Drugs in pregnancy: acknowledging challenges--finding solutions.

ue to obvious ethical issues of experimenting drugs during fetal development, women and their unborn babies are commonly excluded from drug trials. As a result, these two groups of patients are commonly orphaned from the revolution in drug therapy witnessed in the last generation. The removal of Bendectin from the American market despite being safe in pregnancy sent a chilling signal to drug companies, essentially discouraging them from developing or studying drugs for pregnant patients. Even in areas which are exclusively typical of pregnancy (e.g.., morning sickness or tocolysis) no new drug trials are performed. Consequently, the advance in therapeutics in pregnancy lags substantially behind the same conditions or drugs in nonpregnant women, or men. However, this approach is highly unwarranted, as uncontrolled maternal conditions may affect adversely both the mother and her fetus. Hence, a rational approach must also incorporate estimation of the risks of the untreated maternal condition. This has been highlighted painfully in recent years, where anxiety of yet unproven fetal risks of SSRI have received much attention, leading many women to discontinue these drugs, but with very little attention to the tremendous risk of untreated maternal depression. Because embryogenesis is completed by the end of the first trimester of pregnancy, if a drug is not affecting brain development, (which continues throughout gestation), there is no apparent reason not to study it during the second and third trimesters of pregnancy. Several recent developments may mark important milestones in changing the approach to drug trials in pregnancy. Changes in Drug Disposition in Late Pregnancy During the last few years a large body of evidence has suggested that in late pregnancy, there is substantial increase in the clearance rate of various drugs, due to increase function of different cytochrome P450 enzymes, including nicotine (2A6), fluoxetine and citalopram (2D6), and protease inhibitors (3A4). This means that women may need larger doses to achieve therapeutic steady state concentrations. For example, using nicotine replacement therapy has failed to prevent smoking in late pregnancy when compared to placebo, probably because the dose regimen used in late pregnancy was insufficient. Similarly, many women with depression are not controlled clinically in late pregnancy, possibly at least in part because doses that were adequate before pregnancy are grossly inappropriate in late pregnancy.Late pregnancy is also characterized by major changes in glomerular filtration rate (GFR), hepatic blood flow, protein binding and altered drug compliance. These changes lead, in most instances, to lower systemic exposure to medications, both hepatically and renally eliminated.