Congenital Disorders
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A birth defect, also known as a congenital disorder, is an abnormal condition that is present at
birth Birth is the act or process of bearing or bringing forth offspring, also referred to in technical contexts as parturition. In mammals, the process is initiated by hormones which cause the muscular walls of the uterus to contract, expelling the f ...
regardless of its cause. Birth defects may result in disabilities that may be
physical Physical may refer to: *Physical examination In a physical examination, medical examination, or clinical examination, a medical practitioner examines a patient for any possible medical signs or symptoms of a medical condition. It generally co ...
,
intellectual An intellectual is a person who engages in critical thinking, research, and reflection about the reality of society, and who proposes solutions for the normative problems of society. Coming from the world of culture, either as a creator or a ...
, or
developmental Development of the human body is the process of growth to maturity. The process begins with fertilization, where an egg released from the ovary of a female is penetrated by a sperm cell from a male. The resulting zygote develops through mitosi ...
. The disabilities can range from mild to severe. Birth defects are divided into two main types: structural disorders in which problems are seen with the shape of a body part and functional disorders in which problems exist with how a body part works. Functional disorders include metabolic and degenerative disorders. Some birth defects include both structural and functional disorders. Birth defects may result from genetic or chromosomal disorders, exposure to certain medications or chemicals, or certain infections during pregnancy. Risk factors include
folate deficiency Folate deficiency, also known as vitamin B9 deficiency, is a low level of folate and derivatives in the body. Signs of folate deficiency are often subtle. A low number of red blood cells (anemia) is a late finding in folate deficiency and folate ...
,
drinking alcohol Alcohol, sometimes referred to by the chemical name ''ethanol'', is a depressant drug that is the active ingredient in drinks such as beer, wine, and distilled spirits (hard liquor). It is one of the oldest and most commonly consumed recreat ...
or
smoking Smoking is a practice in which a substance is burned and the resulting smoke is typically breathed in to be tasted and absorbed into the bloodstream. Most commonly, the substance used is the dried leaves of the tobacco plant, which have bee ...
during pregnancy, poorly controlled
diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
, and a mother over the age of 35 years old. Many are believed to involve multiple factors. Birth defects may be visible at birth or diagnosed by screening tests. A number of defects can be detected before birth by different prenatal tests. Treatment varies depending on the defect in question. This may include
therapy A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis. As a rule, each therapy has indications and contraindications. There are many different ...
, medication, surgery, or
assistive technology Assistive technology (AT) is a term for assistive, adaptive, and rehabilitative devices for people with disabilities and the elderly. Disabled people often have difficulty performing activities of daily living (ADLs) independently, or even with ...
. Birth defects affected about 96 million people . In the United States, they occur in about 3% of newborns. They resulted in about 628,000 deaths in 2015, down from 751,000 in 1990. The types with the greatest numbers of deaths are
congenital heart disease A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...
(303,000), followed by
neural tube defects Neural tube defects (NTDs) are a group of birth defects in which an opening in the spine or cranium remains from early in human development. In the third week of pregnancy called gastrulation, specialized cells on the dorsal side of the embryo b ...
(65,000).


Classification

Much of the language used for describing congenital conditions antedates
genome mapping Gene mapping describes the methods used to identify the locus of a gene and the distances between genes. Gene mapping can also describe the distances between different sites within a gene. The essence of all genome mapping is to place a co ...
, and structural conditions are often considered separately from other congenital conditions. Many metabolic conditions are now known to have subtle structural expression, and structural conditions often have genetic links. Still, congenital conditions are often classified on a structural basis, organized when possible by primary organ system affected.


Primarily structural

Several terms are used to describe congenital abnormalities. (Some of these are also used to describe noncongenital conditions, and more than one term may apply in an individual condition.)


Terminology

* A congenital physical anomaly is an abnormality of the structure of a body part. It may or may not be perceived as a problem condition. Many, if not most, people have one or more
minor physical anomalies Minor physical anomalies (MPAs) are relatively minor (typically painless and, in themselves, harmless) congenital physical abnormalities consisting of features such as low-set ears, single transverse palmar crease, telecanthus, micrognathism, ma ...
if examined carefully. Examples of minor anomalies can include curvature of the fifth finger (
clinodactyly Clinodactyly is a medical term describing the curvature of a digit (a finger or toe) in the plane of the palm, most commonly the fifth finger (the "little finger") towards the adjacent fourth finger (the "ring finger"). It is a fairly common iso ...
), a third nipple, tiny indentations of the skin near the ears (preauricular pits), shortness of the fourth
metacarpal In human anatomy, the metacarpal bones or metacarpus form the intermediate part of the skeletal hand located between the phalanges of the fingers and the carpal bones of the wrist, which forms the connection to the forearm. The metacarpal bones ...
or
metatarsal The metatarsal bones, or metatarsus, are a group of five long bones in the foot, located between the tarsal bones of the hind- and mid-foot and the phalanges of the toes. Lacking individual names, the metatarsal bones are numbered from the med ...
bones, or dimples over the lower spine (
sacral dimple A sacral dimple (also termed pilonidal dimple or spinal dimple) is a small depression in the skin, located just above the buttocks. The name comes from the sacrum, the bone at the end of the spine, over which the dimples are found. A sacral dimp ...
s). Some minor anomalies may be clues to more significant internal abnormalities. * Birth defect is a widely used term for a congenital malformation, ''i.e.'' a congenital, physical anomaly that is recognizable at
birth Birth is the act or process of bearing or bringing forth offspring, also referred to in technical contexts as parturition. In mammals, the process is initiated by hormones which cause the muscular walls of the uterus to contract, expelling the f ...
, and which is significant enough to be considered a problem. According to the
Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
(CDC), most birth defects are believed to be caused by a complex mix of factors including genetics, environment, and behaviors,Birth Defects Research
. Centers for Disease Control and Prevention.
though many birth defects have no known cause. An example of a birth defect is
cleft palate A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The te ...
, which occurs during the fourth through seventh weeks of gestation. Body tissue and special cells from each side of the head grow toward the center of the face. They join to make the face. A cleft means a split or separation; the "roof" of the mouth is called the palate. * A congenital malformation is a physical anomaly that is deleterious, ''i.e.'' a structural defect perceived as a problem. A typical combination of malformations affecting more than one body part is referred to as a malformation syndrome. * Some conditions are due to abnormal tissue development: ** A malformation is associated with a disorder of tissue development. Malformations often occur in the first trimester. ** A
dysplasia Dysplasia is any of various types of abnormal growth or development of cells (microscopic scale) or organs (macroscopic scale), and the abnormal histology or anatomical structure(s) resulting from such growth. Dysplasias on a mainly microscopic ...
is a disorder at the organ level that is due to problems with tissue development. * Conditions also can arise after tissue is formed: ** A
deformation Deformation can refer to: * Deformation (engineering), changes in an object's shape or form due to the application of a force or forces. ** Deformation (physics), such changes considered and analyzed as displacements of continuum bodies. * Defor ...
is a condition arising from mechanical stress to normal tissue. Deformations often occur in the second or third trimester, and can be due to oligohydramnios. ** A disruption involves breakdown of normal tissues. * When multiple effects occur in a specified order, they are known as a
sequence In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is calle ...
. When the order is not known, it is a
syndrome A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek σύνδρομον, meaning "concurrence". When a syndrome is paired ...
.


