BIRTH DEFECTS

• Abnormalities of structure, function, or body

metabolism that are present at birth.
• Most babies have parents who are normal and
have no risk factors
• More than 4,000 different known birth defects.
• Leading cause of death in the first year of life.
• Annual incidence about 3%
 BIRTH DEFECTS
• Dependent on:
– Gestational age:
• Embryonic period more susceptible to teratogens.
– Nature of teratogen:
• intensity and duration of the exposure.
• Organ systems have difference in susceptibility
– Difference in the duration and timing of their formation
• Susceptibility varies during foetal life
– First week after fertilisation:
• Many abnormal embryos are spontaneously aborted
• Others implant but fail to establish a successful
pregnancy.
• > 2/3 early pregnancy loss due to Chromosomal errors
 BIRTH DEFECTS
Genetic chromosomal problems:
– gene mutations:
• Aniridia:
–Absence of iris
–PAX6 gene
– chromosomal anomalies
• Structural
• Numerical
–Microcephaly:
»Trisomy 13.
 TERATOGENS
• Teratogens (agents that produce congenital
anomalies):
– Infectious:
• Rubella
– Drugs/pharmaceuticals:
• Thalidomide:
– Environmental factors:
• Ionising radiation
– Physical agents
– Maternal disease
 CRITICAL PERIOD OF SENSITIVITY

• Biochemical differentiation before

morphological differentiation:
– Period of sensitivity precedes the stage of
visible development.
• Brain and skeleton:
– Begins in week three:
– Brain:
• First two years
– Skeletal system:
• Adolescence & early adult-hood
• Teeth:
– Long after birth
– Tetracycline between 18/40 and 16 yrs.
 CRITICAL PERIOD OF SENSITIVITY
• CVS:
– Formation during weeks three and four
– Lengthy and complex developmental phases.
– Highest incidence of birth defects
• External genitalia:
– Weeks eight and nine.
• Foetal period:
– Growth and differentiation continues.
– Major structural defects less likely
– Environmental factors can alter normal development:
• Mechanical forces
• Vascular disruptions
• Drugs
• Maternal disease
 ANOMALY
• Deviation from the expected structure, form,
and or function.
• Minor
• Major
• Deformations
• Disruptions
• malformations.
• May be multiple
 DEFORMATIONS
• Eexternal factors alter normal development:
– mechanical forces
– intrauterine constraint
– lack of foetal movement.
– Can result in defects during the last trimester as the
foetus is bigger and has less free space.
– Can cause:
• distortion of facial structures
• abnormal positioning of the extremities and head
• alterations in joint mobility
• joint dislocations
• nerve palsies
• torticollis
 DISRUPTIONS

• Destruction of normally developed tissues or

organs.
• Caused by external factors
• Amniotic band syndrome
 MALFORMATIONS
• Intrinsic defects
• Major:
– Function
– Cosmetic
– 3%
• Minor:
– Cosmetic
– 14%
– Two or more => look for major.
• Multiple malformations:
– Sequence
– Association
– Syndrome
– often not associated
• May be due to:
– Too little growth
– Too little resorption
– Too much resorption
– Resorption in the wrong place
– Normal growth in an abnormal location
– Local overgrowth of a tissue or structure
 SEQUENCE

• First malformation regulates the emergence

of other malformations
Cleft palate sequence
– Lip:
• Palate
• Teeth
• Nostrils.
• May also occur with deformations and
disruptions.
 ASSOCIATION
• Two or more major congenital anomalies in the same person:
– VACTERL (VATER) association
• Vertebral
• Anal-rectal
• Cardiovascular
• Tracheo-oesophageal
• Renal
• Limb
• 3+ for Dx
– CHARGE association
• Colobomas of the iris and retina (absence or defect of tissue in the
eye)
• Heart defects
• Atresia - choanal
• Retarded growth and development
• Genital anomalies
• Ear anomalies.
 SYNDROMES

