Developmental Anomalies & Teratology - PowerPoint Presentation

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Developmental Anomalies & Teratology

ANA 204

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Birth defects (congenital anomalies

)

Developmental disorders present at birth. Leading cause of infant mortalityMay be structural, functional, metabolic, behavioral, or hereditary.

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TERATOLOGY: STUDY

OF ABNORMAL

DEVELOPMENTStudies the causes, mechanisms, and patterns of abnormal development. A fundamental concept is that certain stages of embryonic development are more vulnerable to

disruption than

others. Until the 1940s, it was believed that human embryos were protected from environmental agents by fetal membranes and their mothers’ uterine and abdominal walls. In 1941, rubella virus produced severe birth defects In the 1950s, thalidomide produced severe limb defects.

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Causes of birth defects are divided into:

Genetic factors such as chromosome abnormalitiesEnvironmental factors such as drugs and viruses

Multifactorial

inheritance (genetic and environmental factors acting together) For 50% to 60% of birth defects, the etiology is unknown.

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GENETIC FACTORS

Most important causes

of birth defects. Mitosis or meiosis may occasionally malfunction. Chromosomal abnormalitie

s are

present in 6% to 7% of zygotes.Many abnormal embryos never undergo normal cleavage and become blastocysts. Two kinds of changes occur in chromosome complements:Numerical and structural.

Changes

may

affect the

sex chromosomes

and/or the

autosomes.

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Numerical

Chromosomal Abnormalities

Result from nondisjunction, an error in cell division in which there is failure of a chromosomal pair or two chromatids of a chromosome to

disjoin during mitosis or meiosis.

Chromosomal pair or chromatids pass to one daughter cell and the other daughter cell receives neither.Nondisjunction may occur during maternal or paternal gametogenesis. 7

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GLOSSARY OF TERATOLOGIC TERMS

A birth defect is a structural abnormality of any

typeMalformation: A morphologic defect of an organ, part of an organ, or larger region of the body that results from an intrinsically abnormal developmental process. Disruption

: A morphologic defect of an organ, part

of an organ, or a larger region of the body that results from the extrinsic breakdown of, or an interference with, an originally normal developmental process. Deformation: An abnormal form, shape, or position of a part of the body that results from mechanical forces. Dysplasia: An abnormal organization of cells in tissue(s) and its morphologic result(s) -abnormal tissue formation.

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Polytopic

field defect is a pattern of defects derived from the disturbance of a single developmental field.Sequence is a pattern of multiple defects derived from a single known or presumed structural defect or mechanical factor.Syndrome

is a pattern of multiple defects thought to be

pathogenetically related and not known to represent a single sequence or a polytopic field defect.Association is a nonrandom occurrence in two or more individuals of multiple defects not known to be a polytopic field defect, sequence, or syndrome.Dysmorphology is concerned with the diagnosis and interpretation of patterns of structural defects.

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INACTIVATION OF GENES

During embryogenesis, one of the two X chromosomes

in female somatic cells is randomly inactivated.Occurs during implantation. X inactivation is important clinically because it means that each cell from

a carrier

of an X-linked disease has the mutant gene causing the disease, either on the active X chromosome or on the inactivated X chromosome that is represented by sex chromatin.10

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ANEUPLOIDY AND POLYPLOIDY

Changes in chromosome

number. Aneuploidy is any deviation from the human diploid number of 46 chromosomes e.g., 45 or 47.Polyploid is a chromosome number

that is a multiple of the haploid number of 23

other than the diploid number.Principal cause of aneuploidy is nondisjunction resulting in an unequal distribution of one pair of homologous chromosomes to the daughter cells. As a result, the embryo’s cells may be hypodiploid (45, X0 as in

Turner syndrome),

or

hyperdiploid

(usually

47, as

in trisomy 21 or Down syndrome).

Embryos with

monosomy

—missing a chromosome—usually die

.

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Turner

Syndrome (

Monosomy X)Affected individuals have 45, X0Phenotype of Turner syndrome is female.