Examples of primarily structural congenital disorders

A limb anomaly is called a
dysmelia Dysmelia (from the Greek (), "bad" + (), "limb" + English suffix -ia) is a congenital disorder of a limb resulting from a disturbance in embryonic development.(2006) Dysmelia (Limb Deficiency/Reduction). pp 312-322. In: Atlas of Genetic Diagnos ...
. These include all forms of limbs anomalies, such as amelia,
ectrodactyly Ectrodactyly, split hand, or cleft hand (derived from Greek ''ektroma'' 'abortion' and ''daktylos'' 'finger') involves the deficiency or absence of one or more central digits of the hand or foot and is also known as split hand/split foot malformat ...
,
phocomelia Phocomelia is a condition that involves malformations of human arms and legs. Although many factors can cause phocomelia, the prominent roots come from the use of the drug thalidomide scandal, thalidomide and from genes, genetic inheritance. Occu ...
,
polymelia Polymelia is a birth defect in which an affected individual has more than the usual number of limbs. It is a type of dysmelia. In humans and most land-dwelling vertebrates, this means having five or more limbs. The extra limb is most commonly shr ...
,
polydactyly Polydactyly or polydactylism (), also known as hyperdactyly, is an anomaly in humans and animals resulting in supernumerary fingers and/or toes. Polydactyly is the opposite of oligodactyly (fewer fingers or toes). Signs and symptoms In human ...
,
syndactyly Syndactyly is a condition wherein two or more digits are fused together. It occurs normally in some mammals, such as the siamang and diprotodontia, but is an unusual condition in humans. The term is from Greek σύν, ''syn'' 'together' and δά ...
, polysyndactyly,
oligodactyly Oligodactyly (from Ancient Greek ''oligos'' 'few' and δάκτυλος ''daktylos'' 'finger') is the presence of fewer than five fingers or toes on a hand or foot.
,
brachydactyly Brachydactyly (Greek βραχύς = "short" plus δάκτυλος = "finger"), is a medical term which literally means "short finger". The shortness is relative to the length of other long bones and other parts of the body. Brachydactyly is an in ...
,
achondroplasia Achondroplasia is a genetic disorder with an autosomal dominant pattern of inheritance whose primary feature is dwarfism. In those with the condition, the arms and legs are short, while the torso is typically of normal length. Those affected ha ...
, congenital
aplasia Aplasia (; from Greek ''a'', "not", "no" + ''plasis'', "formation") is a birth defect where an organ or tissue is wholly or largely absent. It is caused by a defect in a developmental process. Aplastic anemia is the failure of the body to produc ...
or hypoplasia,
amniotic band syndrome Constriction ring syndrome (CRS) is a congenital disorder with unknown cause. Because of the unknown cause there are many different, and sometimes incorrect names. It is a malformation due to intrauterine bands or rings that give deep grooves in, ...
, and cleidocranial dysostosis.
Congenital heart defect A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...
s include
patent ductus arteriosus ''Patent ductus arteriosus'' (PDA) is a medical condition in which the ''ductus arteriosus'' fails to close after birth: this allows a portion of oxygenated blood from the left heart to flow back to the lungs by flowing from the aorta, which has ...
,
atrial septal defect Atrial septal defect (ASD) is a congenital heart defect in which blood flows between the atria (upper chambers) of the heart. Some flow is a normal condition both pre-birth and immediately post-birth via the foramen ovale; however, when this d ...
,
ventricular septal defect A ventricular septal defect (VSD) is a defect in the ventricular septum, the wall dividing the left and right ventricles of the heart. The extent of the opening may vary from pin size to complete absence of the ventricular septum, creating one ...
, and
tetralogy of Fallot Tetralogy of Fallot (TOF), formerly known as Steno-Fallot tetralogy, is a congenital heart defect characterized by four specific cardiac defects. Classically, the four defects are: *pulmonary stenosis, which is narrowing of the exit from the ri ...
. Congenital anomalies of the nervous system include neural tube defects such as
spina bifida Spina bifida (Latin for 'split spine'; SB) is a birth defect in which there is incomplete closing of the spine and the membranes around the spinal cord during early development in pregnancy. There are three main types: spina bifida occulta, men ...
,
encephalocele Encephalocele is a neural tube defect characterized by sac-like protrusions of the brain and the membranes that cover it through openings in the skull. These defects are caused by failure of the neural tube to close completely during fetal develop ...
, and
anencephaly Anencephaly is the absence of a major portion of the brain, skull, and scalp that occurs during embryonic development. It is a cephalic disorder that results from a neural tube defect that occurs when the rostral (head) end of the neural tube fai ...
. Other congenital anomalies of the nervous system include the
Arnold–Chiari malformation Chiari malformation (CM) is a structural defect in the cerebellum, characterized by a downward displacement of one or both cerebellar tonsils through the foramen magnum (the opening at the base of the skull). CMs can cause headaches, difficu ...
, the
Dandy–Walker malformation Dandy–Walker malformation (DWM), also known as Dandy–Walker syndrome (DWS), is a rare congenital brain malformation in which the part joining the two hemispheres of the cerebellum (the cerebellar vermis) does not fully form, and the fourth ...
,
hydrocephalus Hydrocephalus is a condition in which an accumulation of cerebrospinal fluid (CSF) occurs within the brain. This typically causes increased intracranial pressure, pressure inside the skull. Older people may have headaches, double vision, poor ...
,
microencephaly Microcephaly (from New Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it m ...
,
megalencephaly Megalencephaly (or macrencephaly; abbreviated MEG) is a growth development disorder in which the brain is abnormally large. It is characterized by a brain with an average weight that is 2.5 standard deviations above the mean of the general populati ...
,
lissencephaly Lissencephaly (, meaning "smooth brain") is a set of rare brain disorders whereby the whole or parts of the surface of the brain appear smooth. It is caused by defective neuronal migration during the 12th to 24th weeks of gestation resulting in ...
,
polymicrogyria Polymicrogyria (PMG) is a condition that affects the development of the human brain by multiple small gyri ( microgyri) creating excessive folding of the brain leading to an abnormally thick cortex. This abnormality can affect either one region o ...
,
holoprosencephaly Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres, typically occurring between the 18th and 28th day of gestation. Normally, the forebrain is formed an ...
, and agenesis of the corpus callosum. Congenital anomalies of the
gastrointestinal system The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
include numerous forms of
stenosis A stenosis (from Ancient Greek στενός, "narrow") is an abnormal narrowing in a blood vessel or other tubular organ or structure such as foramina and canals. It is also sometimes called a stricture (as in urethral stricture). ''Stricture'' ...
and
atresia Atresia is a condition in which an orifice or passage in the body is (usually abnormally) closed or absent. Examples of atresia include: *Aural atresia, a congenital deformity where the ear canal is underdeveloped. * Biliary atresia, a condition i ...
, and perforation, such as
gastroschisis Gastroschisis is a birth defect in which the baby's intestines extend outside of the abdomen through a hole next to the belly button. The size of the hole is variable, and other organs including the stomach and liver may also occur outside the ba ...
. Congenital anomalies of the kidney and urinary tract include renal parenchyma, kidneys, and urinary collecting system. Defects can be bilateral or unilateral, and different defects often coexist in an individual child.


Primarily metabolic

A congenital metabolic disease is also referred to as an
inborn error of metabolism Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances ( substr ...
. Most of these are single-gene defects, usually heritable. Many affect the structure of body parts, but some simply affect the function.


Other

Other well-defined genetic conditions may affect the production of hormones, receptors, structural proteins, and ion channels.


Causes


Alcohol exposure

The mother's consumption of alcohol during pregnancy can cause a continuum of various permanent birth defects: craniofacial abnormalities, brain damage, intellectual disability, heart disease, kidney abnormality, skeletal anomalies, ocular abnormalities. The prevalence of children affected is estimated at least 1% in U.S. as well in Canada. Very few studies have investigated the links between paternal alcohol use and offspring health. However, recent animal research has shown a correlation between paternal alcohol exposure and decreased offspring birth weight. Behavioral and cognitive disorders, including difficulties with learning and memory, hyperactivity, and lowered stress tolerance have been linked to paternal alcohol ingestion. The compromised stress management skills of animals whose male parent was exposed to alcohol are similar to the exaggerated responses to stress that children with fetal alcohol syndrome display because of maternal alcohol use. These birth defects and behavioral disorders were found in cases of both long- and short-term paternal alcohol ingestion. In the same animal study, paternal alcohol exposure was correlated with a significant difference in organ size and the increased risk of the offspring displaying
ventricular septal defect A ventricular septal defect (VSD) is a defect in the ventricular septum, the wall dividing the left and right ventricles of the heart. The extent of the opening may vary from pin size to complete absence of the ventricular septum, creating one ...
s at birth.


