Birth Defects

Birth defects are also termed congenital anomalies or inborn errors. While not always diagnosed at birth, they are believed to have been present at birth and have their origin in some perturbation of the normal developmental process. The causes of birth defects include genetic abnormalities inherited from either or both parents; genetic abnormalities that spontaneously arose in the individual itself; insufficiencies in the mother, such as placental abnormalities or nutritional deficiencies; maternal disease (such as diabetes); exposure to drugs or environmental factors (summarized under the term teratogen, and including such diverse factors as hyperthermia, alcohol, or viruses); or physical trauma during the developmental period.

Developmental defects, as the name implies, occur as a result of changes in development processes that cannot be repaired or compensated for. It is generally believed that earlier perturbations affect the developing embryo more profoundly than later episodes, with the first trimester of pregnancy being the most critical period.

In the first 7 to 10 days after fertilization, the human embryo undergoes several cell divisions, with implantation into the uterine wall marking the successful establishment of pregnancy. Contributing some of its own tissue, the embryo ensures access to nutrients through the formation of the placenta, which is a combination of maternal and embryonic tissue.

Insufficiencies in placental function profoundly affect growth and survival of the developing embryo. In rapid succession, the territories for the primordia of major tissue systems are laid down in a process that defines the overall body pattern of a vertebrate embryo. During a 4to 10-week phase of development, which spans the events scientifically referred to as gastrulation and neutralization, embryos are most sensitive to perturbations that cause birth defects.

Highly coordinated processes of growth, movements, and interactions of cells are critical to proper formation of the primordial of major tissues and body parts and to subsequent development of each organ. Perturbations may affect groups of cells, changing their behavior, or the interactions between cells, resulting in miscommunication, or their growth, causing asynchrony. A single change can thus fundamentally influence one or more subsequent developmental pathways.

In many cases, the primary cause of the developmental defect cannot be unequivocally determined, but for genetic abnormalities, an increasing number of tests are becoming available that detect trisomies, translocations, deletions, rearrangements, and mutations. If the mutation was inherited, there is a higher risk of recurrence in future offspring.

Birth defects are classified as major and minor, generally reflecting clinical severity. Some birth defects are lethal, such as absence of the brain, malformations in brain structures (lissencephaly), severe skeletal dysplasia (thanatophoric dysplasia), or severe heart malformations or lung dysfunction as often seen with premature births. Major malformations include neural tube defects, heart defects, or agenesis of body parts that collectively affect from 1/1,000 up to several percent of births in special populations.

Minor malformations, such as vertebral anomalies, may go undetected at birth and include digit abnormalities, cleft lip or altered facial features, or internal organ defects.

A group of birth defects that may or may not be associated with physical deformities is referred to as inborn errors of metabolism. In these cases, the ability to take up and properly utilize nutritional compounds is diminished or the removal of intermediates or end products is compromised. Cognitive impairment and neural retardation, even though not always detectable at birth, also have strong developmental components, as they often reflect subtle structural abnormalities of the brain.

Blindness and deafness may also be considered birth defects insofar as they result from abnormal development of eyes and ears or inborn tendency to degenerate. Since much of the development of sensory and cognitive systems in humans occurs after birth, the term “developmental defect” rather than “birth defect” would be more appropriate.

Historically, a distinction has been made in classification of birth defects as syndromic or isolated, depending on whether a combination of anomalies was present or not. With more refined combinations of clinical and genetic diagnosis, this distinction has become less meaningful in recent years.

The incidence of certain birth defects appears to be related to maternal nutrition. It has long been recognized that the risk for neural tube defects can be reduced by supplementation of maternal diet with folic acid (folate). In many countries, it is recommended that women supplement their food intake with folate-containing multivitamins; in the United States, grain products such as flour, bread, and cereal are fortified with folic acid. However, for folate to be effective, adequate levels have to be maintained during the early pregnancy, prompting the recommendation that all women of childbearing age consume either supplemental folate at 400 mg/day through a multivitamin that contains this amount or folate-only supplements. This will ensure adequate folate supply even if the pregnancy was unplanned or not recognized early on. Yet, even though folate can lower the risk, it cannot prevent all neural tube defects. Furthermore, it has recently been recognized that folate is also beneficial in reducing the incidence of cleft lip and palate and possibly skeletal defects.

Given that birth defects are the leading cause of child mortality in developed countries, the importance of proper nutrition cannot be overstated. Exposure of the developing embryo to potential teratogens is difficult to assess, unless outcomes point to well-defined syndromes, such as fetal alcohol syndrome. Time of exposure, intensity, and duration may affect embryonic development. In recent years, it has become increasingly recognized that fetal exposure may not only cause acute insults but also predispose to disease later in adult life. For example, maternal use and exposure to tobacco during pregnancy are associated with increased risk for respiratory disease in progeny. Similarly, maternal diabetes during pregnancy appears to predispose to susceptibility for metabolic syndrome in the offspring. A rising concern is the increasing prevalence of babies born small for gestational age or prematurely. While not a birth defect in the classical definition, developmental immaturity at birth is associated with substantially increased childhood morbidity, mortality, and disease susceptibility later in life.

Most progress in understanding the causes of birth defects has been made for anomalies caused by mutations in single genes. In these cases, the availability of diagnostic tests has enabled screening of at-risk pregnancies, although in utero prevention of already manifest birth defects is currently not possible. However, in case of continuing pregnancy and birth, early diagnosis is often critical to choosing treatment options or timely enrollment in appropriate support programs. However, it should be emphasized that even in cases of a well-known genetic origin for a given disorder, the specific manifestation may cover a range of severity from profoundly to mildly affected or even asymptomatic individuals. This phenomenon of variable expressivity and incomplete penetrance makes estimates of recurrence risks difficult. The confounding factors in this variability are of great research interest and have important implications for individual treatment and long-term care.


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