Secondary sexual characteristics do

not develop in 90% of affected females, and hormone replacement is required. Caused by nondisjunctionPaternal X chromosome is usually missing. 12

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Trisomy

of

AutosomesPresence of three chromosome copies in a chromosome pair is called trisomy. Most common abnormalities of chromosome number.

Caused by

meiotic nondisjunction of chromosomes, resulting in a gamete with 24 instead of 23 chromosomes and subsequently in a zygote with 47 chromosomes.13

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Trisomy

21 or Down syndrome

Trisomy 18 or Edwards syndrome Trisomy 13 or Patau syndrome Trisomy of the autosomes

occurs with increasing frequency as maternal age increases.

Trisomy 13 is the most common chromosomal abnormality in neonates.Infants with trisomy 13 and trisomy 18 are severely malformed and mentally deficient; they usually die early in infancy. Translocation or mosaicism occurs in approximately 5% of the affected children.

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TETRASOMY AND

PENTASOMY

Persons with these abnormalities have four or five sex chromosomes, respectivelyThese chromosome complexes have been reported in females: 48, XXXX and 49, XXXXXIn

males: 48, XXXY, 48,

XXYY, 49, XXXYY, and 49, XXXXY. Extra sex chromosomes do not accentuate sexual characteristicsThe greater the number of sex chromosomes present, the greater the severity of mental deficiency and physical impairment.15

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TRIPLOIDY

Most

common type of polyploidy (69 chromosomes).Fetuses have severe intrauterine growth retardation with severe head-body disproportion.Results from fertilization of an oocyte by two sperms

(

dispermy). Failure of one of the meiotic divisions, resulting in a diploid oocyte or sperm, could also account for some cases.16

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TETRAPLOIDY

Doubling of the diploid chromosome number from 46 to 92 (tetraploidy) probably occurs during the first cleavage division of the zygote.

Division

of this abnormal zygote results in an embryo with cells containing 92 chromosomes. Tetraploid embryos abort very early and often all that is recovered is an empty chorionic sac (once called a “blighted embryo”).

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MOSAICISM (

45, X/46)A person who has at least two cell lines with two or more different genotypes (genetic constitutions) is a mosaic.Either the autosomes

or sex chromosomes may be involved.

Defects are less serious than in persons with monosomy or trisomy.XX mosaic females as in the usual 45, X females. Results from nondisjunction during early cleavage of the zygote.May also result from loss of a chromosome by anaphase lagging

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Structural

Chromosomal Abnormalities

Result from chromosome breakage, followed by reconstitution in an abnormal combination. Chromosome breakage may be induced by various environmental factors, such as ionizing radiation, viral infections, drugs, and chemicals.

The only

two aberrations of chromosome structure that are likely to be transmitted from a parent to an embryo are structural rearrangements, such as inversion and translocation.20

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Deletion

When a chromosome breaks, part of it may be lost.A partial terminal deletion from the short arm of chromosome 5 causes the cri du chat syndrome. Affected infants have a weak cat-like cry,

microcephaly

(small neurocranium), severe mental deficiency,and congenital heart disease. A ring chromosome is a type of deletion chromosome from which both ends have been lost, and the broken ends have rejoined to form a ring shaped chromosome.

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Translocation

Transfer of a piece of one chromosome to a nonhomologous chromosome.If two nonhomologous

chromosomes exchange pieces, it is called a

reciprocal translocation.Does not necessarily cause abnormal development. Persons with a translocation between a number 21 chromosome and a number 14 chromosome, are phenotypically normal. Such persons are called balanced translocation carriers and may produce germ cells with an abnormal translocation chromosome.

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MICRODELETIONS AND MICRODUPLICATION

Two

examples are:Prader-Willi syndrome (PWS), disorder associated with short stature, mild mental deficiency, obesity, hyperphagia (overeating), and

hypogonadism

(inadequate gonadal function).Angelman syndrome (AS), characterized by severe mental deficiency, microcephaly (small neurocranium), brachycephaly (shortness of head), seizures, and ataxic (jerky) movements of the limbs and trunk.PWS and AS are often associated with a visible deletion of band q12 on chromosome 15.

