Pergnancy in Drugs.

Drugs in Pregnancy

Teratogenesis and other adverse effects of drugs during Pregnancy.

Teratogenesis means the production monsters or misshapen organisms. Also to include the generation of functional abnormalities in the baby. The effect of a noxious agent reaching the fetus early in pregnancy, whilst the organ systems are forming, is likely to be the cause of anatomical malformation. Later in pregnancy, when the basic structures are fully developed, it is function that is at risk.

                Only 2-3% of pregnancies that survive the first trimester result in a grossly abnormal fetus, though minor malformations are recognizable in at least another 5%. The proportion of these abnormalities to which drugs have contributed in any way is probably small, less than 1 in 20. It follows that only a small, number of newborn babies have been seriously affected by drugs given in pregnancy, since it is in general avoidable.

Causation

Very few drugs that have been used therapeutically cause congenital abnormalities in the sense that a high proportion of fetuses will be affected if the drug is given to a pregnant woman – thalidomide and methotrexate are the only well-known examples.

                With most therapeutic agents where it is accepted there is some hazard to the fetus, the magnitude of risk is small and capable of being further reduced by careful therapeutics. It follows that the causative chain of events leading to an apparently drug-associated anomaly is tenuous, being dependent on conditioning circumstances, many of them imponderable. The lack of specificity of the abnormalities, nearly all of which can occur when no drugs have been taken, confirms their multifactorial origin.

                There is increasing recognition of the role of folic acid, and probably other B vitamins as one of these cofactors. There is no doubt that deficiency of these vitamins can cause abortion and congenital abnormalities. In animals, folic acid will protect against a wider range of teratogenic stimuli than is represented by known foliate antimetabolites. A number of therapeutic agents suspected of teratogenicity have been found to interfere with folic acid absorption and metabolism. Recently it has been demonstrated that supplementation of dietary folate, initiated before conception, tends to prevent recurrence of neural tube defects and other anomalies in women who have previously had an affected baby. The lack of specificity of drug- associated anomalies is consistent with impairment of folate status being a final common pathway for the generation of a proportion of congenital abnormalities.

Placental Transfer of Drugs

Transmission of nearly all drugs to the fetus is by simple diffusion. The rate of transfer relates directly to the concentration gradient of unbound, unionized drug. The diffusion constant is inversely related to molecular weight and directly to lipid solubility. In practice very nearly all therapeutic agents pass through to the fetus; heparin, with its molecular weight of more than 15000, is an exception; curare, which is highly polar, is another.  The rate of transfer is not of much significance except with agents such as anesthetics which are given for short periods of time on a single occasion. When a therapeutic concentration of a drug is maintained in the maternal circulation it will eventually reach the fetus in meaningful amounts.

Metabolism in the Fetus

Subject to conditioning factors, the pharmacodynamics of teratogenic agents is like those of any other drug. That is, the likelihood that they will have an effect is directly related to their concentrating at the appropriate site in the developing fetus. The ability of the fetus to metabolise, detoxicate or exerted a drug is therefore of great importance in reducing its effective concentration. Knowledge of these functions is limited, but there is individual variation in the ability of the fetal liver to metabolise drugs and to generate detoxicating enzymes. Although the fetal kidney starts to function in the third month of pregnancy, some drugs passing into the amniotic fluid, renal function is immature and this is not an important route of elimination. 

                The dependence of fetal plasma concentration of diffusion across the placenta prevents accumulation of free drug in the fetal circulation, but a few agents can be concentrated in specific fetal organs. Examples are iodine, which is accumulated in the fetal thyroid, and radioactive strontium, which is taken  up by developing bone.