Date Published: November 1, 2016
Publisher: Public Library of Science
Author(s): Gali Pariente, Tom Leibson, Alexandra Carls, Thomasin Adams-Webber, Shinya Ito, Gideon Koren, Lucy C Chappell
Abstract: BackgroundWomen are commonly prescribed a variety of medications during pregnancy. As most organ systems are affected by the substantial anatomical and physiological changes that occur during pregnancy, it is expected that pharmacokinetics (PK) (absorption, distribution, metabolism, and excretion of drugs) would also be affected in ways that may necessitate changes in dosing schedules. The objective of this study was to systematically identify existing clinically relevant evidence on PK changes during pregnancy.Methods and FindingsSystematic searches were conducted in MEDLINE (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (Ovid), and Web of Science (Thomson Reuters), from database inception to August 31, 2015. An update of the search from September 1, 2015, to May 20, 2016, was performed, and relevant data were added to the present review. No language or date restrictions were applied. All publications of clinical PK studies involving a group of pregnant women with a comparison to nonpregnant participants or nonpregnant population data were eligible to be included in this review. A total of 198 studies involving 121 different medications fulfilled the inclusion criteria. In these studies, commonly investigated drug classes included antiretrovirals (54 studies), antiepileptic drugs (27 studies), antibiotics (23 studies), antimalarial drugs (22 studies), and cardiovascular drugs (17 studies). Overall, pregnancy-associated changes in PK parameters were often observed as consistent findings among many studies, particularly enhanced drug elimination and decreased exposure to total drugs (bound and unbound to plasma proteins) at a given dose. However, associated alterations in clinical responses and outcomes, or lack thereof, remain largely unknown.ConclusionThis systematic review of pregnancy-associated PK changes identifies a significant gap between the accumulating knowledge of PK changes in pregnant women and our understanding of their clinical impact for both mother and fetus. It is essential for clinicians to be aware of these unique pregnancy-related changes in PK, and to critically examine their clinical implications.
Partial Text: Women frequently take a variety of medications during pregnancy, including prescription, over-the-counter (OTC), and herbal agents [1,2]. During the last three decades the average number of medications (prescription and nonprescription) used per woman in North America during the first trimester increased by 60% from 1.6 to 2.6 . More recently, from 2006 to 2008, over 80% of women reported using at least one medication during the first trimester, and over 90% reported using at least one medication at any point during their pregnancy . Other studies have demonstrated increased rates of use of various OTC medications in the first, second, or third trimester of pregnancy compared to the prepregnancy period . While some studies have found that the proportion of women receiving at least one prescription medicine increases from the first to third trimester of pregnancy [5,6], others have found that rates of prescription drug use are highest in the first trimester of pregnancy [1,7]. The most common medications used in pregnancy are nonprescription or OTC medications . A longitudinal study aimed at identifying the medications that are most often consumed during pregnancy demonstrated that 95.8% of participants took prescription medications, 92.6% self-medicated with OTC medications, and 45.2% used herbal medications .
This research involved a structured review of the literature, according to the PRISMA guidelines  (S1 Checklist).
In this first systematic review, to our knowledge, of pregnancy-associated PK changes, we were able to obtain a clear overview of the landscape of the field. Now that trends of pregnancy PK change have been mapped in major drug categories and responsible metabolism or transport pathways, existing knowledge gaps critical for patient management can be addressed by the combined efforts of regulatory agencies, academia, and industry. As many women presently delay childbearing to an older age  and the frequency of medical conditions seen during pregnancy among older women is dramatically greater than that of younger women , the results of this review raise the question of whether there are sufficient data to manage these health issues appropriately during pregnancy.
Our systematic analyses confirmed that many drugs are subject to pregnancy-associated PK changes, which may alter plasma/serum drug concentration profiles. However, we have also found a paucity of clinically useful data on whether dose adjustment is necessary for these PK changes. Where such PK studies were done, generally only a few PK parameters were estimated, sample sizes were small, and maternal and/or fetal outcomes were not examined. Further studies that address these limitations are needed to optimize drug therapy for pregnant women.