Abstract
Prescribing in pregnancy and breastfeeding requires a thoughtful approach, considering maternal, fetal and neonatal physiology, and the pharmacokinetics of the prescribed drug. This chapter aims to familiarize the reader with pregnancy-related issues that should be taken into account when prescribing medications in the peri-partum period.
Introduction
Prescribing in pregnancy and breastfeeding requires a thoughtful approach, considering maternal, fetal and neonatal physiology, and the pharmacokinetics of the prescribed drug. This chapter aims to familiarize the reader with pregnancy-related issues that should be taken into account when prescribing medications in the peri-partum period.
More often than not, both patients and providers overestimate the risks associated with drug use in pregnancy, while the adverse effects of uncontrolled medical illness on pregnancy remain understated. When prescribing for the pregnant patient, weighing the risk of uncontrolled maternal illness against the small, possibly unknown risk of the medication, can help support and validate the use of pharmacotherapy.
Pharmacokinetics in Pregnancy
Physiologic changes of pregnancy can influence the pharmacokinetics of many medications, including absorption, distribution, metabolism, elimination and transport. These effects may warrant changes in dose or frequency of medications to ensure therapeutic benefits in the pregnant patient.
Effect of Pregnancy on Drug Absorption
Bioavailability of oral medications can be affected by several factors, including blood flow to the stomach, gastric acidity and gut transit time. During pregnancy, progesterone-induced smooth-muscle relaxation alters blood flow to the gut by vasodilatation, and intestinal motility and acid secretion are affected as well. In addition, nausea and vomiting are common in pregnancy and can interfere with oral drug administration and compliance.
Effect of Pregnancy on Drug Distribution
Changes in the cardiac output and maternal total body water during pregnancy result in an increase in the volume of distribution. Hydrophilic drugs can therefore have lower plasma levels, necessitating higher dosing for maintenance of therapeutic concentrations.1,2,3 The volume of distribution of lipophilic drugs is also increased due to an increase in maternal fat stores and fat mass. In normal pregnancy, albumin concentrations decrease on an average by approximately 1% at 8 weeks, 10% at 20 weeks, and 13% at 32 weeks.4 This has important implications for protein-bound medications. Lower albumin concentration can lead to higher levels of free drug, which in turn can increase the likelihood of drug-related toxicity. This is especially of concern when treating with medications that have a narrow therapeutic window, such as digoxin or phenytoin.
Effect of Pregnancy on Drug Metabolism
Physiologic changes associated with pregnancy also affect drug metabolism by inducing enzymatic changes in the liver and placenta. In addition, other medications specifically used in pregnancy for obstetric indications can impact drug metabolism, necessitating dose alterations.
Hepatic drug metabolism includes two phases. Phase I reactions that include oxidation, reduction or hydrolysis reactions are carried out by cytochrome P450 (CYP) enzymes. The activity of several CYP enzymes is increased during pregnancy. Changes in CYP3A4 activity lead to increased metabolism of drugs such as glyburide, nifedipine and indinavir. In contrast, CYP1A2 and CYP2C19 appear to undergo a gradual decrease in activity with advancing gestation.5,6,7 Notable substrates for these enzymes include caffeine, theophylline and citalopram. In contrast, CYP2C19 activity may be increased in patients who are treated with progesterone or 17-hydroxyprogesterone caproate (17-OHPC), used in pregnancy for prevention of pre-term labour. Medications that require CYP2C19 for metabolism, such as tricyclic antidepressants, proton pump inhibitors and propranolol, may require dose increases in patients on 17-OHPC.8
Phase II reactions include conjugation with charged species such as glucuronic acid, sulfate or glutathione to create a larger, less active product. Phase II enzymes include a group of enzymes called uridine 5’-diphosphate glucuronosyltransferases (UGTs) whose activity is increased during pregnancy. Medications that utilize these enzymes for metabolism will therefore require incremental doses to maintain therapeutic levels with pregnancy progression. One example of this is lamotrigine which demonstrates a progressive increase in clearance with advancing gestational age and a rapid rise in levels in the post-partum period.
