Birth defects & prenatal
diagnosis
Birth defects= congenital malformation
=congenital anomalies
Structural, behavioral, functional, & metabolic disorders present at
birth, & ^ study of these disorders is called
teratology or
dysmorphology.
Major structural anomalies occur in 2-3% of liveborn infants &
another 2-3 % are recognized in children by age 5 years to become a
total 4-6%, & it is ^ major cause of infant mortality.
Minor anomalies occur in approximately 15% newborns, ex.
Pigmented spots, these are not determined to health but , in some
cases, are associated with major defects:
(baby with 1 minor anomaly have a 3% chance of major anomaly, 2
minor anomalies->10% chance of major, 3 minor -> 20% chance of
major anomaly)
Types of abnormalities
• Malformations: occur during formation of structures i.e. during
organogenesis(3
rd
-8
th
week of development).
• Disruptions: results in morphological alterations of already formed
structures & are caused by destructive processes for ex. Defects
caused by amniotic bands.
• Deformations: result from mechanical forces that mold a part of ^
fetus over a prolonged period. For ex. Club foot.
• A syndrome: a group of anomalies occurring together that have a
common cause, ex. Down syndrome.
• An association: ^ nonrandom appearance of 2 or more anomalies
that occur together more frequently than by chance alone, but ^
ause is ’t deter i ed, for e . VACTERL ( erte ral, a al, ardia ,
tracheoesophageal, renal, & limb anomalies).
Causes of birth defects
• 1-unknown 40-60%.
• 2-genetic factors (chromosomal or gene mutation) 15%.
• 3-enviromental factors 10%.
• 4-combination of genetic & environmental influences
(multifactorial inheritance ) 20%-25.
Environmental factors
Teratogens:
Factors that cause birth defects.
Principles of teratology:
i.e.
factors that determining ^
capacity of an agent to produce birth defects, which include:
1- Susceptibility to teratogenesis depends on ^ genotype of ^
conceptus, & ^ manner in which this genetic composition
interact with ^ environment.
^ maternal genome is also important with respect to drug
metabolism, resistance to infection, & other biochemical &
molecular processes that affect ^ conseptus.
2-Time of exposure:
susceptibility to teratogens varies
with developmental stage at time of exposure. ^ most important
period for inducing birth defects is ^ period of embryogenesis,
but no stage of development is completely safe.
For ex. Cleft palate can be induced at ^ blastocyst stage (day6),
during gastrulation (day14), at early limb bud stage (5
th
week), or
when ^ palatal shelves are forming (7
th
week).
3- Dose & duration of exposure:
abnormal
development depend on dose & duration of exposure to a
teratogen.
4-
Teratogens act in specific ways (
mechanisms
) on
developing cells & tissues to initiate abnormal embryogenesis
(
pathogenesis
). Mechanisms may involve inhibition of a
specific biochemical or molecular process; pathogenesis may
involve cell death, decreased cell proliferation, or other cell
phenomena.
5-
Manifestations of abnormal development are
death,
malformation, growth retardation, & functional
disorders.
Teratogens include:
1- Infectious Agents:
include a no. of viruses like rubella,
CMV, herpes simplex virus, varicella virus & HIV virus.
Rubella used to be a major problem but this risk is lowered by ^
vaccine giving to ^ women (approximately 85% of women are
vaccinated now). While varicella causes 20% of birth defects,
otherwise HIV & herpes viruses transmitted as a venereal
disease, with a low teratogenic potential.
Other maternal infections include measles, mumps, hepatitis,
influenza viruses may cause malformations.
A complicating factor introduced by these infectious agent is
that most are pyrogenic, & elevated body temperature (
hyperthermia) is teratogenic, causing serious defects like:
anencephaly, spina bifida, mental retardation, cardiac
abnormalities, &others.
Use of hot tubs & saunas can produce sufficient temperature
elevation to cause birth defects.
Toxoplasmosis & syphilis cause birth defects. Poorly cooked
meat; domestic animals especially cats; & feces in contaminated
soil can carry ^ parasite Toxoplasmosis gondii. A characteristic
feature of fetal toxoplasmosis infection is cerebral calcifications.
2-physical agents
• 1- radiation like X-ray which is a potent teratogen, produce
any type of birth defects depending upon ^ dose & ^ stage of
development of ^ conceptus at ^ time of exposure. Radiation
is also mutagenic agent &can lead to genetic alterations of
germ cells & subsequent malformations.
• 2- hyperthermia: as mentioned before.
3- Chemical agents
• ^ Role of chemical agents in ^ production of abnormalities is
difficult to assess for 2 reasons: 1- most studies are
retrospe ti e, rel i g o ^ other’s e or for a histor of
exposure. 2- pregnant women take a large no. of drugs.
• It includes: thalidomide, aminopterin, lithiu , arfari ,…et .
• Isotretinoin , an analogue of vit. A cause a characteristric
pattern of malformations known as isotretinoin or vit. A
embryopathy , this drug is used for treatment of acne, but it
is highly teratogenic & cause any type of malformations.
