Obstetric Pharmacokinetic Dosing Studies are Urgently Needed

Abstract

Use of pharmacotherapy during pregnancy is common and increasing. Physiologic changes during pregnancy may significantly alter the overall systemic drug exposure, necessitating dose changes. A search of PubMed for pharmacokinetic clinical trials showed 494 publications during pregnancy out of 35,921 total pharmacokinetic published studies (1.29%), from the late 1960s through August 31, 2013. Closer examination of pharmacokinetic studies in pregnant women published since 2008 (81 studies) revealed that about a third of the trials were for treatment of acute labor and delivery issues, a third included studies of infectious disease treatment during pregnancy, and the remaining third were for varied ante-partum indications. Approximately, two-thirds of these recent studies were primarily funded by government agencies worldwide, one-quarter were supported by private non-profit foundations or combinations of government and private funding, and slightly <10% were supported by pharmaceutical industry. As highlighted in this review, vast gaps exist in pharmacology information and evidence for appropriate dosing of medications in pregnant women. This lack of knowledge and understanding of drug disposition throughout pregnancy place both the mother and the fetus at risk for avoidable therapeutic misadventures - suboptimal efficacy or excess toxicity - with medication use in pregnancy. Increased efforts to perform and support obstetric dosing and pharmacokinetic studies are greatly needed.

Keywords: maternal–fetal; obstetrics; pharmacokinetics; pharmacology; pregnancy.

Figure 1

Number of pharmacokinetic clinical trials conducted in pregnancy. The year 2013 includes those articles index for MEDLINE by August 31, 2013 only. This figure displays the absolute number of articles meeting the search terms, displayed by year.

Figure 2

Number of pregnancy and non-pregnancy pharmacokinetic clinical trials. The year 2013 includes those articles index for MEDLINE by August 31, 2013 only. This figure displays the number of pregnancy pharmacokinetic articles along with all pharmacokinetic articles (pregnancy search term excluded) found to otherwise match the search terms specified.

Figure 3

Proportions of pharmacokinetic clinical trials conducted in pregnancy. The year 2013 includes those articles index for MEDLINE by August 31, 2013 only. This figure shows the percentage of pregnancy pharmacokinetic articles compared to all pharmacokinetic articles published since the early 1990s.

Figure 4

Trends for classification of search results for recent clinical trials of pharmacokinetics and pregnancy. Data for 2013 only includes those articles indexed for MEDLINE by August 31, 2013. The “intra-partum” category includes medications given at the time of delivery, typically for pain control or infectious disease prophylaxis. The “late ante-partum” category includes pharmacotherapy given for pre-eclampsia; management of syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP); or to induce tocolysis. The remaining categories include medications administered earlier in pregnancy (i.e., prior to labor/delivery) only.

Figure 5

Distribution of primary funding sources. For clinical trials with funding source information provided, the number of studies primarily funded by each source is displayed.