congenital abnormalities

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congenital abnormalities ‘Congenital’ means ‘present at birth’, but malformations that are obvious at birth represent only a small proportion of the seriously malformed products of gestation. The term ‘congenital anomalies’ is also used and these are defined as significant, definable, structural and/or developmental abnormalities observed at birth. Some anomalies are produced by adverse environmental agents, such as viral infection of the mother, specific toxins (including hormones), ionizing radiations, or inadequate supply of oxygenated blood to developing organs; all these together comprise around 5–6% of the total. Abnormalities associated with a mutant gene account for about 5% and identifiable chromosomal aberrations for a further 10%.

It is estimated that between 60 and 80% of all conceptuses are lost early in gestation. These may be the result of ‘bad eggs’ (abnormal cleavage, abnormal chromosomes), major early embryonic maldevelopment, or significant embryonic metabolic abnormalities, with early embryonic death and resorption in some cases. Approximately half of all fetuses spontaneously aborted in the first 3 months have significant chromosomal anomalies.

Anomalies of clinical significance are found in 2–5 of every 100 human infants born alive. This does not include infants with hidden defects or those with disorders that only become evident later. For rather more than half of congenital anomalies present at birth no single cause has yet been identified.

The study of congenital malformations is known as teratology. Abnormalities evident at birth can arise due to failure of development (for example, absent limb(s), microcephaly); failure of parts to unite (cleft lip and palate, spina bifida); failure to divide (syndactyly — joined fingers or toes; conjoined twins); failure to canalize (atresia: no passage through some part of the gut); failure of tissues to migrate to the proper site (malrotation of bowel, Hirschsprung disease); failure to atrophy — to disappear appropriately in the course of development (branchial clefts, thyroglossal cyst); excess division (polydactyly — too many fingers or toes, duplication of kidneys).

Chromosomal and gene mutation abnormalities take effect during all phases of pre- and post-natal life and can cause isolated or multiple congenital anomalies. Regulatory (master) genes code for polypeptides that are active in cell nuclei and modify the array of transcribed genes from the totipotent cells of the 2–8 cell embryo to the specialized cell populations of later organ development, such as that of the brain. Proliferation and differentiation of cells within body organs is largely mediated by growth factors, and by the polypeptides that cause genetic information from the DNA to be transcribed onto messenger RNA in body cells. These transcription factors, controlled by regulatory genes, promote a cascade of temporally and spatially organized events that cause the formation of, for example, the neural tube, or the heart. Abnormal transcription regulation can cause profound errors in the forming of the embryo, and a number of genes have been identified that control development of the different segments of the body, from head to tail, and of the organs. The cell replication, programmed cell death (apoptosis), induction and intercellular communication, cell migration, and movement of contiguous cell populations are all, in part, determined by regulatory genes and their transcription factors. Nutritional factors, toxic factors, and metabolic disorders present at critical stages of embryogenesis have the potential to interfere with the developmental changes controlled and influenced by the regulatory genes. Maternal infections, physical insults, and metabolic disorders, such as diabetes mellitus or phenylketonuria, increase the risk of congenital anomalies, including brain anomalies; likewise maternal ingestion of some substances (including alcohol and thalidomide), which for this reason are known as teratogens.

Mineral and vitamin deficiency states can adversely influence transcriptions through, for example, effects on enzyme systems that depend on particular elements. Notably, severe zinc deprivation during embryonic and fetal development has been shown in animals to have profound effects on virtually all derivatives of the neural tube (the preliminary stage of the central nervous system) and associated structures, including the brain, spinal cord, and eyes. Deficiencies of manganese, copper, iron, selenium, and iodine have all been shown to affect developing organs.

Folic acid is important in, for example, the development of nerve cells, their growth and the myelination of their axons. Normal closure of the neural tube in the human embryo occurs between days 21 and 24. Folate deficiency before and during this stage of development results in neural tube defects (brain and spinal cord abnormalities). A mutation in the genes of some mothers for a certain enzyme (known as MTHFR) is associated with a detectable chemical change in the blood when their dietary folate intake is marginal; this defect has been found in 5–7% of mothers in some European populations. Ensuring adequate maternal dietary intake of folate significantly reduces the incidence of neural tube defects and possibly other central nervous system defects.

Vitamin B1 (thiamine) deficiency is relatively common in the developing world and has been associated with fetal defects; thiamine deficiency may be one of the mechanisms by which chronic maternal alcoholism results in fetal defects. Pyridoxine (Vitamin B6) deficiency, and vitamin A deficiencies and excesses, have also been shown to produce malformations in animals.


The frequency of significant congenital anomalies remained the same or declined slightly overall during the twentieth century in those countries with good registers, despite public apprehension and a number of well-publicized environmental disasters. However, some of the commoner defects have reportedly increased in incidence, according to the birth defects monitoring programme of the Centers for Disease Control in Atlanta. During the 1990s there was a significant increase in ventricular septal defect (‘hole in the heart’), patent ductus arteriosus, renal agenesis (failure of kidney development), and hip dislocation, but a decrease in spina bifida.

In the case of some malformations, their manifestations and the likelihood of survival varies among infants who have essentially the same defect, including variation by maternal race, the infant's sex, and birthplace. Neural tube defects are commoner in the UK and Ireland compared with the rest of Europe; this may be partly related to the high prevalence of gene mutations in MTHFR. In Japan, Taiwan, and Singapore there is a high incidence of anencephaly (absence of skull and brain) compared with other neural tube defects, and two-thirds of anencephalic infants are female. It may be that anencephalic male embryos are expelled unrecognized from the womb at an early stage.

Whilst about 2% of new-born infants have major malformations, a further 6% have minor ones; also major and minor malformations may co-exist.

Multiple malformations

may be part of(i) a syndrome in which there is a single cause for the various malformations, e.g. Down's syndrome (extra chromosome 21) and fetal alcohol syndrome (FAS);(ii) a sequence whereby one malformation has led to other malformations — e.g. failure of kidney development, with lack of fetal urine production, leads to lack of amniotic fluid (oligohydramnios), and that in turn to underdevelopment of the lungs (pulmonary hypoplasia) because of restriction of fetal breathing movements;(iii) a condition in which various malformations are statistically associated but there is no known or common cause — e.g. VATER association, which is an acronym for vertebral, anal, tracheal, oesophageal, and renal malformations.

Minor malformations include haemangiomas and naevi (birthmarks); skin tags; hydrocoeles; webbing of fingers and toes or supernumerary digits; malformed ears; and pigmented skin lesions. Although some of these defects can cause major health problems, malformations considered by convention to be major are those affecting the heart (which may or may not prevent blood from flowing normally through the lungs, and therefore may or may not result in a ‘blue baby’: cyanotic or acyanotic congenital heart disease); the central nervous system (hydrocephalus, meningocoele, and encephalocoele); the urinary system (including hydronephrosis and polycystic kidney); the digestive system (various herniae, malrotations, and atresias); cleft lip and/or palate; limb defects (including dislocated hip and club foot); genital disorders (such as undescended testes, hypospadias (see penis), and ambiguous genitalia); and eye defects (cataract and microphthalmos — small eyes). Finally, there may be multiple system defects combining several of these.

Treatment and prevention

There are now medical and surgical therapies available for some malformations detected before birth. Prevention strategies include immunization against rubella; avoidance of alcohol and other potentially embryotoxic chemicals and agents during pregnancy; strict control of metabolic disturbances in the mother; and a balanced nutrient intake from before the time of conception.

Forrester Cockburn

See also antenatal development; cleft lip and palate; club foot; hydrocephalus.