Treating life-threatening diseases and those associated with morbidities
There is a considerable increase in maternal comorbidity including obesity, hyperlipidemia, diabetes, and hypertension in recent years worldwide. Many of these comorbid conditions have been linked to higher rates of pregnancy-related morbidity and mortality [30]. Asthma for example can be common in pregnancy and in some cases worsens due to physiological changes. In one study, it has been shown that there has been a reduction in prescriptions of asthma medication during the first trimester of pregnancy [31, 32]. However, it is important to control asthma symptoms during pregnancy despite the safety profile of some medications used. Uncontrolled asthma can lead to complications including preeclampsia, preterm delivery and low birth weight [33]. This is a compelling example where risks of uncontrolled asthma outweigh potential risks of neonatal fetotoxicity from exposure. Another example are oral steroids like prednisone. Prior observational studies have reported cleft lip and cleft palate when prednisone was used early in pregnancy but those results were not consistent over time [34].Table 2 highlights controversial medications that need additional counseling given their possible or known adverse effects on the fetus. There is much controversy in interpreting population-based studies and animal studies when it comes to teratogenicity and fetotoxicity. Some drugs that showed adverse effects in animal models were not matched when studying human population and vice versa. Statins, which are now being investigated as potential drugs to prevent preeclampsia have been previously contraindicated in pregnancy. However, a recent meta-analysis including 16 human studies showed no relationship between statins and teratogenicity [35]. More recently, the FDA has requested removal of the contraindication of statins in pregnancy [36].
Improving the infrastructure of research seems to be something that would benefit the moral imperative to incorporate pregnant women into clinical drug trials. Pharmacoepidemiologic studies are limited by the fact that often disease and severity are related to exposure and adverse outcome and that systematic bias is not usually accounted for when the pharmacologic exposure or the disease itself was the cause of fetotoxicity. For example, autoimmune diseases like rheumatoid arthritis, inflammatory bowel disease or lupus might exacerbate during pregnancy. In these diseases it has been noted that there is an increased risk of low birth weight, preterm birth and associated morbidities with current treatment options, but whether this is in an effect of the treatment per se or the disease itself is hard to decipher [37-39].