Pharmacotherapy during pregnancy

Pharmacotherapy during pregnancy is often inevitable for medical treatment of the mother, the fetus or both; the number of pregnant women treated with pharmacological drugs has been steadily increasing, partly due to advanced diagnostics and partly due to increasing rates of maternity in older women (Thomas and Yates, 2012). In addition, time-lapse between conception and realization of pregnancy may lead to unconscious medication during pregnancy. A recent systematic review on drug use during pregnancy in developed countries has revealed that 27–93% of pregnant women filled at least one prescription excluding vitamins and minerals; the use of medicines with positive evidence of risk ranged from 2.0% in Italy to 59.3% in France and use of drugs contraindicated in pregnancy ranged from 0.9% in Denmark to 4.6% in the USA (Daw et al., 2011). Several other studies support these findings (Lee et al., 2006; Yang et al., 2008; Irvine et al., 2010). Importantly, many of the compounds that are administered for maternal treatment of acute or chronic disorders may cross the placenta and elicit harmful effects in the developing fetal tissues and organs (Jacqz-Aigrain and Koren, 2005). The transplacental passage of drugs is thus complicating the treatment and, therefore, placental protective function is of an advantage. Compromising its role through inhibition of transporter proteins or their polymorphisms might lead to unexpected fetal intoxication. To prevent materno-fetal transport of drugs and to decrease fetal drug exposure and fetal toxicity, pharmaceutical research has focused on the development of special technologies and delivery forms such as liposomal encapsulation (Barzago et al., 1996) or drug conjugation with dendrimers (Menjoge et al., 2011), however, with little clinical impact so far.

The most widely used drugs in gestation include, but are not limited to, analgesics, antidepressives, antihistamines, antiemetics, hypoglycemics, antiasthmatics, antiepileptics, antibiotics, antivirals, and diuretics. Drugs are generally not tested for use during pregnancy and are, therefore, used off-label without detailed information on dosing and fetal and maternal safety. Obviously, inappropriate dosing can result in inadequate treatment of the mother or developmental toxicity of the fetus. Here we address two clinical situations of pharmacotherapy during pregnancy:

• treatment of the mother where her fetus should stay out of the reach of the drug and the transplacental passage is not appreciated
• transplacental treatment of the fetus where transport of the drug across the placenta is mandatory

Detailed knowledge on the transplacental pharmacokinetics and the role of placental drug transporters should help in optimizing transplacental treatment and choosing the right drugs and dosage algorithms. In addition, pharmacological regulation of placental transporter activity has become a new possibility to upgrade pharmacotherapy of the fetus. In the following section, we specifically focus on four situations in which pregnant women need to take medication frequently and regularly throughout the whole period of pregnancy to treat themselves or their fetus, i.e. epilepsy, diabetes, HIV infection and fetal arrhythmias. We have chosen these conditions as they are often treated by co-administration of two or more compounds that are substrates of placental drug transporters.

• Transplacental pharmacotherapy of fetal arrhythmias
• Treatment of HIV infection in pregnant women
• Treatment of epilepsy in pregnant women
• Treatment of gestational diabetes mellitus