Toxic substances

Substances whose
toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...
can cause congenital disorders are called
teratogens Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The related ...
, and include certain pharmaceutical and recreational
drugs in pregnancy Drugs and medications should be avoided while pregnant. Women should speak to their doctor or healthcare professional before starting or stopping any medications while pregnant. Tobacco, alcohol, marijuana, and illicit drug use while pregnant may ...
, as well as many
environmental toxins in pregnancy Environmental toxicants and fetal development is the impact of different toxic substances from the environment on the development of the fetus. This article deals with potential adverse effects of environmental toxicants on the prenatal development ...
. A review published in 2010 identified six main teratogenic mechanisms associated with medication use: folate antagonism,
neural crest cell Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, ...
disruption,
endocrine disruption Endocrine disruptors, sometimes also referred to as hormonally active agents, endocrine disrupting chemicals, or endocrine disrupting compounds are chemicals that can interfere with endocrine (or hormonal) systems. These disruptions can cause ca ...
,
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
,
vascular The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away f ...
disruption, and specific receptor- or enzyme-mediated teratogenesis. An estimated 10% of all birth defects are caused by prenatal exposure to a teratogenic agent. These exposures include medication or drug exposures, maternal infections and diseases, and environmental and occupational exposures. Paternal smoking has also been linked to an increased risk of birth defects and childhood cancer for the offspring, where the paternal germline undergoes oxidative damage due to cigarette use. Teratogen-caused birth defects are potentially preventable. Nearly 50% of pregnant women have been exposed to at least one medication during gestation. During pregnancy, a woman can also be exposed to teratogens from contaminated clothing or toxins within the seminal fluid of a partner. An additional study found that of 200 individuals referred for genetic counseling for a teratogenic exposure, 52% were exposed to more than one potential teratogen. The
United States Environmental Protection Agency The Environmental Protection Agency (EPA) is an independent executive agency of the United States federal government tasked with environmental protection matters. President Richard Nixon proposed the establishment of EPA on July 9, 1970; it be ...
studied 1,065 chemical and drug substances in their ToxCast program (part of the
CompTox Chemicals Dashboard The CompTox Chemicals Dashboard is a freely accessible online database created and maintained by the U.S. Environmental Protection Agency (EPA). The database provides access to multiple types of data including physicochemical properties, environm ...
) using ''
in silico In biology and other experimental sciences, an ''in silico'' experiment is one performed on computer or via computer simulation. The phrase is pseudo-Latin for 'in silicon' (correct la, in silicio), referring to silicon in computer chips. It ...
'' modeling and a human
pluripotent Pluripotency: These are the cells that can generate into any of the three Germ layers which imply Endodermal, Mesodermal, and Ectodermal cells except tissues like the placenta. According to Latin terms, Pluripotentia means the ability for many thin ...
stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
-based assay to predict
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
developmental intoxicants based on changes in cellular
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
following chemical exposure. Findings of the study published in 2020 were that 19% of the 1065 chemicals yielded a prediction of
developmental toxicity Development of the human body is the process of growth to maturity. The process begins with fertilization, where an egg released from the ovary of a female is penetrated by a sperm cell from a male. The resulting zygote develops through m ...
.


Medications and supplements

Probably, the most well-known teratogenic drug is
thalidomide Thalidomide, sold under the brand names Contergan and Thalomid among others, is a medication used to treat a number of cancers (including multiple myeloma), graft-versus-host disease, and a number of skin conditions including complications o ...
. It was developed near the end of the 1950s by Chemie Grünenthal as a sleep-inducing aid and
antiemetic An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may ...
. Because of its ability to prevent nausea, it was prescribed for pregnant women in almost 50 countries worldwide between 1956 and 1962. Until William McBride published the study leading to its withdrawal from the market in 1961, about 8,000 to 10,000 severely malformed children were born. The most typical disorders induced by thalidomide were reductional deformities of the long bones of the extremities.
Phocomelia Phocomelia is a condition that involves malformations of human arms and legs. Although many factors can cause phocomelia, the prominent roots come from the use of the drug thalidomide scandal, thalidomide and from genes, genetic inheritance. Occu ...
, otherwise a rare deformity, therefore helped to recognise the teratogenic effect of the new drug. Among other malformations caused by thalidomide were those of ears, eyes, brain, kidney, heart, and digestive and respiratory tracts; 40% of the prenatally affected children died soon after birth. As thalidomide is used today as a treatment for
multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...
and
leprosy Leprosy, also known as Hansen's disease (HD), is a long-term infection by the bacteria ''Mycobacterium leprae'' or ''Mycobacterium lepromatosis''. Infection can lead to damage of the nerves, respiratory tract, skin, and eyes. This nerve damag ...
, several births of affected children were described in spite of the strictly required use of contraception among female patients treated by it.
Vitamin A Vitamin A is a fat-soluble vitamin and an essential nutrient for humans. It is a group of organic compounds that includes retinol, retinal (also known as retinaldehyde), retinoic acid, and several provitamin A carotenoids (most notably bet ...
is the sole vitamin that is embryotoxic even in a therapeutic dose, for example in multivitamins, because its metabolite,
retinoic acid Retinoic acid (used simplified here for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that mediates the functions of vitamin A1 required for growth and development. All-''trans''-retinoic acid is required in ...
, plays an important role as a signal molecule in the development of several tissues and organs. Its natural precursor,
β-carotene β-Carotene is an organic, strongly coloured red-orange pigment abundant in fungi, plants, and fruits. It is a member of the carotenes, which are terpenoids (isoprenoids), synthesized biochemically from eight isoprene units and thus having 40 ...
, is considered safe, whereas the consumption of animal liver can lead to malformation, as the liver stores lipophilic vitamins, including retinol.
Isotretinoin Isotretinoin, also known as 13-''cis''-retinoic acid and sold under the brand name Accutane among others, is a medication primarily used to treat severe acne. It is also used to prevent certain skin cancers ( squamous-cell carcinoma), and in t ...