• Minor and major malformations with

recognisable pattern from a common cause.
• Categorised according to major finding, such
as:
– Mental retardation
– Short stature.
• More than 1000 syndromes:
– Most rare
– 10% chromosomal
 DYSPLASIA
• Lack of normal organisation of cells into
tissues
– Achondroplasia:
• Fibroblast growth factor receptor 3 gene
• Abnormal cartilage formation
 STRUCTURAL DEFECTS
• Specific body part is missing or formed
incorrectly:
– Heart defects.
– Spina bifida
– Hypospadias.
 METABOLIC DEFECTS
• Inborn problem in body chemistry.
• 1/3,500
• Missing or incorrectly formed enzyme.
• Harmful or even fatal
• Usually no visible abnormalities
• Include:
– Tay-Sachs disease:
• AR genetic disorder
• A member of the sphingolipidoses
• Mutation in HEXA gene on chromosome 15
• No cure or Rx
• Affects the CNS
• Fatal
– Phenylketonuria (PKU):
• Affects the way the body processes protein.
 PRESENTATIONS OF CONGENITAL ANOMALIES
– Visible externally
– Internal
– Microscopic
– Macroscopic
 EPIDEMIOLOGY

• Second most common cause of death in

developed countries.
• 20 % perinatal deaths
• Global prevalence 1.5% to 3%.
• Variation is present:
– Between populations
– Within a populations
– Genetic characteristics of ethnicity
– Geographical location:
• An important environment factor
 EPIDEMIOLOGICAL VARIATIONS
• Neural tube defects closely related to:
– Poverty
– Low intake of folate and other B vitamins.
• Mexico:
– High incidence of poverty
– High frequency of mutations of the MTHFR gene,
which codes for an enzyme in folate metabolism
• Higher incidence of neural tube defects than
many other countries
– Prevalence of hypospadias is lower in Mexico than
in other countries around the world
BIRTH DEFECTS
 CAUSES
• Single gene mutation and specific inheritance pattern:
– About 25%
• Known environmental causes
– About 8%
• Alterations in chromosome structure or number:
– About 7%
• Unknown causes:
– About 60%
• Some causes multi-factorial
 GENETICS
• Dominant inheritance:
– Only one defective gene present
– Achondroplasia
– Marfan syndrome
– Polydactyly
• Recessive inheritance:
– Requires two defective genes
– Tay-Sachs disease
– CF
– CAH
– Microcephaly
 X-LINKED BIRTH DEFECTS
• Defective gene on the X chromosome:
– Hemophilia
– colour-blindness
• Because males have only the one X chromosome a
faulty gene on the X chromosome will cause a
problem:
– They don't have a normal copy of the gene on the
other X chromosome as females.
 CHROMOSOMAL BIRTH DEFECTS
• Too few
• Too many
• Damaged
• E.g:
– Down syndrome:
• Risk increases with maternal age.
• Persons usually have characteristic phenotypes
 CHROSOMAL BIRTH DEFECTS

• Numerical abnormality:
–Non-disjunction
• Aneuploidy
• Polyploidy
• Structural / functional abnormality
• Combination of aneuploid cells with a
haploid cell produces an embryo that is:
–hypodiploid (45) = monosomy
–hyperdiploid (47) = trisomy.
 ANEUPLOIDY
• Monosomic embryos:
– Extremely rare to find a living autosomal
monosomy.
– 97% of sex monosomic embryos die:
• Survivors usually have features of Turner
syndrome (45xo).
 AUTOSOMAL TRISOMIES

