Transplacental Pharmacotherapy of the Fetus

(excerpted from Staud et al., 2012)

Transplacental pharmacotherapy of fetal diseases is a relatively novel discipline of noninvasive medicine in which the mother is administered a drug that, after transplacental transport, reaches fetal circulation to fulfill its mission. To maximize fetal drug exposure (and therefore drug effectiveness) and to minimize drug activity/toxicity in the mother remains a challenging task.

It should be pointed out that it is not only the mother that is the target of therapy. Over the past several decades, modern technologies of prenatal diagnosis have changed the attitude to fetal diseases from simply terminating the pregnancy by interruption to possible active therapy of the fetus. Fetal therapy began almost 60 years ago in the form of peritoneal transfusion for the treatment of fetal anemia (Liley, 1963). About a decade later, transplacental therapy was introduced as a non-invasive intervention to treat the fetus through administration of the drug to the mother. One of the first examples of transplacental delivery was reported in 1975 by Ampola and colleagues who administered large doses of vitamin B12 to the mother during the last nine weeks of gestation for successful treatment of methylmalonic acidemia of the fetus (Ampola et al., 1975). Since then, transplacental medication has been used as a novel approach of modern medicine for the treatment of various fetal disorders; e.g. cardiovascular drugs to treat life-threatening fetal cardiac arrhythmias, antiretrovirals to prevent transmission of HIV from mother to fetus, glucocorticoids to promote fetal lung maturation in cases of threatening premature birth, immunoglobulin and many others (see recent reviews (Hui and Bianchi, 2011; Westgren, 2011)). In the transplacental treatment, the drug is given to the mother and expected to cross the placenta in reasonable time and amount to provide treatment for the fetus. In this scenario, placental transporters might, and in many cases they indeed do, reduce drug availability for the fetus and, therefore, minimize their effectiveness. For example, P-glycoprotein is blamed for decreasing fetal exposure to maternal digoxin. Inevitably, the transplacental treatment possesses some risks of drug toxicity to the mother raising the challenge of fetus-specific drug delivery systems. In the late 1990s, selective drug targeting during pregnancy was being discussed (Audus, 1999) and several reports by Bajoria and colleagues appeared suggesting specific fetus-targeted delivery forms for drugs that cross the placenta sparingly, such as unilamellar liposomes for thyroxin delivery to the fetus (Bajoria and Contractor, 1997a; Bajoria and Contractor, 1997b; Bajoria et al., 1997a; Bajoria et al., 1997b); however, since then, this line of research has been rather quiet. Pharmacological manipulations, such as modulation of placental drug transporters might offer another option to optimize the transplacental pharmacotherapy and to maximize fetal drug exposure. For example, inhibition of placental P-glycoprotein may be beneficial in the treatment of HIV positive pregnant women to increase transplacental passage of antiretroviral agents and to reduce the rate of mother-to-child viral transmission. Similarly, for the treatment of fetal tachycardia, pharmacological inhibition of placental P-glycoprotein would offer the advantage of enhanced digoxin availability to the fetus, while minimizing drug exposure of the mother.

It is evident, that proper understanding of transplacental passage of drugs and the role of placental transporters in this event will guide the clinicians to more accurate and safer pharmacotherapy during gestation, avoiding or, on the other hand, taking advantage of drug interactions. In addition to clinicians, the discovery of the interactions of drugs with placental transporters is of great interest also to pharmaceutical industry for future drug development to control the degree of fetal exposure (Gedeon and Koren, 2006; Malek and Mattison, 2010).

Further reading:

Transplacental pharmacotherapy of fetal arrhythmias

Treatment of HIV infection in pregnant women