(13-cis-retinoic-acid; brand name Roaccutane), vitamin A analog, which is often used to treat severe
acne Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...
, is such a strong teratogen that just a single dose taken by a pregnant woman (even
transdermal Transdermal is a route of administration wherein active ingredients are delivered across the skin for systemic distribution. Examples include transdermal patches used for medicine delivery. The drug is administered in the form of a patch or ointme ...
ly) may result in serious birth defects. Because of this effect, most countries have systems in place to ensure that it is not given to pregnant women and that the patient is aware of how important it is to prevent pregnancy during and at least one month after treatment. Medical guidelines also suggest that pregnant women should limit vitamin A intake to about 700 μg/day, as it has teratogenic potential when consumed in excess. Vitamin A and similar substances can induce spontaneous abortions, premature births, defects of eyes ( microphthalmia), ears, thymus, face deformities, and neurological (
hydrocephalus Hydrocephalus is a condition in which an accumulation of cerebrospinal fluid (CSF) occurs within the brain. This typically causes increased intracranial pressure, pressure inside the skull. Older people may have headaches, double vision, poor ...
, microcephalia) and cardiovascular defects, as well as
intellectual disability Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation,Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...
.
Tetracycline Tetracycline, sold under various brand names, is an oral antibiotic in the tetracyclines family of medications, used to treat a number of infections, including acne, cholera, brucellosis, plague, malaria, and syphilis. Common side effects in ...
, an
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...
, should never be prescribed to women of reproductive age or to children, because of its negative impact on
bone A bone is a Stiffness, rigid Organ (biology), organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red blood cell, red and white blood cells, store minerals, provid ...
mineralization and teeth mineralization. The "tetracycline teeth" have brown or grey colour as a result of a defective development of both the
dentine Dentin () (American English) or dentine ( or ) (British English) ( la, substantia eburnea) is a calcified tissue of the body and, along with enamel, cementum, and pulp, is one of the four major components of teeth. It is usually covered by e ...
and the
enamel of teeth Tooth enamel is one of the four major tissues that make up the tooth in humans and many other animals, including some species of fish. It makes up the normally visible part of the tooth, covering the crown. The other major tissues are dentin, ...
. Several
anticonvulsants Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...
are known to be highly teratogenic.
Phenytoin Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The intr ...
, also known as diphenylhydantoin, along with
carbamazepine Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other m ...
, is responsible for the
fetal hydantoin syndrome Fetal hydantoin syndrome, also called fetal dilantin syndrome, is a group of defects caused to the developing fetus by exposure to teratogenic effects of phenytoin. Dilantin is the brand name of the drug phenytoin sodium in the United States, com ...
, which may typically include broad nose base, cleft lip and/or palate, microcephalia, nails and fingers hypoplasia,
intrauterine growth restriction Intrauterine growth restriction (IUGR), or fetal growth restriction, refers to poor growth of a fetus while in the womb during pregnancy. IUGR is defined by clinical features of malnutrition and evidence of reduced growth regardless of an infant's ...
, and intellectual disability.
Trimethadione Trimethadione (Tridione) is an oxazolidinedione anticonvulsant. It is most commonly used to treat epileptic conditions that are resistant to other treatments. It is primarily effective in treating absence seizures, but can also be used in ref ...
taken during pregnancy is responsible for the fetal trimethadione syndrome, characterized by craniofacial, cardiovascular, renal, and spine malformations, along with a delay in mental and physical development.
Valproate Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those ...
has
antifolate Antifolates are a class of antimetabolite medications that antagonise (that is, block) the actions of folic acid (vitamin B9). Folic acid's primary function in the body is as a cofactor to various methyltransferases involved in serine, methionin ...
effects, leading to
neural tube In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural fold become elevated, a ...
closure-related defects such as spina bifida. Lower IQ and
autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
have recently also been reported as a result of intrauterine valproate exposure.
Hormonal contraception Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The origin ...
is considered harmless for the embryo. Peterka and Novotná do, however, state that synthetic progestins used to prevent miscarriage in the past frequently caused masculinization of the outer reproductive organs of female newborns due to their
androgen An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This inc ...
ic activity.
Diethylstilbestrol Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication, which is presently rarely used. In the past, it was widely used for a variety of indications, including pregnancy support for those with a ...
is a synthetic
estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
used from the 1940s to 1971, when the prenatal exposition has been linked to the
clear-cell adenocarcinoma of the vagina Clear-cell adenocarcinoma (CCA) of the vagina or cervix is a rare adenocarcinoma often linked to prenatal exposure to diethylstilbestrol (DES), a drug which was prescribed in high-risk pregnancy. Presentation After age 30 it was thought that wome ...
. Following studies showed elevated risks for other tumors and congenital malformations of the sex organs for both sexes. All
cytostatics Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
are strong teratogens;
abortion Abortion is the termination of a pregnancy by removal or expulsion of an embryo or fetus. An abortion that occurs without intervention is known as a miscarriage or "spontaneous abortion"; these occur in approximately 30% to 40% of pregn ...
is usually recommended when pregnancy is discovered during or before chemotherapy.
Aminopterin Aminopterin (or 4-aminopteroic acid), the 4-amino derivative of folic acid, is an antineoplastic drug with immunosuppressive properties often used in chemotherapy. Aminopterin is a synthetic derivative of pterin. Aminopterin works as an enzyme inh ...
, a cytostatic drug with anti
folate Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...
effect, was used during the 1950s and 1960s to induce
therapeutic abortion Abortion is the termination of a pregnancy by removal or expulsion of an embryo or fetus. An abortion that occurs without intervention is known as a miscarriage or "spontaneous abortion"; these occur in approximately 30% to 40% of pregn ...
s. In some cases, the abortion did not happen, but the newborns had a fetal aminopterin syndrome consisting of growth retardation, craniosynostosis, hydrocephalus, facial dismorphities, intellectual disability, or leg deformities