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DUPLICATIONS

Represented

as a duplicated part of a chromosome, within a chromosome, attached to a chromosome or as a separate fragment.Duplications are more common than deletions and are less harmful because there is no loss of genetic material.

Duplication may

involve part of a gene, a whole gene, or a series of genes.24

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INVERSION

Chromosomal

aberration in which a segment of a chromosome is reversed. Paracentric inversion is confined to a single arm of the chromosome

,

whereas pericentric inversion involves both arms and includes the centromere. Carriers of pericentric inversions are at risk of having offspring with abnormalities because of unequal crossing over and malsegregation at meiosis.

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Birth Defects

Caused by

Mutant GenesMutationInvolves a loss or change in the function of a genePermanent, heritable change in the sequence of genomic DNA

.

Deleterious and some are lethal.Rate can be increased by environmental agents, such as large doses of ionizing radiation. An example of a dominantly inherited birth defect— achondroplasiaAutosomal recessive genes manifest themselves only when homozygous; many carriers of these genes (heterozygous persons) remain undetected

.

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Achondroplasia

showing

short stature, short limbs and fingers, normal length

of trunk, bowed legs, a relatively large head, prominent forehead, and depressed nasal bridge.

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Fragile X syndrome

Most commonly inherited cause of moderate mental deficiency. Associated with mental impairment. May account for much of the excess of males in the mentally deficient population.

Human genome comprises an estimated 20,000 to 25,000 genes per haploid set or 3 billion base pairs.

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Genomic

imprinting

is an epigenetic process whereby the female and male germ lines confer a sex-specific mark on a chromosome subregion, so that only the paternal or maternal allele of a gene is active in the offspring.

- Sex

of the transmitting parent will influence expression or nonexpression of certain genes in the offspring. Homeobox genes are a group of genes found in all vertebrates.- Involved in early embryonic development and specify identity and spatial arrangements of body segments

.

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BIRTH DEFECTS CAUSED

BY ENVIRONMENTAL

FACTORSTeratogen is any agent that can produce a birth defect (congenital anomaly) or increase the incidence of a defect in the population.

Environmental factors

, such as infections and drugs, may simulate genetic conditions.High levels of ionizing radiation produce defects of the CNS (brain and spinal cord) and eyes.During this organogenetic period (fourth to eighth weeks), teratogens may induce major birth defects.

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Principles of

Teratogenesis

Dose of the drug or chemicalGenotype (genetic constitution) of the embryoCritical period of development Stage

of development of an embryo when an

agentMost critical period is at cell division, differentiation and morphogenesis. Critical period for brain development is from 3 to 16 weeksDevelopment of permanent teeth may be disrupted by tetracyclines from 18 weeks to 16 years.

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Dose of the Drug or Chemical

Animal research has shown that there is a

dose-response relationship for teratogensGenotype (Genetic Constitution) of the EmbryoThere are genetic differences in response to a teratogen.

Phenytoin

is a well-known human teratogen which develops the fetal hydantoin syndrome. One third of exposed embryos have only some of the birth defects, and more than half of the embryos are unaffected.Determines whether a teratogenic agent will disrupt its development.32

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Drugs as teratogens

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Cigarette

Smoking

Maternal smoking during pregnancy is a well-established cause of intrauterine growth restriction (IUGR).Low birth weight is

the chief predictor

of infant death.Infants present with conotruncal heart defects and limb deficiencies urinary tract anomalies, behavioral problems.NicotineConstricts uterine blood vessels, causing a decrease in uterine blood flow, lowering the supply of oxygen and nutrients available to the embryo/fetus

from the

maternal

blood.

