DRUGS IN PREGNANCY

The use of drugs in pregnancy is complicated by the potential for harmful effects on the growing fetus, altered maternal physiology and the paucity and difficulties of research in this field.

There is potential for harmful effects on the growing fetus.
Because of human variation, subtle effects to the fetus may be virtually impossible to identify.
There is altered maternal physiology.
There is notable paucity of and difficulties in research in this area.

HARMFUL EFFECTS ON THE FETUS

Because experience with many drugs in pregnancy is severely limited, it should be assumed that all drugs are potentially harmful until sufficient data exist to indicate otherwise. ‘Social’
drugs (alcohol and cigarette smoking) are definitely damaging and their use must be discouraged.

In the placenta, maternal blood is separated from fetal blood by a cellular membrane. Most drugs with a molecular weight of less than 1000 can cross the placenta. This is usually by passive diffusion down the concentration gradient, but can involve active transport. The rate of diffusion depends first on the concentration of free drug (i.e. non-protein bound) on each side of the membrane, and second on the lipid solubility of the drug, which is determined in part by the degree of ionization. Diffusion occurs if the drug is in the unionized state. Placental function is also modified by changes in blood flow, and drugs which reduce placental blood flow can reduce birth weight. This may be the mechanism which causes the small reduction in birth weight following treatment of the mother with atenolol in pregnancy. Early in embryonic development, exogenous substances accumulate in the neuro-ectoderm. The fetal blood–brain barrier is not developed until the second half of pregnancy, and the susceptibility of the cen-
tral nervous system (CNS) to developmental toxins may be partly related to this. The human placenta possesses multiple enzymes that are primarily involved with endogenous steroid
metabolism, but which may also contribute to drug metabolism and clearance.

The stage of gestation influences the effects of drugs on the fetus. It is convenient to divide pregnancy into four stages, namely fertilization and implantation (Ͻ17 days), the organogenesis/embryonic stage (17–57 days), the fetogenic stage and delivery.

FERTILIZATION AND IMPLANTATION

Animal studies suggest that interference with the fetus before 17 days gestation causes abortion, i.e. if pregnancy continues the fetus is unharmed.

ORGANOGENESIS/EMBRYONIC STAGE

At this stage, the fetus is differentiating to form major organs, and this is the critical period for teratogenesis. Teratogens cause deviations or abnormalities in the development of the embryo that are compatible with prenatal life and are observable postnatally. Drugs that interfere with this process can cause gross structural defects (e.g. thalidomide phocomelia).

Some drugs are confirmed teratogens, but for many the evidence is inconclusive. Thalidomide was unusual in the way in which a very small dose of the drug given on only one or two occasions between the fourth and seventh weeks of pregnancy predictably produced serious malformations.

DELIVERY

Some drugs given late in pregnancy or during delivery may cause particular problems. Pethidine, administered as an analgesic can cause fetal apnoea (which is reversed with naloxone). Anaesthetic agents given during Caesarean section may transiently depress neurological, respiratory and muscular functions. Warfarin given in late pregnancy causes a haemostasis defect in the baby, and predisposes to cerebral haemorrhage during delivery.