Toxic substances

Drinking water Drinking water is water that is used in drink or food preparation; potable water is water that is safe to be used as drinking water. The amount of drinking water required to maintain good health varies, and depends on physical activity level, a ...
is often a medium through which harmful toxins travel. Heavy metals, elements, nitrates, nitrites, and fluoride can be carried through water and cause congenital disorders. Nitrate, which is found mostly in drinking water from ground sources, is a powerful teratogen. A case-control study in rural Australia that was conducted following frequent reports of prenatal mortality and congenital malformations found that those who drank the nitrate-containing groundwater, as opposed to rain water, ran the risk of giving birth to children with central nervous system disorders, muscoskeletal defects, and cardiac defects. Chlorinated and aromatic solvents such as benzene and trichloroethylene sometimes enter the water supply due to oversights in waste disposal. A case-control study on the area found that by 1986, leukemia was occurring in the children of Woburn, Massachusetts, at a rate that was four times the expected rate of incidence. Further investigation revealed a connection between the high occurrence of leukemia and an error in water distribution that delivered water to the town with significant contamination with manufacturing waste containing trichloroethylene. As an
endocrine disruptor Endocrine disruptors, sometimes also referred to as hormonally active agents, endocrine disrupting chemicals, or endocrine disrupting compounds are chemicals that can interfere with endocrine (or hormonal) systems. These disruptions can cause c ...
,
DDT Dichlorodiphenyltrichloroethane, commonly known as DDT, is a colorless, tasteless, and almost odorless crystalline chemical compound, an organochloride. Originally developed as an insecticide, it became infamous for its environmental impacts. ...
was shown to induce
miscarriage Miscarriage, also known in medical terms as a spontaneous abortion and pregnancy loss, is the death of an embryo or fetus before it is able to survive independently. Miscarriage before 6 weeks of gestation is defined by ESHRE as biochemical lo ...
s, interfere with the development of the
female reproductive system The female reproductive system is made up of the internal and external sex organs that function in the reproduction of new offspring. In humans, the female reproductive system is immature at birth and develops to maturity at puberty to be ...
, cause the
congenital hypothyroidism Congenital hypothyroidism (CH) is thyroid hormone deficiency present at birth. If untreated for several months after birth, severe congenital hypothyroidism can lead to growth failure and permanent intellectual disability. Infants born with cong ...
, and suspectably childhood obesity. Fluoride, when transmitted through water at high levels, can also act as a teratogen. Two reports on fluoride exposure from China, which were controlled to account for the education level of parents, found that children born to parents who were exposed to 4.12 ppm fluoride grew to have IQs that were, on average, seven points lower than their counterparts whose parents consumed water that contained 0.91 ppm fluoride. In studies conducted on rats, higher fluoride in drinking water led to increased acetylcholinesterase levels, which can alter prenatal brain development. The most significant effects were noted at a level of 5 ppm. The fetus is even more susceptible to damage from carbon monoxide intake, which can be harmful when inhaled during pregnancy, usually through first- or second-hand tobacco smoke. The concentration of carbon monoxide in the infant born to a nonsmoking mother is around 2%, and this concentration drastically increases to a range of 6%–9% if the mother smoked tobacco. Other possible sources of prenatal carbon monoxide intoxication are exhaust gas from combustion motors, use of dichloromethane (paint thinner, varnish removers) in enclosed areas, defective gas water heaters, indoor barbeques, open flames in poorly ventilated areas, and atmospheric exposure in highly polluted areas. Exposure to carbon monoxide at toxic levels during the first two trimesters of pregnancy can lead to intrauterine growth restriction, leading to a baby who has stunted growth and is born smaller than 90% of other babies at the same gestational age. The effect of chronic exposure to carbon monoxide can depend on the stage of pregnancy in which the mother is exposed. Exposure during the embryonic stage can have neurological consequences, such as telencephalic dysgenesis, behavioral difficulties during infancy, and reduction of cerebellum volume. Also, possible skeletal defects could result from exposure to carbon monoxide during the embryonic stage, such as hand and foot malformations,
hip dysplasia Hip dysplasia is an abnormality of the hip joint where the socket portion does not fully cover the ball portion, resulting in an increased risk for joint dislocation. Hip dysplasia may occur at birth or develop in early life. Regardless, it doe ...
, hip subluxation, agenesis of a limb, and inferior maxillary atresia with
glossoptosis Glossoptosis is a medical condition and abnormality which involves the downward displacement or retraction of the tongue. It may cause non-fusion of the hard palate, causing cleft palate. It is one of the features of Pierre Robin sequence and Down ...
. Also, carbon monoxide exposure between days 35 and 40 of embryonic development can lead to an increased risk of the child developing a cleft palate. Exposure to carbon monoxide or polluted ozone exposure can also lead to cardiac defects of the ventrical septal, pulmonary artery, and heart valves. The effects of carbon monoxide exposure are decreased later in fetal development during the fetal stage, but they may still lead to
anoxic The term anoxia means a total depletion in the level of oxygen, an extreme form of hypoxia or "low oxygen". The terms anoxia and hypoxia are used in various contexts: * Anoxic waters, sea water, fresh water or groundwater that are depleted of diss ...
encephalopathy Encephalopathy (; from grc, ἐνκέφαλος "brain" + πάθος "suffering") means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but r ...
. Industrial pollution can also lead to congenital defects. Over a period of 37 years, the
Chisso The , since 2012 reorganized as JNC (Japan New Chisso), is a Japanese chemical company. It is an important supplier of liquid crystal used for LCDs, but is best known for its role in the 34-year-long pollution of the water supply in Minamata, ...
Corporation, a petrochemical and plastics company, contaminated the waters of
Minamata Bay Minamata is a small factory town. Minamata Bay is a bay on the west coast of Kyūshū island, located in Kumamoto Prefecture, Japan. The bay is part of the larger Shiranui Sea which is sandwiched between the coast of the Kyūshū mainland and the ...
with an estimated 27 tons of methylmercury, contaminating the local water supply. This led many people in the area to develop what became known as the "
Minamata disease Minamata disease is a neurological disease caused by severe mercury poisoning. Signs and symptoms include ataxia, numbness in the hands and feet, general muscle weakness, loss of peripheral vision, and damage to hearing and speech. In extrem ...
". Because methylmercury is a teratogen, the mercury poisoning of those residing by the bay resulted in neurological defects in the offspring. Infants exposed to mercury poisoning ''in utero'' showed predispositions to
cerebral palsy Cerebral palsy (CP) is a group of movement disorders that appear in early childhood. Signs and symptoms vary among people and over time, but include poor coordination, stiff muscles, weak muscles, and tremors. There may be problems with sensa ...
,
ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...
, inhibited psychomotor development, and intellectual disability. Landfill sites have been shown to have adverse effects on fetal development. Extensive research has shown that landfills have several negative effects on babies born to mothers living near landfill sites: low birth weight, birth defects, spontaneous abortion, and fetal and infant mortality. Studies done around the
Love Canal Love Canal is a neighborhood in Niagara Falls, New York, United States, infamous as the location of a landfill that became the site of an enormous environmental disaster in the 1970s. Decades of dumping toxic chemicals harmed the health of hund ...
site near Niagara Falls and the
Lipari Landfill The Lipari Landill is an inactive landfill on a former gravel pit in Mantua Township, New Jersey. It was used from 1958 to 1971 as a dump site for household and industrial wastes. Toxic organic compounds and heavy metals dumped at the site have pe ...
in New Jersey have shown a higher proportion of low birth-weight babies than communities farther away from landfills. A study done in California showed a positive correlation between time and quantity of dumping and low birth weights and neonatal deaths. A study in the United Kingdom showed a correlation between pregnant women living near landfill sites and an increased risk of congenital disorders, such as neural tube defects,
hypospadias Hypospadias is a common variation in fetal development of the penis in which the urethra does not open from its usual location in the head of the penis. It is the second-most common birth abnormality of the male reproductive system, affecting abou ...
,
epispadia An epispadias is a rare type of malformation in which the urethra ends, in males, in an opening on the upper aspect of the penis, and in females when the urethra develops too far anteriorly. It occurs in around 1 in 120,000 male and 1 in 500,000 ...
, and abdominal wall defects, such as
gastroschisis Gastroschisis is a birth defect in which the baby's intestines extend outside of the abdomen through a hole next to the belly button. The size of the hole is variable, and other organs including the stomach and liver may also occur outside the ba ...
and exomphalos. A study conducted on a Welsh community also showed an increased incidence of gastroschisis. Another study on 21 European hazardous-waste sites showed that those living within 3 km had an increased risk of giving birth to infants with birth defects and that as distance from the land increased, the risk decreased. These birth defects included neural tube defects, malformations of the cardiac septa, anomalies of arteries and veins, and chromosomal anomalies. Looking at communities that live near landfill sites brings up environmental justice. A vast majority of sites are located near poor, mostly black, communities. For example, between the early 1920s and 1978, about 25% of Houston's population was black. However, over 80% of landfills and incinerators during this time were located in these black communities. Another issue regarding
environmental justice Environmental justice is a social movement to address the unfair exposure of poor and marginalized communities to harms from hazardous waste, resource extraction, and other land uses.Schlosberg, David. (2007) ''Defining Environmental Justic ...
is lead poisoning. A fetus exposed to lead during the pregnancy can result in learning difficulties and slowed growth. Some paints (before 1978) and pipes contain lead. Therefore, pregnant women who live in homes with lead paint inhale the dust containing lead, leading to lead exposure in the fetus. When lead pipes are used for drinking water and cooking water, this water is ingested, along with the lead, exposing the fetus to this toxin. This issue is more prevalent in poorer communities because more well-off families are able to afford to have their homes repainted and pipes renovated.


Smoking

Paternal smoking prior to conception has been linked with the increased risk of congenital abnormalities in offspring. Smoking causes DNA mutations in the germline of the father, which can be inherited by the offspring. Cigarette smoke acts as a chemical mutagen on germ cell DNA. The germ cells suffer oxidative damage, and the effects can be seen in altered mRNA production, infertility issues, and side effects in the embryonic and fetal stages of development. This
oxidative damage Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal r ...
may result in epigenetic or genetic modifications of the father's germline. Fetal
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
s have been damaged as a result of a father's smoking habits prior to conception. Correlations between paternal smoking and the increased risk of offspring developing childhood cancers (including acute
leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...
, brain tumors, and
lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlar ...
) before age five have been established. Little is currently known about how paternal smoking damages the fetus, and what window of time in which the father smokes is most harmful to offspring.