Impairs

cell growth

and mental development. High levels

of

carboxyhemoglobin

,

appear

in the maternal and fetal blood and

may alter

the capacity of the blood to transport oxygen.

Chronic

fetal

hypoxia may occur

and affect fetal growth and development.

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Alcohol

Infants born

to chronic alcoholic mothers exhibit prenatal and postnatal growth deficiency, mental deficiency, and other defects.Microcephaly (small neurocranium), short

palpebral

fissures, epicanthal folds, maxillary hypoplasia, short nose, thin upper lip, abnormal palmar creases, joint defects, and congenital heart disease are also present in most infants. This pattern of defects—fetal alcohol syndrome (FAS).Cognitive impairment,

behavioral

problems and

neurodevelopmental

impairments

.

Preferred term for the whole range of

prenatal alcohol

effects is

fetal alcohol spectrum disorder (FASD

).

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Androgens and

Progestogens

Progestogens and progestins induce some or all the biologic changes produced by progesteroneHave

androgenic (

masculinizing) properties that may affect the producing masculinization of the external genitaliaThe infants of mothers who had taken progestogen-estrogen birth control pills during the critical period of development exhibited

the

VACTERL

syndrome -

Vertebral

, Anal, Cardiac, Tracheal, Esophageal, Renal, and Limb anomalies.

Diethylstilbestrol (DES) is a human

teratogen

.

Males who were exposed to DES in

utero

,

before

the 11th week of

gestation presents with

epididymal

cysts

and

hypoplastic

(underdeveloped) testes

.

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Antibiotics

Tetracyclines

Cross the placental membrane and are deposited in the embryo’s bones and teeth at sites of active calcification. During the fourth to ninth months of pregnancy may also cause

tooth defects (e.g., enamel

hypoplasia), yellow to brown discoloration of the teeth, and diminished growth of long bones. Long-term tetracycline therapy during childhood can affect the permanent teeth.Streptomycin and dihydrostreptomycinDeafness has been reported in infants of mothers who have been treated with high doses.

Penicillin

Used during

pregnancy and appears to be

harmless to

the human embryo and fetus.

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Anticoagulants

All

anticoagulants except heparin cross the placental membrane and may cause hemorrhage in the embryo or fetus. Warfarin and other coumarin

derivatives are antagonists of vitamin K. Warfarin is definitely a teratogen; there are reports of infants with hypoplasia of the nasal cartilage, stippled epiphyses, CNS defects ,mental deficiency, optic atrophy, and microcephaly.Heparin is not a teratogen

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Anticonvulsants

Trimethadione

Fetal trimethadione syndrome present growth retardation, developmental delay, V-shaped eyebrows, low-set ears, cleft lip and/or palate, and cardiac, genitourinary,

and limb

defects. PhenytoinDefects consists of IUGR, microcephaly, mental deficiency, ridged frontal suture, inner epicanthal folds, eyelid ptosis, broad depressed nasal bridge, nail and/or distal phalangeal hypoplasia, and hernias.Valproic

acid

Drug

of choice

for epilepsy

Defects consist of craniofacial, heart, limb defects, and postnatal cognitive

developmental

delay, neural

tube defects -

spina

bifida

cystica

.

Phenobarbital

Might be

a safe antiepileptic drug for use during

pregnancy

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Antineoplastic

AgentsTumor-inhibiting chemicals are highly teratogenic because these agents inhibit mitosis in rapidly dividing cells. Results in intrauterine death of the embryos.

Busulfan

and 6-mercaptopurine produced multiple severe abnormalities, but neither drug alone appears to cause major defects.MethotrexateMultiple skeletal and other birth defects40

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Corticosteroids

Low

doses of corticosteroids, including cortisone and hydrocortisone do not induce cleft palate May increase risk of fetal bleeding and premature closure of the ductus arteriosus

.