• Increasing frequency as maternal age

increases.
• Primarily three syndromes:
– Down
– Edwards’
– Patau’s
 SEX TRISOMIES, TETRASOMY AND PENTASOMY
• Sex trisomy:
– Rarely detected until adolescence as there are no characteristic physical
findings in infants or children. :
– 47xxx
• Females with two masses of X-chromatin / sex chromatin
– 47xyy
• Males showing two fluorescing Y-chromatin bodies
– 47xxy
• Males showing one fluorescing Y-chromatin body
– Small testes
– Hyalinization of seminiferous tubules
– Aspermatogenesis
– Gynaecomastia
• Often tall with disproportionately long lower limbs
• Sex tetrasomy and pentasomy:
– Mentally retarded
– xxxx / xxxxx
– xxyy / xxxyy
– xxxy xxxxy
 POLYPLOIDY
• Multiples of the haploid number.
• Significant cause of spontaneous abortion and early neonatal
death
• Triploidy:
– 69 chromosomes.
– Commonest type.
– Result from:
• Second polar body failing to separate from oocyte
• Dispermy:
– One ovum fertilized by two spermatozoa almost
simultaneously.
• Tetraploidy:
– 92 chromosomes.
– Probably occurs during preparation for first cleavage
division:
• Chromosome division without zygote division
 MOSAICISM
• Two or more cell lines with different
karyotypes in the same individual.
– Example, 45x & 46xx.
• Autosomal / sex
• Less severe than monosomy or trisomy
• Caused by:
– Non-disjunction during early mitotic cleavage
division (mostly).
– Anaphase lagging:
• Chromosomes separate normally
• One is delayed in its migration and is
eventually lost
 STRUCTURAL / FUNCTIONAL CHROMOSOMAL ABNORMALITIES
• Chromosomal breaks (mostly).
• Drugs, viruses, radiation
• Translocation:
– Non-homologous chromosomal transfer:
• One-way or reciprocal.
• Example between # 21 & # 14.
• Does not normally lead to abnormality
• May be just translocation carriers:
– Phenotypically normal.
• 3 % of Downs.
• Deletions:
– Part of the chromosome breaks off and is lost.
– May lead to formation of ring chromosome:
• Some trisomy 18 and Turner syndrome.
– Example Cri du Chat:
• Short arm of chromosome # 5
 STRUCTURAL / FUNCTIONAL CHROMOSOMAL ABNORMALITIES

• Duplications:
– Within a chromosome
– Attached to a chromosome
– Formation of a separate fragment
– More common than deletions
– No loss of genetic material
– Less harmful than deletions.
• Inversion:
– A segment of the chromosome is reversed.
• Paracentric:
– Confined to a single arm
• Pericentric:
– Both arms and the centromere involved.
– Some Downs syndrome
 STRUCTURAL / FUNCTIONAL CHROMOSOMAL ABNORMALITIES

• Isochromosome:
– Centromere divides transversely
– Probably the commonest type of structural
abnormality in the X chromosome.
– Often short with signs of Turner synd:
• Features due to loss of short arm of one of
the X chromosome.
– Autosomal or sex chromosomes:
 CHROMOSOMAL SYNDROMES

• NUMERICAL:
– Down
– Edward
– Patau syndrome
– Turner syndrome = 45 X
– Klinefelter syndrome = XXY
– XYY syndrome
• STRUCTURAL:
– CRI-du-CHAT syndrome
– Angelman syndrome
– Wolf-Hirschhorn syndrome
 GENETIC DEFECTS

• Autosomal Dominant:
• X-linked:
• Nonan syndrome
• Fragil X syndrome
• Ehlers Danlos syndrome
• Muscular dystrophy
• Achondroplasia
– Duchenne’s
• Osteogenesis Inperfecta
– Becker’s
• Marfan syndrome
• Hunter’s disease
• Apert syndrome
• William
• Cruzon syndrome
• Prader-Willi syndrome
• Van der Woode syndrome
• Thrombocytopenia-Absent-Radius
• Polydactyly
syndrome
• Autosomal Recessive:
– Phenylketonuria
– Sickle cell anaemia
– Cystic fibrosis
– Tay-Sachs disease
– Congenital adrenal hyperplasia
– Hurler’s disease
– Smith-LeMli-Oplitz syndrome
– Ellis-van Creveld
 UNKNOWN/UNCLEAR
AETIOLOGY
• UNKNOWN:
– CHARGE SYNDROME
• UNCLEAR:
– Cornellia de Lange syndrome – maybe autosomal
dominant
– Proteus syndrome
 ALCOHOL

Foetal alcohol syndrome (FAS):