Infections

A
vertically transmitted infection A vertically transmitted infection is an infection caused by pathogenic bacteria or viruses that use mother-to-child transmission, that is, transmission directly from the mother to an embryo, fetus, or baby during pregnancy or childbirth. It ...
is an
infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...
caused by
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
,
virus A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's 1 ...
es, or in rare cases,
parasite Parasitism is a close relationship between species, where one organism, the parasite, lives on or inside another organism, the host, causing it some harm, and is adapted structurally to this way of life. The entomologist E. O. Wilson has ...
s transmitted directly from the mother to an
embryo An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
,
fetus A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal deve ...
, or baby during pregnancy or childbirth. Congenital disorders were initially believed to be the result of only hereditary factors. However, in the early 1940s, Australian pediatric ophthalmologist
Norman Gregg Sir Norman McAlister Gregg, (7 March 1892 – 27 July 1966) was an Australian ophthalmologist, who discovered that rubella suffered by a pregnant woman could cause birth defects in her child ( congenital rubella syndrome). Early life and educat ...
began recognizing a pattern in which the infants arriving at his surgery were developing congenital cataracts at a higher rate than those who developed it from hereditary factors. On October 15, 1941, Gregg delivered a paper that explained his findings-68 out of the 78 children with congenital cataracts had been exposed'' in utero'' to rubella due to an outbreak in Australian army camps. These findings confirmed, to Gregg, that, in fact, environmental causes for congenital disorders could exist.
Rubella Rubella, also known as German measles or three-day measles, is an infection caused by the rubella virus. This disease is often mild, with half of people not realizing that they are infected. A rash may start around two weeks after exposure and ...
is known to cause abnormalities of the eye, internal ear, heart, and sometimes the teeth. More specifically, fetal exposure to rubella during weeks five to ten of development (the sixth week particularly) can cause
cataracts A cataract is a cloudy area in the lens of the eye that leads to a decrease in vision. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colors, blurry or double vision, halos around light, trouble w ...
and microphthalmia in the eyes. If the mother is infected with rubella during the ninth week, a crucial week for internal ear development, destruction of the
organ of Corti The organ of Corti, or spiral organ, is the receptor organ for hearing and is located in the mammalian cochlea. This highly varied strip of epithelial cells allows for transduction of auditory signals into nerve impulses' action potential. Transd ...
can occur, causing deafness. In the heart, the
ductus arteriosus The ''ductus arteriosus'', also called the ''ductus Botalli'', named after the Italian physiologist Leonardo Botallo, is a blood vessel in the developing fetus connecting the trunk of the pulmonary artery to the proximal descending aorta. It a ...
can remain after birth, leading to hypertension. Rubella can also lead to atrial and ventricular septal defects in the heart. If exposed to rubella in the second trimester, the fetus can develop central nervous system malformations. However, because infections of rubella may remain undetected, misdiagnosed, or unrecognized in the mother, and/or some abnormalities are not evident until later in the child's life, precise incidence of birth defects due to rubella are not entirely known. The timing of the mother's infection during fetal development determines the risk and type of birth defect. As the embryo develops, the risk of abnormalities decreases. If exposed to the rubella virus during the first four weeks, the risk of malformations is 47%. Exposure during weeks five through eight creates a 22% chance, while weeks 9–12, a 7% chance exists, followed by 6% if the exposure is during the 13th-16th weeks. Exposure during the first eight weeks of development can also lead to premature birth and fetal death. These numbers are calculated from immediate inspection of the infant after birth. Therefore, mental defects are not accounted for in the percentages because they are not evident until later in the child's life. If they were to be included, these numbers would be much higher. Other infectious agents include cytomegalovirus, the herpes simplex virus,
hyperthermia Hyperthermia, also known simply as overheating, is a condition in which an individual's body temperature is elevated beyond normal due to failed thermoregulation. The person's body produces or absorbs more heat than it dissipates. When extreme ...
,
toxoplasmosis Toxoplasmosis is a parasitic disease caused by ''Toxoplasma gondii'', an apicomplexan. Infections with toxoplasmosis are associated with a variety of neuropsychiatric and behavioral conditions. Occasionally, people may have a few weeks or months ...
, and
syphilis Syphilis () is a sexually transmitted infection caused by the bacterium ''Treponema pallidum'' subspecies ''pallidum''. The signs and symptoms of syphilis vary depending in which of the four stages it presents (primary, secondary, latent, an ...
. Maternal exposure to cytomegalovirus can cause
microcephaly Microcephaly (from New Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it ...
, cerebral calcifications, blindness,
chorioretinitis Chorioretinitis is an inflammation of the choroid (thin pigmented vascular coat of the eye) and retina of the eye. It is a form of posterior uveitis. If only the choroid is inflamed, not the retina, the condition is termed choroiditis. The ophtha ...
(which can cause blindness),
hepatosplenomegaly Hepatosplenomegaly (commonly abbreviated HSM) is the simultaneous enlargement of both the liver (hepatomegaly) and the spleen (splenomegaly). Hepatosplenomegaly can occur as the result of acute viral hepatitis, infectious mononucleosis, and hist ...
, and meningoencephalitis in fetuses. Microcephaly is a disorder in which the fetus has an atypically small head, cerebral calcifications means certain areas of the brain have atypical calcium deposits, and meningoencephalitis is the enlargement of the brain. All three disorders cause abnormal brain function or intellectual disability. Hepatosplenomegaly is the enlargement of the liver and spleen which causes digestive problems. It can also cause some
kernicterus Kernicterus is a bilirubin-induced brain dysfunction. The term was coined in 1904 by Christian Georg Schmorl. Bilirubin is a naturally occurring substance in the body of humans and many other animals, but it is neurotoxic when its concentratio ...
and petechiae. Kernicterus causes yellow pigmentation of the skin, brain damage, and deafness. Petechaie is when the capillaries bleed resulting in red/purple spots on the skin. However, cytomegalovirus is often fatal in the embryo. The
Zika virus ''Zika virus'' (ZIKV; pronounced or ) is a member of the virus family ''Flaviviridae''. It is spread by daytime-active '' Aedes'' mosquitoes, such as '' A. aegypti'' and '' A. albopictus''. Its name comes from the Ziika Forest of Uganda, w ...
can also be transmitted from the pregnant mother to her baby and cause microcephaly. The herpes simplex virus can cause
microcephaly Microcephaly (from New Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it ...
, microphthalmus (abnormally small eyeballs), retinal dysplasia,
hepatosplenomegaly Hepatosplenomegaly (commonly abbreviated HSM) is the simultaneous enlargement of both the liver (hepatomegaly) and the spleen (splenomegaly). Hepatosplenomegaly can occur as the result of acute viral hepatitis, infectious mononucleosis, and hist ...
, and intellectual disability. Both microphthalmus and retinal dysplasia can cause blindness. However, the most common symptom in infants is an inflammatory response that develops during the first three weeks of life. Hyperthermia causes
anencephaly Anencephaly is the absence of a major portion of the brain, skull, and scalp that occurs during embryonic development. It is a cephalic disorder that results from a neural tube defect that occurs when the rostral (head) end of the neural tube fai ...
, which is when part of the brain and skull are absent in the infant. Mother exposure to toxoplasmosis can cause cerebral calcification, hydrocephalus (causes mental disabilities), and intellectual disability in infants. Other birth abnormalities have been reported as well, such as chorioretinitis, microphthalmus, and ocular defects. Syphilis causes congenital deafness, intellectual disability, and diffuse fibrosis in organs, such as the liver and lungs, if the embryo is exposed.


Malnutrition

For example, a lack of
folic acid Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...
, a B vitamin, in the diet of a mother can cause cellular
neural tube In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural fold become elevated, a ...
deformities that result in spina bifida. Congenital disorders such as a neural tube deformity can be prevented by 72% if the mother consumes 4 mg of folic acid before the conception and after twelve weeks of pregnancy. Folic acid, or vitamin B9, aids the development of the foetal nervous system. Studies with mice have found that food deprivation of the male mouse prior to conception leads to the offspring displaying significantly lower blood glucose levels.


Physical restraint

External physical shocks or constraints due to growth in a restricted space may result in unintended deformation or separation of cellular structures resulting in an abnormal final shape or damaged structures unable to function as expected. An example is
Potter syndrome Potter sequence is the atypical physical appearance of a baby due to oligohydramnios experienced when in the uterus. It includes clubbed feet, pulmonary hypoplasia and cranial anomalies related to the oligohydramnios. Oligohydramnios is the decrea ...
due to oligohydramnios. This finding is important for future understanding of how genetics may predispose individuals for diseases such as obesity, diabetes, and cancer. For multicellular organisms that develop in a
womb The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ut ...
, the physical interference or presence of other similarly developing organisms such as
twins Twins are two offspring produced by the same pregnancy.MedicineNet > Definition of TwinLast Editorial Review: 19 June 2000 Twins can be either ''monozygotic'' ('identical'), meaning that they develop from one zygote, which splits and forms two em ...
can result in the two cellular masses being integrated into a larger whole, with the combined cells attempting to continue to develop in a manner that satisfies the intended growth patterns of both cell masses. The two cellular masses can compete with each other, and may either duplicate or merge various structures. This results in conditions such as
conjoined twins Conjoined twins – sometimes popularly referred to as Siamese twins – are twins joined ''Uterus, in utero''. A very rare phenomenon, the occurrence is estimated to range from 1 in 49,000 births to 1 in 189,000 births, with a somewhat higher in ...
, and the resulting merged organism may die at birth when it must leave the life-sustaining environment of the womb and must attempt to sustain its biological processes independently.