Angiotensin-Converting Enzyme InhibitorsCauses oligohydramnios, fetal death, hypoplasia of the bones of the calvaria, IUGR, and renal dysfunction. Insulin and Hypoglycemic DrugsInsulin

Not

teratogenic

in

human embryos except possibly in

maternal insulin coma therapy. Incidence

of birth defects (e.g., sacral agenesis)

is increased in

the offspring of

diabetic mothers

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Retinoic Acid (Vitamin A

)

Isotretinoin (13-cis-retinoic acid), used for treating severe cystic acne, is a known human teratogen. Defects include spontaneous abortion , craniofacial

dysmorphism

(microtia, micrognathia), cleft palate and/or thymic aplasia, cardiovascular defects, and neural tube defects. Vitamin ACauses an increased risk of birth defects among the offspring of women who took more than 10,000 IU of vitamin

A.

Analgesics (

Aspirin and acetaminophen)

Clinical

trials suggest that

large doses

are potentially harmful to the embryo or

fetus.

Use

of single-ingredient acetaminophen during the

first trimester

does not

increase

the risk of

major birth

defects.

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Thyroid

Drugs

Potassium iodide in cough mixtures and large doses of radioactive iodine may cause congenital goiter. Iodides cross the placental membrane and interfere with thyroxin production. They may also

cause thyroid

enlargement and cretinism. Tranquilizers -ThalidomidePresents with meromelia, amelia (absence of limbs), micromelia (abnormally small and/or short limbs), Phocomelia (“seal limbs”).

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Psychotropic

Drugs

Benzodiazepines (diazepam and oxazepam)Drugs cross the placental membrane and is associated with craniofacial anomalies in neonates.

Illicit Drugs (Street drugs

)Hallucinogenic properties. Marijuana is not a human teratogen; it affects fetal length and birth weight. Cocaine - prenatal effects of cocaine include spontaneous abortion, prematurity, IUGR,

microcephaly

, cerebral

infarction,

urogenital

anomalies,

neurobehavioral disturbances, and neurologic abnormalities.

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Methadone

(Treatment of heroin addiction)Infants born to narcotic-dependent women maintained on methadone therapy were found to have CNS dysfunction, lower birth weights, and smaller head circumferences than nonexposed infants.

Lithium

(For bipolar disorders)Birth defects, mainly of the heart and great vessels.

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Environmental Chemicals as

teratogens

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Organic Mercury

High

levels of organic mercury —neurologic and behavioral disturbances resembling cerebral palsy. Severe brain damage, mental deficiency, and blindness.Methylmercury causes cerebral atrophy, spasticity, seizures, and mental deficiency

.

LeadPasses through the placental membrane and accumulates in embryonic and fetal tissues - increased abortions, fetal defects, IUGR, and functional deficits. Polychlorinated BiphenylsProduce IUGR and skin discoloration. 47

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Infectious Agents as

Teratogens

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Embryo

and fetus

are endangered by a variety of microorganisms. Microorganisms cross the placental membrane and enter the embryonic and fetal bloodstream.

Fetal

blood–brain barrier offers little resistance to microorganisms.49

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Rubella (German Measles)

Rubella virus crosses the placental membrane and infects the embryo/fetus.Clinical features of congenital rubella syndrome are cataracts, cardiac defects, and deafness; mental deficiency, chorioretinitis, glaucoma, microphthalmia

, and tooth defects.

Most infants have birth defects if the disease occurs during the first 4 to 5 weeks after fertilization. Risk of defects during the second and third trimesters is low

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Cytomegalovirus (CMV

)

Most common viral infection of the fetusMost pregnancies end in spontaneous abortion in the first trimester. CMV result in severe birth defects: IUGR,

microphthalmia

, chorioretinitis, blindness, microcephaly, cerebral calcification, mental deficiency, deafness, cerebral palsy, and hepatosplenomegaly.51

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Varicella

(Chickenpox)

Varicella and herpes zoster (shingles) are caused by the same virus, varicella-zoster virus, which is highly infectious. Maternal varicella infection during the first two trimesters of pregnancy causes the following birth defects: skin scarring, muscle atrophy,

hypoplasia

of limbs, rudimentary digits, eye and brain damage, and mental deficiency. 52

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Herpes Simplex Virus

Infection of the fetus with this virus usually occurs very late in pregnancy, probably most often during delivery.

