lecture notes on birth defects and prenatal diagnosis for medical students

1. BIRTH DEFECTS AND
PRENATAL DIAGNOSIS
Marami binti Mustapa
Anatomy Unit
FMDH NDUM

2. Desired Learning Outcomes
This lecture will enable you to:
1. explain malformation, disruption & deformation
2. explain the common chromosomal & genetic causes of birth defect
3. list the common teratogens (environmental factors) for birth defect
4. list the common maternal factors causing the birth defect
5. explain / describe the common birth defects
6. explain the different types twin pregnancy
7. explain the common prenatal techniques to detect the fetal malformations

3. Contents
1. Causes of birth defect
2. Types of birth defect
3. Twin pregnancy
4. Prenatal detection of birth defect

4. Birth defect
• Terms used to describe structural, behavioral, functional, and metabolic
disorders present at birth
• Major anomalies occur in 2 to 3% of liveborn infants, and an additional 2 to
3% in children by age 5 years
• Birth defects cause 21% of infant deaths
• The causes is unknown for 40% of persons with birth defects:
• Genetic factors: chromosome abnormalities and mutant genes (15%)
• Environmental factors (10%)
• Combination of genetic and environmental influences (20 to 25%)
• Twinning (0.5 to 1%)

5. Causes of 2.7 million neonatal deaths in 193
countries in 2010
Source: Adapted from WHO. Born too soon. The global action report on preterm birth. Geneva, World Health Organization, 2012

6. Birth defect
• Minor anomalies occur in approximately 15% of newborns:
• microtia (small ears)
• pigmented spots
• short palpebral fissures
• Minor anomalies can be associated with major anomalies
• Clue to detect major anomalies
• Ear defect is a good indicator for major anomalies
• Infants with 1 minor anomaly have a 3% chance of having a major
malformation;2 minor anomalies have a 10% chance; 3 or more
minor anomalies have a 20% chance

7. Types of abnormalities
1. Malformations
• Occur during organogenesis (3rd to 8th week of gestation)
• Result in complete/partial absence of a structure or in alterations of
its normal configuration
• Caused by environmental/genetic factors
2. Disruptions
• Changes in the morphology of already form structures
and due to destructive processes
• E.g. bowel atresia due to vascular accident

8. Types of abnormalities
3. Deformations
• Prolonged mechanical force to the growing fetus
• Always involve musculoskeletal system
• Can be treated/reversible

9. Chromosomal and Genetic factors
1. Chromosomal abnormalities
• Numerical
• Structural
2. Gene mutations

10. Chromosomal abnormalities
• Numerical/structural
• 50% of spontaneous abortion is cause by major chromosomal
abnormalities
• Causes 7% of major birth defects
• Occur due to: late maternal age at the time of pregnancy (leads to
chromosomal non-disjunction), radiation (causes chromosome
deletions, translocations or breaks), viruses (German measles),
chemical agents (anti-mitotic drugs)

11. Chromosomal abnormalities
Numerical abnormalities
• Aneuploid is present of extra
chromosomes (trisomy) or when one is
missing (monosomy)
• Cause by nondisjunction resulting in
individual with 47 chromosomes
(trisomy) or 45 chromosomes
(monosomy)
• Nondisjunction increases with maternal
age (> 35)

12. Trisomy 21 (Down syndrome)
• Extra copy of chromosome 21
• Mentally challenge, upward slanting eyes,
small ears, cardiac defects, hypotonia
• Incidence increase with maternal age

13. Trisomy 18
• Mental retardation, congenital heart defects, low set ears, flexion of
fingers and hands, renal anomalies, syndactyly, micrognathia (small
jaw)
• 85% lost during 10 weeks gestation to term, those born alive, die by 2
month of age

14. Klinefelter syndrome
• Occurs in male and detected at puberty
• Features: small testes (lack of testosterone),
gynecomastia, micropenis, reduced facial and
body hair, and infertility
• Learning disabilities and delayed speech and
language development
• 1 in 500 to 1,000 newborn males
• Extra copy of the X chromosome in each cell
(47,XXY)
• Cause by nondisjunction of XX homologues

15. Turner syndrome
• 45 X, 98% of fetus with this karyotype
are spontaneously aborted
• Features: short stature, premature
ovarian failure (ovaries develop
normally at first, but oocytes usually
die prematurely and most ovarian
tissue degenerates before birth),
webbed neck, lymphedema of the
hands and feet, skeletal
abnormalities, coarctation of the
aorta
• Have normal intelligence
• 1 in 2,500 newborn girls worldwide

