Congenital malformations.

The search for causes Whilst stillbirth and infant mortality rates in Great Britain have been falling to gratifying low levels, the number of perinatal deaths attributable to congenital malformations has shown remarkably little change over the years. The mortality from some defects (e.g. congenital heart disease, intestinal obstructions, myelomeningocele) has been reduced, but the prevention of malformations must await wider knowledge of their causes. The concept of congenital anomalies being caused either by genetic or by environmental factors has given way to the belief that most are of multifactorial origin. There are apparent exceptions, such as mutant genes and thalidomide, but mutations may be triggered by environmental factors and the action of teratogenic agents may be modified by genetic constitution. In the last analysis, the division between 'nature' and 'nurture' is untenable. This probably explains the disappointing results of single-factor studies. In the quarter-century since Gregg demonstrated the significance of maternal rubella, extensive animal and human virus studies have failed to incriminate any other virus. Suspicions have been cast on the viruses of poliomyelitis, Asian influenza, infective hepatitis and smallpox but the doubts have not been confirmed. The latest to come under scrutiny is mumps virus, and the results of further work in this field will be awaited with interest (St. Geme, Noren & Adams, 1966). It is more difficult to investigate the teratogenic properties of drugs in the human, particularly once it has been alleged that the drug in question is harmful to the embryo. Since the identification of thalidomide as a teratogen in 1961, many other drugs have been accused of embryopathic activity. Only one of these, meclozine, has been extensively studied by acceptable techniques, and no teratogenic action has been demonstrated. Chromosome studies have been of limited help. Since the discovery in 1959 of an extra autosome in mongols, two other autosomal trisomy syndromes have been identified and a number of rare syndromes have been associated with structural chromosome abnormalities. Apart from mongolism, these conditions account for only a very small proportion of congenital defects. In the investigation of particular malformed infants, chromosome studies are unlikely to be fruitful unless there are multiple physical defects associated with mental defect. The environment of the embryo is, broadly speaking, the mother. There may therefore be something to learn from a comparison of the mothers of malformed infants with the mothers of normal infants. In studies of this kind it is now almost traditional to compare maternal age, parity, blood groups and socio-economic status. The effect of maternal age is only really striking in mongolism. Socio-economic factors appear relevant to neural tube defects. Blood group studies have so far been unfruitful. More recently a search has been made for biochemical differences between these two groups of mothers. The somewhat increased incidence of congenital defects amongst the offspring of diabetic and pre-diabetic women has been recognized for a long time. A recent study showed the presence of insulin antagonists in the serum of non-diabetic mothers of malformed infants much more frequently than in controls (Wilson & Vallance-Owen, 1966). The suggestion that the mothers of mongols excrete increased amounts of urinary dehydroepiandrosterone has not been confirmed. Outside the endocrine field, a preliminary study has shown a correlation between maternal folic acid deficiency and congenital anomalies in the offspring, particularly neural tube defects (Hibbard & Smithells, 1965). This finding awaits confirmation but has well-known parallels in experimental animal teratology. An entirely different approach from the search for causes is through studies of groups rather than of individuals. Family studies, twin studies and pedigree analyses help to elucidate the genetic contribution to specific defects. Population studies coright.