Congenital defects include cutaneous lesions, microcephaly, microphthalmia, spasticity, retinal dysplasia, and deficiency.

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Human Immunodeficiency Virus

Retrovirus causes

acquired immunodeficiency syndrome (AIDS).Some of the birth defects are growth failure, microcephaly, and specific craniofacial features. Most cases of transmission of the virus from mother to fetus probably occur at the time of delivery. Breast-feeding increases the risk of transmitting the virus to the neonate.

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Toxoplasmosis (

Toxoplasma

gondii)An intracellular parasite may be found in the bloodstream, tissues, or reticuloendothelial cells, leukocytes, and epithelial cells.

Maternal infection is

acquired by:Eating raw or poorly cooked meat containing Toxoplasma cystsContact with infected domestic animals (usually cats) or infected soilT. gondii organism crosses the placental membrane and infects the fetus, causing

destructive changes in the

brain and

eyes (

chorioretinitis

) that result in

mental deficiency, microcephaly

,

microphthalmia

, and hydrocephaly.

Death

follow

infection during

the early stages of pregnancy

.

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Congenital

Syphilisa

(Treponema pallidum)Rapidly crosses the placental membrane as early as 6 to 8 weeks of development. Primary maternal infections (acquired during pregnancy)Nearly always cause serious fetal infection and birth defects

Secondary maternal infections (acquired before pregnancy)

Seldom result in fetal disease and birth defects. Early fetal manifestationsCongenital deafness, abnormal teeth and bones, hydrocephalus, and mental deficiency.Late fetal manifestations Destructive lesions of the palate and nasal septum, dental abnormalities, and facial defects 56

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Radiation as a

Teratogen

Severity of damage is related to the absorbed dose of radiation, the dose rate, and the stage of development when the exposure to radiation occurs.Growth retardation, microcephaly

,

spina bifida cystica, pigment changes in the retina, cataracts, cleft palate, skeletal and visceral abnormalities, and mental deficiency. Large doses of radiation (>25,000 mrad) are harmful to the developing CNS.

Obstetric

ultrasonography

indicates

that there are no confirmed

harmful effects

on the fetus from the use of routine

diagnostic ultrasound

examination.

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Maternal Factors as Teratogens

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Diabetes mellitus

Associated

with an increased rate of spontaneous miscarriages and a higher incidence of birth defects. - Neonates are usually large (macrosomia), with

prominent

fat pads over the upper back and lower jaw, brain anomalies, skeletal defects, sacral agenesis, and congenital heart defects. Phenylalanine hydroxylase deficiency (phenylketonuria and hyperphenylalaninemia)Microcephaly, cardiac defects and mental deficiency.

Low levels of

folic acid and vitamin B12.

Neural tube defects

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Mechanical Factors as

Teratogens

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Amniotic fluid absorbs mechanical pressures, thereby protecting the embryo from most external trauma.

A reduction in amniotic fluid (

oligohydramnios) may result in mechanically induced deformation of the limbsCongenital dislocation of the hip and clubfoot may be caused by mechanical forces. Reduced mobility of the fetus causes prolonged compression in an abnormal posture. Intrauterine amputations or other anomalies caused by local constriction during fetal growth may result from

amniotic bands—

rings formed as a result of rupture of the amnion during early pregnancy61

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BIRTH DEFECTS CAUSED BY MULTIFACTORIAL INHERITANCE

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BIRTH DEFECTS CAUSED

BY MULTIFACTORIAL

INHERITANCECommon birth defects (e.g., cleft lip with or without cleft palate) are consistent with multifactorial inheritance.Multifactorial inheritance may

be represented

by genetic and environmental factorsMultifactorial traits are often single major defects, such as cleft lip, isolated cleft palate, neural tube defects63