism when they are
pregnant as reflected by an increase in serum thyroid stimulating hormone
concentrations. Because hypothyroidism in pregnancy may adversely affect the
fetus possibly by increasing prematurity it is prudent to monitor thyroid
function throughout pregnancy and to adjust the thyroid dose to maintain a
normal TSH level. It is recommended that women with hypothyroidism increase
their levothyroxine dose by about 30% as soon as pregnancy is confirmed and
then have dosing adjustments based on TSH levels.
Take
home message on drugs & teratogenic by Drugs : Illegal drugs, including cocaine, marijuana and Ecstasy, may
cause birth defects and must be stopped if a women contemplates a pregnancy,
medical help may be required to help her .Infections & cog abnormality : Certain infections can cause
birth defects when a woman gets them during pregnancy. About 30,000 babies a
year (about 1 in 150 newborns) in the US are born with a viral infection called
cytomegalovirus (CMV) . About 8,000 infected babies each year develop permanent
disabilities, including mental retardation and loss of vision and hearing . Pregnant
women often get CMV from young children who have few or no symptoms. Sexually
transmitted infections (STIs) : Untreated syphilis can cause stillbirth,
newborn death or bone defects
Biology of embryo & embryopathy: What the
obstetricians need to know: we have to play safe Five weeks after conception
the embryo first begins to assume features of human appearance. The face is
recognizable with the formation of discernible eyes nose and ears. Limbs emerge
from protruding buds digits cartilage and muscles develop . The cerebral
hemispheres begin to fill the drain area and the optic stalk becomes apparent.
Nerve connections are established between the retina and the brain. The
digestive tract rotates from its prior tubular structure and the liver starts
to produces blood cells and bile. Two tubes emerge from the pharynx to become
bronchi and the lungs have lobes and
bronchioles. The heart is beating at 5 weeks and is almost completely developed
by 8 weeks after conception. The diaphragm begins to divide the heart and lungs
from the abdominal cavity . The kidneys approach their final form at this time.
The urogenital and rectal passages separate and germ cells migrate toward the
genital ridges for future transformation into ovaries or testes.
Differentiation of internal ducts begins with persistence of either mullerian
or Wolffian embryos. The embryo increases from about 6 to 33 mm in length and
increases 50 times in weight.
Three things to consider before U
sign the order of “HANG THE EMBRYO TILL
DEATH” !! A hard task indeed!!! : Fight
by artillery/Nave./ by Air force?? Is the arms of stone age (Timing of Exposure),
Dose of drug . & duration exposed and obviously what drug was prescribed-Was
theta two agents alcohol& antiepileptics operating on a single woman w]backed up elderly husband with sperms exhibiting
much telomere damage , increased DNA Fragmentation?? All these need to be addressed before offering a sc judgment.
A hard task indeed to kill an imbrue-hang the embryo to death and sign the handing
order hay prescribing Mifepristone !!!!
The second
principle is that susceptibility of the conceptus to teratogenic agents varies
with the developmental stage at the time exposure. This concept of critical
stages of developmental is particularly applicable to alterations in structure.
It is during the second to the eighth weeks of development after conception –
the embryonic period – that most structural defects occur. For such defects it
is believed that there is a critical stage in the developmental process after
which abnormal embryogenesis cannot be initiated. For example neural tube
defects result from the failure of the neural tubes to close. Given that this
process occurs between 22 and 28 days post conception any exogenous effect on
development must be present at o before this time. The neural tube has five
distinct closure sites that may respond differentially to agents and may
respond differently in timing. Investigation of thalidomide teratogenicity have
clearly shown that effects of the drug differ as function of the developmental
stage at which the pregnant woman took it.
The fourth
principle is irrespective of the specific deleterious agent the final
manifestations of abnormal development are death malformation growth
restriction and functional disorder. The manifestation is thought to depend
largely on the stage of development at which exposure occurs; a teratogen may
have one effect if exposure occurs during embryogenesis and another if the
exposure is during the fetal period. Embryonic exposure is likely to lead to
structural abnormalities or embryonic death; fetal exposure is likely to lead
to functional deficits or growth restriction.
Despite the
importance of teratogen timing on specificity of anomalies a general pattern
usually emerges with respect to any given teratogen. This will be evident
throughout this chapter as we consider various agents. If no pattern is evident
for a purported teratogen, it increases the suspicion that any purported
association is spurious the observation reflecting confounding variables not
recognize and hence not taken into account.
Which drug?? (The
issue of time of ingestion , dose & for what period –for how many days?)
The fifth
principle is that access of adverse environmental influences to developing
tissues depends on the nature of the influence . This principle relates to such
pharmacologic factors as maternal metabolism and placental passage. Although
most clearly understood for chemical agents or drugs the principle also applies
to physical agents such as radiation or heat. For an adverse effect to occur an
agent must reach the conceptus either transmitted indirectly through maternal
tissues or directly traversing the maternal body.
At what does the
offending agent was prescribed?? Dose Effect(The issue of time
of ingestion , dose & for what period –for how many days?)
The final
principle is that manifestations of abnormal development increase in degree
from the no-effect level to the lethal level as dosage increases. This means
that the response may be expected to vary according to the dose duration or
amount of exposure. For most human teratogens, this dose response relationship
is not clearly understood but along with the principle of critical stages of
development these concepts are important in supporting causal inferences about
human reproductive hazards. Data regarding in utero exposure to ionizing
radiation clearly show the importance of dose on observed effects for
teratogens has been noted
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