A shortcoming detected at birth of a neonate/newborn is termed
as birth defect. Clinically termed as congenital abnormalities or
congenital anomalies, these occur due to errors in development.
Congenital anomalies include a wide range of structural and functional
abnormalities that can occur in isolation or as a group of defects in
neonates. According to World Health Organization (WHO) and March
of Dimes (MOD) report, these defects account for 7% of neonatal mortality.
In the Indian scenario, birth defect prevalence varies from 61 to 69.9
per 1000 live births, and the risk factors include:
- Universality as a concept of marriage (Participation is a compulsion)
- Unplanned pregnancies
- Poor information on antenatal care
- Poor maternal nutritional status
- High rate of hemoglobinopathies
- Consanguineous marriage
The first largest democracy of the world ranks second in the
statistics for number of infants born annually with birth defects.
Low birth weight has been documented to be the cause of high
rates of newborn death, and under-five mortality rate continues
to trend on the higher side. The Indian Newborn Action Plan
(INAP) started in the year 2014 was initiated with a focus to
eliminate preventable newborn deaths and stillbirths.
The plan is to attain 'Single-digit Neonatal mortality rate
by 2020' and 'Single-digit stillbirth rate by 2020'. It
combines approaches for prevention and care of a
newborn with birth defects into primary health care,
and emphasizes on maternal and child health
The present article provides the readers with general information
on types, causes, and preventive strategies for birth defects as
well as the prenatal screening choices.
Types of Birth Defects
Based on the mechanism of pathogenicity, birth defects can
broadly be classified under the following categories:
Abnormalities that arise from an aberrant mechanical force
resulting in distortion of a normally developing structure
is termed as deformation. Abnormality can be of a shape,
form or position of body part, resulting in loss of body
symmetry and fetal movement. The causative force is
usually external and very rarely internal. Talipes deformities
(club foot), plagiocephaly and developmental dysplasia
of hip are some of the examples.
This defect results from destructive processes such as tissue
breakdown or injury that alters normally formed structure
leading to loss or division of body parts, the abnormal fusion
of body part or alteration in shape. Terminal transverse defects
of ring, index and middle fingers due to amniotic bands is a
prime example of birth defect due to disruption event.
Defect that result due to failure or inadequate completion
of developmental processes is called malformation. These
inherited anomalies may be limited to a local region of a
single organ, also called single system defect (eg. Cleft lip
and palate, spinal bifida and congenital defect) or may
appear as a syndrome wherein several abnormalities
manifest simultaneously (eg. Down syndrome, Turner syndrome).
These result from abnormal cellular organization or function
within a specific tissue type throughout the body, resulting
in structural changes. These include metabolic disorders
such as storage disease, skeletal dysplasia, ectodermal
dysplasia. Radial dysplasia involves an under development
or absence of radial or thumb side of the forearm and is
potentially disfiguring. It can physically manifest as slightly
small or missing thumb, missing radial wrist bones or the
entire radius bone. It can range from mild to severe and
affects the forearm, thumb or wrist or all in some cases.
Causes of Birth Defects
Birth defect results from a variety of factors, but every
factor does not attribute to a specific cause. There are
three major categories of causes:
Genetic birth defect:
Genetic factors account for 25% of all birth defects. Genetic
causes include chromosomal aberrations, single-gene disorder,
and multi-factorial disorders.
(CA)-CA may arise due to non-hereditary losses or rearrangement
of genetic material or inherited from a parent with the same
chromosomal aberration. These include:
Numerical abnormalities, which result due to nondisjunction
during cell division which comprises of:
- Autosomal aneuploidy such as Down syndrome (Trisomy 21),
Edward syndrome (Trisomy 18), Patau syndrome (Trisomy 13)
- Sex chromosomal aneuploidy such as Klinefelter syndrome
(47, XXY karyotype), Triple X (47, XXX karyotype),
Turner syndrome (45, X karyotype)
- Extra Structurally Abnormal Chromosome (ESAC), also
known as marker chromosome can be from any of the
autosomes or sex chromosomes. Pallister-Killian
(extra isochromosome 12p) is one of the examples
associated with ESAC.