(See tab 8.1)
4-Hormones
• Includes androgenic agents like synthetic progestins were
frequently used during pregnancy to prevent abortion, oral
contraceptive pills, environmental estrogens( may cause
masculinization of female brain & feminization of male brains)
which is present in industrial purposes & pesticides.
• Endocrine disrupters are exogenous agents that interfere with
^ normal regulatory actions of hormones controlling
developmental processes. Most commonly, these agents
interfere with ^ action of estrogen through its receptors to
cause developmental anomalies of CNS & reproductive
system, such as diethylstilbestrol( used to prevent abortion).
5- Maternal diseases
• 1- Diabetes: cause stillbirth, neonatal death, large infant, &
congenital malformation. Insulin is not teratogenic while oral
hypo glycemic agents such as biguanides & sulfonylureas may
act as teratogens.
• 2- Phenyl ketonuria (PKU) : Mothers with PKU has increase in
serum concentration of phenylalanine, are at risk of having
mental retardation, microcephaly, & cardiac defects.
6- Nutritional deficiencies
Iodine deficiency cause endemic cretinism. However, poor
maternal nutrition prior & during pregnancy contributes to low
birth wt.& birth defects.
7-Obesity
Pregnancy obesity, defined as having body mass index >30
kg/m2 , associated with a 2 -3 fold increased risk of having a
child with neural tube defects. Prepregnancy obesity also
increases risk of having a baby with heart defects, omphalocele,
ultiple a o alies…et .
8-hypoxia
It cause congenital malformations in experimental animals. But
in humans children born in high altitude in are lighter in wt. &
smaller than born near sea level, without gross congenital
anomalies.
9-Heavy metals
Such as organic mercury, cause multiple neurological
problems, which is present mercury-containing fungicides.
Lead has been associated with increased abortions, growth
retardation, & neurological disorders.
Prenatal diagnosis
• Ultrasonography : non-invasive technique either trans-
abdominal, & trans-vaginal. Important parameters revealed
by US include characteristics of fetal age& growth; presence
or absence of congenital anomalies; status of uterine
involvement, including ^ amount of amniotic fluid; placental
position & umbilical blood flow; weather multiple gestations
are present.
Congenital anomalies that can be determined by US include
neural tube defects( anencephaly& spina bifida); abdominal wall
defects such as omphalocele & gastroschiasis; & heart ; & facial
defects, including cleft lip & palate.
2- Maternal serum screening
• A search for biochemical markers of fetal status, include:
1
– alfa-fetoprotein (AFP), is produced by fetal liver, peaks at 14
weeks & leaks into maternal blood via placenta, & then begin to
decline after 30 weeks.
In congenital malformations such as NTD, GIT disorders,
amniotic band syndrome, bladder exstrophy,& sacrococcygeal
teratomas
AFP increases in amniotic fluid &maternal serum.
But its level decreases in other instances; Down syndrome,
trisomy 18, sex chromosome abnormalities, & triploidy. These
conditions associated with lower serum concentrations of HCG&
unconjugated estriol.
3-Amniocentesis
• A needle is inserted trans-abdominally into ^ amniotic cavity
(identified by US), & approximately 20-30 ml of fluid is
withdrawn. This is invasive technique not done before 14
weeks & ^ risk of fetal loss is 1%.
• ^ fluid is analyzed for biochemical factors such as AFP, &
acetylcholinesterase. In addition, fetal cells can be recovered
& used for genetic analysis.
4- Chorionic Villus Sampling
• Inserting a needle trans-abdominally or trans-vaginally into
placental mass & aspirating 5-30 mg of villous tissue.
• Cells may be analyzed immediately, but accuracy of results is
problematic because of ^ high frequency of chromosomal
errors in ^ normal placenta. ^ results is obtained faster than
amniocentesis, ^ risk of fetal loss is2 fold greater than
amniocentesis. This procedure carries an increased risk for
limb reduction defects.
Generally, these pre-natal diagnostic tests are
not used on a routine basis( except US)M but it
may be done if:
1-Advanced maternal age (35 older).
2-Previous family history for a genetic problem
such as having a baby with Down syndrome or
NTDs.
3-^ presence of maternal disease, such as
diabetes.
4-An abnormal US or serum screening test.
Fetal therapy
1-fetal transfusion: in a case of fetal anemia produced by
maternal antibodies or other causes, blood transfusions for ^
fetus can be performed, under US guide, to ^ umbilical vein.
2-fetal medical treatment: treatment for infections , fetal cardiac
arrhythmias, low thyroid function test, & other medical
pro le s, it’s usuall pro ided to ^ other & rea hes to ^ fetus,
but sometimes giving directly to ^ fetus.
3-fetal surgery: performed in well trained centers under guide of
US like placing shunts to remove fluid from organs or cavities, for
ex. Obstructive urinary disease by inserting a shunt into fetal
bladder. Sometimes fetal surgery done while ^ uterus is opened
for repairing defects like diaphragmatic hernias.
quiz
1-draw a diagram showing ^ development of a
villus, during development of trophoblast.
2-
hat’s ^ e
r ologi al origi of eural rest
cells? To what structures do they contribute?