16. Chromosomal and Genetic factors
1. Chromosomal abnormalities
• Numerical
• Structural
2. Gene mutations

17. Chromosomal abnormalities
Structural abnormalities
• Due to chromosome breakage
caused by environmental factors
(viruses, radiation, and drugs)
broken piece of a chromosome is
lost abnormal infant
• Cri-du-chat syndrome
• partial deletion of the short arm of
chromosome 5
• cat like cry, microcephaly, mentally
challenge, widely set eyes, low-set
ears, small jaw, rounded face and
congenital heart disease

18. Structural abnormalities
• Angelman syndrome
• Deletion on long arm of chromosome 15
• Mentally challenge, cannot speak, exhibit
poor motor development, and are prone to
unprovoked and prolonged periods of
laughter
• Prader-Willi syndrome
• If the defect is inherited on the paternal
chromosome
• Hypotonia, obesity, mentally challenge,
hypogonadism, and cryptorchidism (no testes)
a)Angelman syndrome b) Prader-Willi syndrome

19. Chromosomal and Genetic factors
1. Chromosomal abnormalities
• Numerical
• Structural
2. Gene mutations

20. Chromosomal and Genetic factors
Gene mutations
• Alter the functions of a normal
gene
• Mutations rate increased by a
number of environmental agents
(ionizing radiation)
• E.g.: fragile X syndrome,
achondroplasia, suprarenal
hyperplasia

21. Environmental factors
1. Infectious agents
2. Radiation
3. Drugs
4. Hormones
5. Maternal diseases

22. Infectious agents
1. Rubella (German measles)
• Communicable disease
• Features: cataracts, cardiac defects, deafness
2. Cytomegalovirus (CMV)
• Features: IUGR, microphthalmia, blindness, deafness, cerebral palsy,
hepatosplenomegaly
3. Herpes simplex virus
• Often occur during delivery
• Features: cutaneous lesions, microcephaly, microphthalmia, retinal dysplasia
4. Varicella (chickenpox)
• Before 20 weeks of gestation, causes skin scarring, muscle atrophy,
hypoplasia of limbs, eye and brain damage
5. Human immunodeficiency virus (HIV)
• Transmitted during delivery
German measles
Cutaneous lesion of HSV

23. Infectious agents
5. Toxoplasmosis
• Maternal infection acquired by eating
raw/poorly cooked meat containing
toxoplasma cysts
• Close contact with infected domestic
animals (cats) or infected soil with animal
faeces
• Causes intracranial calcifications,
chorioretinitis, hydrocephaly
6. Congenital syphilis
• Congenital deafness, hydrocephalus,
abnormal teeth and bones
Intracranial calcifications

24. Radiation
• Ionizing radiation kills rapidly proliferating cells birth defect depending upon
the dose and stage of development of the conceptus at the time of exposure
• Pregnant women at the time of the atomic bomb explosions over Hiroshima and
Nagasaki:
• 28% aborted;25% gave birth to children who died in their first year of life
• 25% had severe birth defects involving the central nervous system
• Radiation: mutagenic agent and can lead to genetic alterations of germ cells and
subsequent malformations

25. Drugs
Some can cause severe disruption of development, the effect vary
1. Cigarette smoking
• IUGR
• Premature delivery
• Behavioral problems
2. Antinauseant and sleeping pill
• Thalidomide: meromelia (limb reduction)/amelia (absent of limb/s)
3. Anticonvulsants
• Trimethadione, phenytoin, valproic acid-teratogen
• Causes: neural tube defects, craniofacial, heart, limb defects,
eyelid ptosis
Nick
vujicic
meromelia

26. 4. Antibiotics
Drugs
• Tetracycline – tooth defects, diminished growth of long bones
5. Anticoagulants
• All except heparin are teratogenic – warfarin
• Hypoplasia of nasal cartilage, CNS defects
6. Antineoplastic agents
• It inhibit mitosis - highly teratogenic
• Methotrexate – severe skeletal defects

27. 7. Alcohol
Drugs
• Alcohol cause fetal alcohol syndrome (FAS)
• FAS is a pattern of mental and physical birth defects that is common in babies
of mothers who drink heavily during pregnancy