Genetics

Genetic causes of birth defects include
inheritance Inheritance is the practice of receiving private property, Title (property), titles, debts, entitlements, Privilege (law), privileges, rights, and Law of obligations, obligations upon the death of an individual. The rules of inheritance differ ...
of abnormal
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
s from the mother or the father, as well as new
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s in one of the
germ cell Germ or germs may refer to: Science * Germ (microorganism), an informal word for a pathogen * Germ cell, cell that gives rise to the gametes of an organism that reproduces sexually * Germ layer, a primary layer of cells that forms during emb ...
s that gave rise to the fetus. Male germ cells mutate at a much faster rate than female germ cells, and as the father ages, the DNA of the germ cells mutates quickly. If an egg is fertilized with sperm that has damaged DNA, a possibility exists that the fetus could develop abnormally.
Genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
s are all congenital (present at birth), though they may not be expressed or recognized until later in life. Genetic disorders may be grouped into single-gene defects, multiple-gene disorders, or chromosomal defects. Single-gene defects may arise from abnormalities of both copies of an
autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosom ...
gene (a
recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
disorder) or of only one of the two copies (a dominant disorder). Some conditions result from deletions or abnormalities of a few genes located contiguously on a chromosome. Chromosomal disorders involve the loss or duplication of larger portions of a chromosome (or an entire chromosome) containing hundreds of genes. Large chromosomal abnormalities always produce effects on many different body parts and organ systems.


Socioeconomics

A low socioeconomic status in a deprived neighborhood may include exposure to "environmental stressors and risk factors". Socioeconomic inequalities are commonly measured by the Cartairs-Morris score, Index of Multiple Deprivation, Townsend deprivation index, and the Jarman score. The Jarman score, for example, considers "unemployment, overcrowding, single parents, under-fives, elderly living alone, ethnicity, low social class and residential mobility". In Vos' meta-analysis these indices are used to view the effect of low SES neighborhoods on maternal health. In the meta-analysis, data from individual studies were collected from 1985 up until 2008. Vos concludes that a correlation exists between prenatal adversities and deprived neighborhoods. Other studies have shown that low SES is closely associated with the development of the fetus in utero and growth retardation. Studies also suggest that children born in low SES families are "likely to be born prematurely, at low birth weight, or with asphyxia, a birth defect, a disability, fetal alcohol syndrome, or AIDS". Bradley and Corwyn also suggest that congenital disorders arise from the mother's lack of nutrition, a poor lifestyle, maternal substance abuse and "living in a neighborhood that contains hazards affecting fetal development (toxic waste dumps)". In a meta-analysis that viewed how inequalities influenced maternal health, it was suggested that deprived neighborhoods often promoted behaviors such as smoking, drug and alcohol use. After controlling for socioeconomic factors and ethnicity, several individual studies demonstrated an association with outcomes such as perinatal mortality and preterm birth.


Radiation

For the survivors of the
atomic bombing of Hiroshima The United States detonated two atomic bombs over the Japanese cities of Hiroshima and Nagasaki on 6 and 9 August 1945, respectively. The two bombings killed between 129,000 and 226,000 people, most of whom were civilians, and remain the onl ...
and
Nagasaki is the capital and the largest city of Nagasaki Prefecture on the island of Kyushu in Japan. It became the sole port used for trade with the Portuguese and Dutch during the 16th through 19th centuries. The Hidden Christian Sites in the ...
, who are known as the ''
Hibakusha ''Hibakusha'' ( or ; ja, 被爆者 or ; "person affected by a bomb" or "person affected by exposure o radioactivity) is a word of Japanese origin generally designating the people affected by the atomic bombings of Hiroshima and Nagasaki at th ...
'', no statistically demonstrable increase of birth defects/congenital malformations was found among their later conceived children, or found in the later conceived children of cancer survivors who had previously received radiotherapy. The surviving women of Hiroshima and Nagasaki who were able to conceive, though exposed to substantial amounts of radiation, later had children with no higher incidence of abnormalities/birth defects than in the Japanese population as a whole. Relatively few studies have researched the effects of paternal radiation exposure on offspring. Following the
Chernobyl Chernobyl ( , ; russian: Чернобыль, ) or Chornobyl ( uk, Чорнобиль, ) is a partially abandoned city in the Chernobyl Exclusion Zone, situated in the Vyshhorod Raion of northern Kyiv Oblast, Ukraine. Chernobyl is about no ...
disaster, it was assumed in the 1990s that the germ line of irradiated fathers suffered
minisatellite A minisatellite is a tract of repetitive DNA in which certain DNA motifs (ranging in length from 10–60 base pairs) are typically repeated 5-50 times. Minisatellites occur at more than 1,000 locations in the human genome and they are notable for ...
mutations in the DNA, which was inherited by descendants. More recently, however, the World Health Organization states, "children conceived before or after their father's exposure showed no statistically significant differences in mutation frequencies". This
statistically insignificant In statistical hypothesis testing, a result has statistical significance when it is very unlikely to have occurred given the null hypothesis (simply by chance alone). More precisely, a study's defined significance level, denoted by \alpha, is the p ...
increase was also seen by independent researchers analyzing the children of the liquidators. Animal studies have shown that incomparably ''massive'' doses of X-ray irradiation of male mice resulted in birth defects of the offspring. In the 1980s, a relatively high prevalence of pediatric leukemia cases in children living near a nuclear processing plant in West Cumbria, UK, led researchers to investigate whether the cancer was a result of paternal radiation exposure. A significant association between paternal irradiation and offspring cancer was found, but further research areas close to other nuclear processing plants did not produce the same results. Later this was determined to be the Seascale cluster in which the leading hypothesis is the influx of foreign workers, who have a different rate of leukemia within their race than the British average, resulted in the observed cluster of 6 children more than expected around Cumbria.


Parent's age

Certain birth complications can occur more often in
advanced maternal age Advanced maternal age, in a broad sense, is the instance of a woman being of an older age at a stage of reproduction, although there are various definitions of specific age and stage of reproduction. Fathers contribute proportionally more DNA mutations to their offspring via their germ cells than the mother, with the paternal age governing how many mutations are passed on. This is because, as humans age, male germ cells acquire mutations at a much faster rate than female germ cells. Around a 5% increase in the incidence of
ventricular septal defects A ventricular septal defect (VSD) is a defect in the ventricular septum, the wall dividing the left and right Ventricle (heart), ventricles of the heart. The extent of the opening may vary from pin size to complete absence of the ventricular sep ...
, atrial septal defects, and
patent ductus arteriosus ''Patent ductus arteriosus'' (PDA) is a medical condition in which the ''ductus arteriosus'' fails to close after birth: this allows a portion of oxygenated blood from the left heart to flow back to the lungs by flowing from the aorta, which has ...
in offspring has been found to be correlated with advanced paternal age. Advanced paternal age has also been linked to increased risk of
achondroplasia Achondroplasia is a genetic disorder with an autosomal dominant pattern of inheritance whose primary feature is dwarfism. In those with the condition, the arms and legs are short, while the torso is typically of normal length. Those affected ha ...
and
Apert syndrome Apert syndrome is a form of acrocephalosyndactyly, a congenital disorder characterized by malformations of the skull, face, hands and feet. It is classified as a branchial arch syndrome, affecting the first branchial (or pharyngeal) arch, the ...
. Offspring born to fathers under the age of 20 show increased risk of being affected by patent ductus arteriosus, ventricular septal defects, and the
tetralogy of Fallot Tetralogy of Fallot (TOF), formerly known as Steno-Fallot tetralogy, is a congenital heart defect characterized by four specific cardiac defects. Classically, the four defects are: *pulmonary stenosis, which is narrowing of the exit from the ri ...
. It is hypothesized that this may be due to environmental exposures or lifestyle choices. Research has found that there is a correlation between advanced paternal age and risk of birth defects such as limb anomalies, syndromes involving multiple systems, and
Down syndrome Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual dis ...
. Recent studies have concluded that 5-9% of Down syndrome cases are due to paternal effects, but these findings are controversial. There is concrete evidence that advanced paternal age is associated with the increased likelihood that a mother will have a
miscarriage Miscarriage, also known in medical terms as a spontaneous abortion and pregnancy loss, is the death of an embryo or fetus before it is able to survive independently. Miscarriage before 6 weeks of gestation is defined by ESHRE as biochemical lo ...
or that
fetal death Perinatal mortality (PNM) refers to the death of a fetus or neonate and is the basis to calculate the perinatal mortality rate. Variations in the precise definition of the perinatal mortality exist, specifically concerning the issue of inclusion o ...
will occur.