- Polyploidy, arises due to the presence of more than
two complete sets of haploid chromosome complement
Hydrocephalus, cleft lip/ palate, congenital heart
diseases are some of the examples of birth detects
seen in the fetus with triploidy.
Structural abnormalities arise due to a part of chromosome
either being deleted or duplicated. It includes:
- Deletions and microdeletions such as DiGeorge syndrome
and Pierre-Robin sequence
- Duplication and micro-duplications such as Trisomy
9p syndrome and 22q11 micro-duplication syndrome
- Chromosomal rearrangements such as translocations,
inversion, and insertions
- Other structural abnormalities such as isochromosome
composed of either two long or short arms joined at centromere)
or ring chromosome (deletion of distal regions of short and long
arm of chromosome with the fusion of arms)
Single gene mutation -
This approximately accounts for 6% of the birth defects, caused
by a variant in one of the genes in every cell of the body. It mostly
constitutes of malformations or dysplasia affecting multiple
systems. Based on the mode of inheritance, it can be classified
as autosomal recessive or dominant or as X-linked recessive
or dominant. The popular ones include:
- Thalassemia- An inherited hemoglobin disorder, in
which the production of hemoglobin is deficient due
to mutations in genes that synthesize a and ?? globin
chain of hemoglobin.
- Sickel cell anemia- An inherited hemoglobinopathy
caused by an A-T point mutation in codon 6 of the betaglobin
gene resulting in abnormal Hemoglobin S (HbS). This
hemoglobin molecule polymerizes in the deoxygenated
state, causing physical deformation or sickling of red blood cells.
- Glucose-6-phosphate dehydrogenase deficiency. The most
common enzyme deficiency which arises due to recessive
X-linked mutation in the gene responsible for enzyme G6PD.
Newborn affected with this syndrome develop severe
hemolytic jaundice and kernicterus, resulting in death
or serious neurologic impairment.
- Cystic Fibrosis (CF)- A single-gene autosomal recessive
disorder caused by mutation in Cystic Fibrosis Membrane
Conductance Regulator (CFTR) protein. Characterized by
chronic pulmonary disease, pancreatic deficiency, gastrointestinal
dysfunction, abnormally high levels of electrolytes in sweat and
occasionally by biliary cirrhosis.
- Phenyl ketonuria- An autosomal recessive disorder that causes
congenital absence of phenylalanine hydroxylase, resulting in
phenylalanine accumulation in blood and impairment of early
- Hemophilia A and B- X-linked disorder cause deficiency of
coagulation factor VIII and IX respectively. Characterized by
subcutaneous and intramuscular hemorrhages, bleeding
from gums, lips, hematuria.
Environmental birth defect:
Exposure of developing embryo to a teratogen can be
partially or completely responsible for some birth defects.
Effect of exposure depends on factors such as timing of
exposure concerning the stage of development, dose
levels and genetic susceptibility. The encounter may
be from the maternal environment or an external agent.
Environmental factors have been detected to be responsible
for approximately 10% of congenital anomalies. The major
teratogens include following agents:
- Alcohol associated with Fetal Alcohol Syndrome (FAS) and
Alcohol-Related Neuro-Developmental Disorder (ARND) resulting
in alterations in facial features and fetal growth reduction, as well
as behavioral and cognitive effects.
- Anticonvulsant drugs such as phenobarbital, sodium valproate,
phenytoin, and carbamazepine cause major malformations such
as Neural Tube Defects (NTDs), microcephaly and growth restriction.
- Misoprostol used for cervical ripening, induction of labor and
early abortion also leads to several birth defects in the skull and
limbs, caused by vascular disruption.
Throughout prenatal life, fetuses are exposed to a variety of
infectious agents. Although majority of maternal infections
do not affect the fetus, some can result in fetal loss or
severe birth defects.
Examples of congenital infections that can result in
fetal birth defects include:
- Rubella viral infection- Interferes with organ development
of the fetus, causing blindness, deafness, cardiovascular anomalies,
and mental retardation, also collectively known as Congenital
Rubella Syndrome (CRS).