28. Hormones
• Androgenic agents (synthetic progestins to prevent abortion) cause
masculinization of the genitalia of female fetus
• Endocrine hormones as Diethylstilbestrol (DES) cause malformation of
the uterus, uterine tubes, upper vagina, vaginal cancer and
malformed testes of the baby

29. Maternal diseases
Diabetes
• Disturbances in carbohydrate metabolism during pregnancy in diabetic
mothers
• Causes a high incidence of stillbirths, neonatal deaths, abnormally large
infants, and congenital malformations
• Embryos use glucose as an energy source during gastrulation and
neurulation: low blood glucose are teratogenic
Phenylketonuria
• Deficient in enzyme phenylalanine hydroxylase increased phenylalanine
• High phenylalanine causes mental retardation, microcephaly, and cardiac
defects

30. Twinning
• Risk of chromosomal anomalies are higher
• Elevated risk congenital anomalies appears limited to same sex twins and,
hence, is probably related to monozygosity
• Twins have about twice the risk of congenital abnormalities including
neural tube defects (such as spina bifida), gastrointestinal, and heart
abnormalities
• Mother at the age of 32 has higher risk to get Down syndrome baby in
multiple pregnancy in compare with singleton pregnancy (>35)

31. TWINS
DIZYGOTIC
2/3
MONOZYGOTIC
1/3
Monochorionic monoamniotic <1%
Monochorionic diamniotic -75%
Dichorionic diamniotic -25%
Dichorionic
Diamniotic

33. Prenatal diagnosis
• Growth and development of the fetus in vitro can be monitor using:
• Ultrasound scan
• Amniocentesis
• Chorionic villus sampling
• Maternal serum screening
• To detect malformations, genetic abnormalities, placental or uterine
abnormalities

34. Ultrasonography
• Non-invasive
• High frequency sound waves transmitted through the abdomen via a device
called a transducer to look inside the abdomen
• 2 approaches:
• Transabdominal
• Transvaginal
• In Malaysia, at least 3 uss per pregnancy: 1st trimester, 2nd trimester and 3rd
trimester
• Use to manage pregnancy:
• Reduced 60% mortality rate of low birth weight babies
• Decide mode of delivery: SVD/LSCS

35. Ultrasonography
• Functions:
• To confirm the gestational week of the fetus
• To monitor the growth of the fetus:
• Femur length (FL)
• Abdominal circumference (AC)
• Biparietal diameter (BPD)
• Crown-rump length (CRL)
• To measure the amniotic fluid index
• To determine the position of the placenta
• To detect any abnormalities to the fetus or
mother
• Ovarian cyst
• Oligohydramnios/polihydramnios
• Down syndrome, anencephaly, spina bifida
• Ectopic pregnancy

36. Maternal serum screening
• Alpha fetoprotein (AFP)
• Produce by fetal liver
• Peeks at 14 weeks, increase in the maternal serum during 2nd
trimester, begin a steady decline after 30 weeks of gestation
• AFP increases in:
• Neural tube defect, omphalocele, bladder exstrophy, amniotic
band syndrome, sacrococcygeal teratoma, intestinal atresia
• AFP decreases in:
• Down syndrome, Trisomy 18, sex chromosomes abnormalities,
triploidy
• Decrease in human chorionic gonadotropin (hCG) and
unconjugated estriol

37. Amniocentesis
• To look for certain type of birth defect:
• Down syndrome, neural tube defect
• Needle is inserted into the amniotic cavity and
20 to 30 ml of amniotic fluid is withdrawn
• Cultured amniotic fluid cells could be used to
obtain fetal karyotype
• Safe to be done between 15 to 18 weeks of
gestation
• Risk of miscarriage: 0.1%

38. Chorionic villus sampling (CVS)
• Indications:
• To detect genetic abnormality of the fetus - Down syndrome
• Maternal age > 35 years old
• History of neural tube defects in the family
• Chromosome abnormalities in either parent
• Mother who is x-linked disorder: haemophilia
• Needle is inserted transabdominally/transvaginally into
the placental mass 5 to 30 mg of villus tissue is
aspirated
• Done at 10-12 weeks of gestation
• Complications: miscarriage less than 1%, leakage of
amniotic fluid, uterine infection

39. Question
The birth defects due to chromosomal abnormalities include
A. Down syndrome.
B. Fetal alcohol syndrome.
C. Turner syndrome.
D. Acquired immunodeficiency syndrome (AIDS).
E. Klinefelter syndrome.