• Even moderate consumption ( 2-3 ozs/day ) may produce
the synd.
– Prenatal/postnatal growth retardation
– Multiple anomalies
– MR
– Microcephaly
– Maxillary hypoplasia
– Problems with the eyes, short palpebral fissure
– Problems with the joints, abnormal palmar crease
– CHD- septal defects
– poor coordination
– problems with learning
– short memories
– Cannot be cured or treated
– Can be prevented
 ANTICONVULSANTS
DILANTIN / PHENYTOIN
• Foetal hydantoin synd.
• IUGR
• Microcephaly , ridged metopic sutures
• Broad depressed nasal bridge
• Eyelid ptosis, inner epicantal folds
• MR
• Cleft lip
• Hypoplasia of distal phalanx and nails
• Hernias
• CHD- PS, AS, CoA, PDA
• Vit. K deficiency
 ANTICONVULSANTS
Phenobarbitone:
• Could cause foetal withdrawal in neonates
• Foetal barbiturate syndrome is controversial
• VK deficiency:
– Give mom VK one month before delivery
Valporic acid:
• FA metabolism
• Neural tube
• Craniofacial,
• CVS
 HORMONAL AGENTS
• Androgenic agents:
– Progestins:
• Ethisterone
• Norethisterone
– Testosterone
– Female masculinization:
• Labial fusion, cliteromegaly
• Progestin may cause CHD
• O.C. containing oestrogen & progestin:
– VACTERAL
• DES:
– Probably not teratogenic
– IU exposure linked to adenocarcinoma of the vagina
• Corticosteroid:
– Possibly weak teratogen
– Cleft lip & cardiac defects in some mice
 CYTOTOXIC AGENTS
• Highly teratogenic
• Busulfan
• 6 mercaptopurine
• Thalidomide:
– Meromelia-Amelia, micromelia, Phocomelia
– Absence of internal & external ears & Hearing loss
– Haemangioma on the forehead
– CHD- truncus arteriosus, septal defects, ToF
– Urinary & alimentary malformations
– A potent hypnotic.
– Once used as tranquilizer & sedative
 DRUGS
• Lithium:
– CHD- ASD, TA, Ebstein’s anomaly
– Used to treat bipolar/manic disorders
– First & early second trimesters critical
• Diazepam:
– Cleft lip/palate
– First trimester risk
• Sulfonamide/ VK anologues:
– Hyperbilirubinaemia/kernicterus
• Tetracycline:
– Deposited in bones and teeth at sites of active calcification.
– Second and third trimester use could cause:
– Hypoplasia of tooth enamel.
– Yellow-brown teeth
– Diminished growth of long bones
 DRUGS
• Aminoglycosides
– Deafness
• Penicillins
– Appears to be safe
• Quinine/chloroquine
– Deafness
• Antithyroid
– Propylthiouracil interferes with foetal thyroxine formation
– Goiter
– MR
– Anticoagulants
– Warfarin – second and third trimester exposure may cause microcephaly, optic atrophy,
MR. Foetal demise may occur. Vik. K antagonist, nasal hypoplasia, IUGR, developmental
delay, stippling of bone epiphyses
– All except heparin cross the placenta and may cause foetal haemorrhage
• Hypoglycaemic agents
– Insulin appears safe Eventhough not convincing
– Oral agents may be linked
• Salicylates
– Large doses potentially harmful
• ACE inhibitors
– Renal tubular dysplasia / anuria, oiigohydramnios, IUGR, defects of ossification
– Late second & third trimesters critical
 DRUGS
Alkaloids:
• Cigarette:
– Nicotine causes
• High level of carboxy-Hb impairs O2 supply & lead to foetal hypoxia
• Decreased uterine blood flow leads to decreased cell growth & may
affect mental development.
• Some believe the growth defect is due to the direct toxic effect of
cigarette smoking
• LBW – IUGR/prematurity
• Caffeine:
– Not known to be a teratogen. However, best to avoid excess coffee, tea,
& colas
Illicit drugs:
• LBW
• Withdrawal syn.
• No evidence of teratogenicity with marijuana
• Amphetamines & cocaine theorized to cause agenesis of corpus callosum &
brain cleft
 DRUGS
Mercury:
• High doses can lead to foetal minamata disease.
– Neurological and behavioural disturbances
resembling cerebral palsy
• Severe brain damage, MR, & blindness may be
present
Iodides:
• Readily cross the placenta and may cause cretinism.
• Sources may be:
Radioactive iodides
Cough mixtures containing potassium iodides
 RADIATION
• Dose below 10 Rads not known to
cause malformation
• Large doses cause malformation.
–Eyes
–CNS
–Mental retardation
 INFECTIONS