- Cytomegalovirus infected infants are mostly asymptomatic
at birth but at a risk of developing severe abnormalities
associated with damage to the Central Nervous System
(CNS) or sensory organs.
- Herpes Simplex Virus (HSV) infection in neonatal is a
life-threatening illness involving CNS diseases such as
microcephaly, hydranencephaly, and meningoencephalitis.
Maternal factors. Some maternal illnesses can
result in birth defects in neonates, if poorly controlled.
- Insulin-dependent diabetes mellitus. Risk of congenital
anomalies (diabetic embryopathy) like CNS, cardiovascular,
renal anomalies and limb defects.
- Phenylketonuria- Risk of infant with congenital malformation
and neurological impairment.
- Hyperthermia- Increases the risk of NTDs and other birth defects.
Deficiency in nutrients in the pregnant mother increases the risk of
birth defects. These include:
- Folic acid deficiency- Predominant cause of NTDs (spina bifida,
anencephaly, and encephalocele)
- lodine deficiency disorder- Affects fetus during the second
trimester of pregnancy resulting in endemic cretinism, endemic goiter,
and reduced intellectual ability.
Common teratogens include heavy metals such as mercury, lead, and pesticides
such as DDT (Dichloro Diphenyl Trichloroethane), that causes defects in CNS,
growth retardation and increases risk of abortion.
Effect of prenatal exposure to ionizing radiation depends on gestation age
at exposure and dose of radiation absorbed by the fetus. Exposure to
radiation between 8 to 15" week of gestation can damage the developing brain.
Birth defect of complex and unknown origin:
Popularly termed as multi-factorial birth defect, it is caused due to the
additive effect of genetic and environmental factors. These are usually
limited to a single organ system and include the following:
Neural Tube Defect-
Encloses a range of congenital malformations from underdeveloped
brain and spinal cord including their protective coverings. Mutations
in the Methylenetetrahydrofolate Reductase (MTHFR) gene and reduced
intake/absence of a folate-rich diet have been associated with increased
risk of NTDs. Thus, pre-conception folate supplements have been
recommended as a must in early pregnancy. There are three types of NTDS:
- Spina bifida-
It is incomplete closure of the neural tube. The obstructed development
of spinal cord manifests in the first 4-5 weeks of fetal development and
results in hydrocephalus, paralysis, incontinence or skeletal deformities
depending on the location and nature of the defect.
It is congenital absence of the cranial vault producing characteristic
bulging of the eyes and absence of the neck.
It is characterized by protrusion of the brain and its covering membranes
through the skull.
Congenital Heart Disease -
This is the most common birth defect which results in cyanosis, pulmonary
hypertension and growth retardation. Conditions such as maternal rubella
infection, maternal diabetes, alcohol, chromosomal aneuploidy such
as Down syndrome can result in congenital cardiac malformations.
Cleft lip/ Cleft palate-
Caused due to a gap in between the oral soft palate and roof of the
mouth, and sometimes extended to the upper lip. Affected neonates
have difficulty with speech development, hearing, and tooth formation.
Talipes/ Club foot-
Involves abnormalities in ankle joints, bones, muscles and ligaments of
the foot. If untreated, it causes arthritis and can hinder the growth of
the entire leg.
There are several approaches for assessing the growth and development
of fetus in utero. Following screening/diagnostic options are recommended
in routine as well as high-risk pregnancies to detect malformation,
genetic abnormalities, assess overall fetal growth and complications
This non-invasive techniques help in detection of structural anomalies
in fetus by studying anatomical markers which include Ultrasonography,
assessing Maternal serum markers and Non-invasive prenatal screening.
Invasive confirmatory test involves Amniocentesis and Chorionic Villus
Although progress has been made to identify the cause of birth defect,
it is important to accept that no cause can identify for a significant
proportion of birth defects. Knowledge of the pathway leading to a
birth defect can be a foundation for better primary prevention. It is
important to understand the role of preconception care to prevent
any congenital abnormalities.
Also, investigation of causes of birth defects at the time of
diagnosis can aid in management and counseling of patients to
avoid any anxiety and guilt.