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.

 


Literature:
Barzago MM, Bortolotti A, Stellari FF, Diomede L, Algeri M, Efrati S, Salmona M and Bonati M (1996) Placental transfer of valproic acid after liposome encapsulation during in vitro human placenta perfusion. J Pharmacol Exp Ther 277:79-86.
Daw JR, Hanley GE, Greyson DL and Morgan SG (2011) Prescription drug use during pregnancy in developed countries: a systematic review. Pharmacoepidemiol Drug Saf 20:895-902.
Irvine L, Flynn RW, Libby G, Crombie IK and Evans JM (2010) Drugs dispensed in primary care during pregnancy: a record-linkage analysis in Tayside, Scotland. Drug Saf 33:593-604.
Jacqz-Aigrain E and Koren G (2005) Effects of drugs on the fetus. Semin Fetal Neonatal Med 10:139-147.
Lee E, Maneno MK, Smith L, Weiss SR, Zuckerman IH, Wutoh AK and Xue Z (2006) National patterns of medication use during pregnancy. Pharmacoepidemiol Drug Saf 15:537-545.
Menjoge AR, Rinderknecht AL, Navath RS, Faridnia M, Kim CJ, Romero R, Miller RK and Kannan RM (2011) Transfer of PAMAM dendrimers across human placenta: prospects of its use as drug carrier during pregnancy. J Control Release 150:326-338.
Thomas SH and Yates LM (2012) Prescribing without Evidence-Pregnancy. Br J Clin Pharmacol.
Yang T, Walker MC, Krewski D, Yang Q, Nimrod C, Garner P, Fraser W, Olatunbosun O and Wen SW (2008) Maternal characteristics associated with pregnancy exposure to FDA category C, D, and X drugs in a Canadian population. Pharmacoepidemiol Drug Saf 17:270-277.

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