• Not all maternal infections result in congenital

anomaly
• Rubella carries the highest risk for birth defects
If the mother is infected during early pregnancy:
– Approximately 20%.
 RUBELLA
• 15-20 % first trimester exposure results in malformations
• Typical triad:
– Cataract
– CHD:
• PDA, septal defects, peripheral pulmonary artery stenosis
– Deafness
• Occasional:
– Microcephaly, micropthalmia, chorioretinitis, glaucoma, tooth defect
• Thrombocytopenia
• Hepatosplenomegaly
• DM
• MR & CP
• Low risk in second and third trimesters
• Late insult:
– Functional defects of CNS & ears
 TOXOPLASMA GONDII
• Protozoan
• Intracellular parasite
• Maternal sources:
– Poorly cooked or raw meat
– Close contact with infected animals:
• E.g. cats
– Soil
• Probably crosses placenta
• Brain and the eyes primarily affected:
– Chorioretinitis
– micropthalmia
– Micro/hydro-cephaly
– MR
– CP
– Learning disabilities
• Hepatosplenomegaly
• Hearing loss
 CMV & HSV
• CMV:
– Probably the most common viral infection of human foetus
– Most first trimester infections probably end in abortion.
– Malformations with late infection
– Chorioretinitis, micropthalmia, blindness
– Microcephaly, cerebral calcification, MR, deafness, CP
– Hepatosplenomegaly
– IUGR
• HSV:
– Late Infection:
• Possibly during delivery
– Micropthalmia, retinal dysplasia
– Microcephaly, MR,cerebral palsy
 SYPHILIS
• Rapidly penetration of placenta after 20/40:
– Cytotrophoblast has disappeared
• Adequate Rx before 16/20:
– Kills organism before it can cross placenta
• Pre-pregnancy maternal infection seldom
affects foetus
• 25% of untreated mothers may have stillbirth
• Skeletal lesions
• Skin lesions
• Hepatomegaly
 FIFTH Dz & VARICELLA
• Fifth disease:
– Anemia
– Heart failure
– Foetal death
• Congenital varicella syndrome:
– Chicken pox
– Scars
– Defects of muscle and bone
– Malformed and paralyzed limbs
– Microcephaly
– Blindness
– Seizures
– Mental retardation
 MATERNAL ILLNESS
• Diabetes:
– VSD, TGA, ToF, CoA, anencephaly, spinabifida, caudal
regression syndrome (rare)
• Phenylketonuria:
– ToF
• SLE:
– Complete heart block
• Epilepsy:
– ??? teratogenic
• Pyrexia:
– Associated with bowel atresia & NTD in animal studies
• Others:
– Rh conflict
Combination of genetic and environmental
 DIAGNOSING
• Routine prenatal screening can:
– Help determine if the mother has an infection or other
condition that is dangerous to the fetus
– Determine if the fetus has certain birth defects
• The list of defects that may be detected through prenatal
screening includes:
– neural tube defects (spina bifida, anencephaly)
– Down syndrome and other chromosomal abnormalities
– inherited metabolic disorders
– congenital heart defects
– gastrointestinal and kidney malformations
– cleft lip or palate
– certain birth defects of the limbs
– congenital tumors
• Screening identifies only the possibility that a baby has a
defect.
• Possible to give birth to a healthy baby after a screening test
shows that a defect may be present
 DIAGNOSING
• Postnatal screening:
– PKU
– congenital hypothyroidism
– Sickle cell anemia
– Cystic fibrosis
– Congenital adrenal hyperplasia
– hearing loss
 PREVENTION
• The best thing that pregnant women can do to
increase their likelihood of having a healthy baby is to
make sure they take care of their bodies during
pregnancy by:
– not smoking, and avoiding secondhand smoke
– avoiding alcohol
– avoiding all illicit drugs
– eating a healthy diet and taking prenatal vitamins
(make sure you're getting enough folic acid)
– getting exercise and plenty of rest
– getting early and regular prenatal care