Drug therapy during pregnancy

Drug therapy in pregnancy may cause anxiety to both providers and patients due to uncertainty regarding dosing and safety. Nevertheless, the needs for medications are high as the incidence of maternal chronic illnesses such as hypertension or diabetes are rising. In a nationwide study in the United States over 33 years, the prevalence of prescription medication use by pregnant women in the first trimester increased by 62.5% between the first 2 years of the study and the last 2 years. Furthermore, the average number of medications used anytime in pregnancy increased twofold during that period. More recent research from different countries have found that medications are widely used during pregnancy, with the prevalence of using at least one drug ranging from 60% to 90%, excluding vitamins and minerals. Prescription of drugs with potential teratogenicity has also increased in pregnancy, including folate antagonists or angiotensin converting enzyme inhibitors. This suggests that many women enter pregnancy with chronic conditions that require medications, including those may pose some degrees of risk to the fetus, since the maternal benefit may outweigh the risk or if the pregnancy is unplanned. Successful treatment of pregnant patients requires a correct diagnosis and providing treatment that not only is effective but also balances risks and benefits, as maternal health is a large predictor of fetal health. However, concomitant health conditions and the intrinsic complex physiological changes associated to pregnancy can make prescribing in this population a particularly challenging balancing act. Very few drugs have specific pregnancy dosing regimens supported by scientific evidence in spite of well-known pharmacokinetics changes during pregnancy affecting many medications (Table 1). Drug efficacy and safety data are sorely lacking for pregnant women, even for drugs that have been available for decades. Pregnant patients are excluded from clinical trials during the drug development process. Guidance on drug dosage and selection in pregnancy are extrapolated from studies conducted in males and non-pregnant females. However, using extrapolated data in pregnancy has a number of major drawbacks as the resulting recommended regimens fail to account for the changes in drug distribution and elimination related to pregnancy. Multiple physiological changes in pregnancy, including those affecting pharmacokinetics, must be considered when prescribing. Furthermore, these processes can also be affected by genetic variability. A classic example of altered pharmacology in pregnancy is with thyroid hormone. Thyroid hormone requires a 30% to 45% higher dose in order to maintain euthyroid state due to limited compensation in pregnant patients with underlying thyroid disease. One of the biggest physiologic changes in pregnancy is the expansion of plasma volume by approximately 50% in part due to hormone-mediated vasodilation, leading to activation of the reninangiotensin-aldosterone system. The growing fetomaternal compartment also contributes to this enhanced volume. This change results in and increased volume of distribution for hydrophilic drugs and reduced peak concentrations. Increased glomerular filtration rate in pregnancy also increases elimination of renally cleared drugs; a classic example of this effect is lithium. Changes in hepatic enzyme activity in pregnancy, including upregulation of cytochrome P450 and glucuronidation, are another cause of increased metabolism and elimination of drugs. Increased phase 2 metabolism of lamotrigine by glucuronidation results in lower drug levels in pregnancy, and this can be further affected by polymorphism of UDP-glucuronosyltransferases. One strategy to address gestational changes in pharmacokinetics is to use therapeutic drug monitoring (TDM) with analysis of blood levels; however, TDM analysis is not readily available for the majority of drugs used in pregnancy, limiting the usefulness of this strategy in clinical practice to drugs with a narrow therapeutic window where assays are readily available (i.e., digoxin and vancomycin). Furthermore, for hepatically eliminated drugs with a low extraction ratio, lower total drug levels do Received: 28 April 2020 Revised: 16 August 2020 Accepted: 26 August 2020