Unknown

Although significant progress has been made in identifying the etiology of some birth defects, approximately 65% have no known or identifiable cause. These are referred to as sporadic, a term that implies an unknown cause, random occurrence regardless of maternal living conditions, and a low recurrence risk for future children. For 20-25% of anomalies there seems to be a "multifactorial" cause, meaning a complex interaction of multiple minor genetic anomalies with environmental risk factors. Another 10–13% of anomalies have a purely environmental cause (e.g. infections, illness, or drug abuse in the mother). Only 12–25% of anomalies have a purely genetic cause. Of these, the majority are chromosomal anomalies.Kumar, Abbas and Fausto, eds., ''Robbins and Cotran's Pathologic Basis of Disease, 7th edition'', p.473.


Prevention

Folate supplements decrease the risk of neural tube defects. Tentative evidence supports the role of
L-arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the a ...
in decreasing the risk of
intrauterine growth restriction Intrauterine growth restriction (IUGR), or fetal growth restriction, refers to poor growth of a fetus while in the womb during pregnancy. IUGR is defined by clinical features of malnutrition and evidence of reduced growth regardless of an infant's ...
.


Screening

Newborn screening tests were introduced in the early 1960s and initially dealt with just two disorders. Since then
tandem mass spectrometry Tandem mass spectrometry, also known as MS/MS or MS2, is a technique in instrumental analysis where two or more mass analyzers are coupled together using an additional reaction step to increase their abilities to analyse chemical samples. A com ...
,
gas chromatography–mass spectrometry Gas chromatography–mass spectrometry (GC-MS) is an analytical method that combines the features of gas-chromatography and mass spectrometry to identify different substances within a test sample. Applications of GC-MS include drug detection, ...
, and DNA analysis has made it possible for a much larger range of disorders to be screened. Newborn screening mostly measures metabolite and enzyme activity using a dried blood spot sample. Screening tests are carried out in order to detect serious disorders that may be treatable to some extent. Early diagnosis makes possible the readiness of therapeutic dietary information, enzyme replacement therapy and organ transplants. Different countries support the screening for a number of metabolic disorders (
inborn errors of metabolism Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances ( substra ...
(IEM)), and genetic disorders including
cystic fibrosis Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. O ...
and
Duchenne muscular dystrophy Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy that primarily affects boys. Muscle weakness usually begins around the age of four, and worsens quickly. Muscle loss typically occurs first in the thighs and pelvis fol ...
. Tandem mass spectroscopy can also be used for IEM, and investigation of sudden infant death, and shaken baby syndrome. Screening can also be carried out prenatally and can include
obstetric ultrasonography Obstetric ultrasonography, or prenatal ultrasound, is the use of medical ultrasonography in pregnancy, in which sound waves are used to create real-time visual images of the developing embryo or fetus in the uterus (womb). The procedure is a stan ...
to give scans such as the
nuchal scan A nuchal scan or nuchal translucency (NT) scan/procedure is a sonographic prenatal screening scan (ultrasound) to detect chromosomal abnormalities in a fetus, though altered extracellular matrix composition and limited lymphatic drainage can also ...
. 3D ultrasound scans can give detailed information of structural anomalies.


Epidemiology

Congenital anomalies resulted in about 632,000 deaths per year in 2013 down from 751,000 in 1990. The types with the greatest death are
congenital heart defect A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...
s (323,000), followed by
neural tube defects Neural tube defects (NTDs) are a group of birth defects in which an opening in the spine or cranium remains from early in human development. In the third week of pregnancy called gastrulation, specialized cells on the dorsal side of the embryo b ...
(69,000). Many studies have found that the frequency of occurrence of certain congenital malformations depends on the sex of the child (table). For example, pyloric stenosis occurs more often in males while congenital hip dislocation is four to five times more likely to occur in females. Among children with one kidney, there are approximately twice as many males, whereas among children with three kidneys there are approximately 2.5 times more females. The same pattern is observed among infants with excessive number of ribs, vertebrae, teeth and other organs which in a process of evolution have undergone reduction—among them there are more females. Contrarily, among the infants with their scarcity, there are more males. Anencephaly is shown to occur approximately twice as frequently in females.World Health Organization reports. "Congenital malformations", Geneve, 1966, p. 128. The number of boys born with 6 fingers is two times higher than the number of girls. Now various techniques are available to detect congenital anomalies in fetus before birth. About 3% of newborns have a "major physical anomaly", meaning a physical anomaly that has cosmetic or functional significance. Physical congenital abnormalities are the leading cause of infant mortality in the United States, accounting for more than 20% of all infant deaths. Seven to ten percent of all children will require extensive medical care to diagnose or treat a birth defect. : * Data obtained on opposite-sex twins. ** — Data were obtained in the period 1983–1994. P. M. Rajewski and A. L. Sherman (1976) have analyzed the frequency of congenital anomalies in relation to the system of the organism. Prevalence of men was recorded for the anomalies of phylogenetically younger organs and systems.Rajewski P. M., Sherman A. L. (1976) The importance of gender in the epidemiology of malignant tumors (systemic-evolutionary approach). In: Mathematical treatment of medical-biological information. M., Nauka, p. 170–181. In respect of an etiology, sexual distinctions can be divided on appearing before and after differentiation of male's gonads during embryonic development, which begins from the eighteenth week. The testosterone level in male embryos thus raises considerably. The subsequent hormonal and physiological distinctions of male and female embryos can explain some sexual differences in frequency of congenital defects. It is difficult to explain the observed differences in the frequency of birth defects between the sexes by the details of the reproductive functions or the influence of environmental and social factors.


United States

The CDC and National Birth Defect Project studied the incidence of birth defects in the US. Key findings include: * Down syndrome was the most common condition with an estimated prevalence of 14.47 per 10,000 live births, implying about 6,000 diagnoses each year. * About 7,000 babies are born with a cleft palate, cleft lip or both.


See also

*
Idiopathic An idiopathic disease is any disease with an unknown cause or mechanism of apparent wikt:spontaneous, spontaneous origin. From Ancient Greek, Greek ἴδιος ''idios'' "one's own" and πάθος ''pathos'' "suffering", ''idiopathy'' means approxi ...
*
List of congenital disorders List of congenital disorders {{TOC right Numerical * 5p syndrome - see Cri du chat syndrome A * Albinism * Amelia and hemimelia * Amniotic band syndrome * Anencephaly * Angelman syndrome * Aposthia * Arnold–Chiari malformation B * ...
* List of ICD-9 codes 740-759: Congenital anomalies * Malformative syndrome *
March of Dimes March of Dimes is a United States nonprofit organization that works to improve the health of mothers and babies. The organization was founded by President Franklin D. Roosevelt in 1938, as the National Foundation for Infantile Paralysis, to comba ...
*
Mitochondrial disease Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy of ...
*
National Birth Defects Prevention Network The National Birth Defects Prevention Network (NBDPN) was founded in 1997. It is a 501(c)3 not-for-profit volunteer organization whose members are involved in birth defects surveillance, prevention and research. It was created with help from the Ce ...
, founded 1997 * Supernumerary body part


References


External links


CDC's National Center on Birth Defects and Developmental Disabilities
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