Effect of Pregnancy on Drug Elimination
Pregnancy is associated with an increase in glomerular filtration rate (GFR), which can reduce levels of renally cleared medications. In addition, there may be changes in renal tubular transport that can result in differing effects on renally cleared drugs.9,10
Effect of Pregnancy on Drug Transport
Many drugs are eliminated through the kidneys, not just by filtration, but via active transfer across drug transporters. The activity of several renal transporters, including the organic anion transporters (OAT) or organic cation transporters (OCT) and phospho-glycoprotein (P-gp) is notably increased in pregnancy, affecting the renal clearance of many medications.11
Transport across the placenta is obviously an important consideration in pregnancy. Despite the widespread belief to the contrary, no ‘placental barrier’ exists. In fact, active transport between maternal and fetal circulations is necessary for transfer of nutrients and fetal products of metabolism. Drug transporters that are expressed in the placenta play a role in the influx or efflux of medications. Active drug transport across these transporters may increase or decrease fetal drug exposure, depending on the direction of drug transport.
As an example, placental P-gp, an efflux transporter, can decrease fetal drug levels by transporting the drug from the fetal to the maternal side of the placenta. A clinical application of this would be during treatment of fetal supraventricular tachycardia with digoxin. In this clinical setting, maternal concentrations of digoxin (a P-gp substrate) have to be pushed toward toxicity in order to achieve therapeutic fetal concentrations. Other transporters, such as placental breast cancer resistance protein (BCRP) may play a protective role by decreasing fetal delivery of glyburide, while the placental OCT3, which is involved in metformin transport, likely transports metformin toward the fetus resulting in fetal concentrations ranging from 70% to >100% of maternal concentrations.11
Evaluating Drug Safety in Pregnancy
Traditionally, teratogenic effects of drugs have been noted as anatomic malformations, and the fetus is most vulnerable to these in the first trimester. However, medications may adversely affect fetal neurological and behavioural development, fetal survival or function of specific organs, even after the first trimester. For most drugs, it is not known whether an absolutely ‘safe’ period exists when the medication can be deemed to be without effect. Fortunately, the list of known teratogens is small, and few, if any, of those drugs would fall within the purview of the pulmonary physician.
The Food and Drug Administration (FDA) has regulated the labelling of drug safety since 1979, and the pregnancy categories – A, B, C, D and X – have long been used as a guide to determine whether a medication can be safely used in pregnancy or not. However, there are several shortcomings with such oversimplification. The categories are often seen as a grading system where the risk increases from the lowest in Category A to highest in Category X, while the safety information in the accompanying narrative is disregarded. Drugs in a particular category may be perceived as carrying a similar risk but the severity of risk may wary widely within a category. Therefore, while the FDA pregnancy risk classification is useful as a quick reference with regards to available safety data, it is inadequate when used as the only source. Similarly, past labeling for safety in lactation has been sparse and usually gave vague recommendation to either stop a medication if possible or to use it with caution.
Since 2015 however, due to the above-mentioned problems, the FDA has made an official change to its labeling rules.12 The first and most significant change has been the elimination of the pregnancy drug categories. The rules instead require a narrative summary of available evidence in pregnancy and lactation, and effects on reproductive potential. If a pregnancy registry exists for the drug, information about how to enroll in the registry is required as well. Prescribing during pregnancy requires multifaceted consideration of maternal, fetal, and infant risk–benefit and the new labelling rules, with narrative summaries, gives providers detailed information to make individualized decisions for their patient.
Breast Feeding and Prescribing
Whether acutely or on a chronic basis, many lactating women will need to be exposed to therapeutic medications, making it very important to have a basic understanding behind the physiology of breast milk and the mechanisms by which drugs enter breast milk.
When prescribing medications to a breastfeeding woman, the general principles to consider include the level of need for the drug by the mother, the possible effect on breast milk production, the drug level present in breast milk, the amount of oral absorption by the infant and the possible adverse effect on the infant. Furthermore, the latter two are strongly influenced by the infant’s age at exposure as well as the infant’s own possible medical conditions, such as prematurity or congenital/genetic illnesses.13
Once the need for medication has been established, choosing which drug is appropriate should be guided by evaluating how a drug enters breast milk and the drug levels within breast milk. Maternal plasma concentrations, maternal protein binding, lipid solubility, oral bioavailability, half-life and molecular weight of the drug are all important factors that influence this.14
Drugs enter breast milk mainly by diffusion; therefore maternal plasma concentration of a drug is the most important factor for drug transmission. Secondly, due to the increased fat content of breast milk, highly lipid-soluble drugs enter breast milk in higher concentrations. Conversely, drugs that are highly protein bound in maternal circulation are less likely to enter, since the free form of a drug is what passively diffuses into breast milk. Lastly, molecular weight contributes to drug penetration into breast milk; with smaller weights (<300 daltons) diffusing more readily than larger weights (>600 daltons).
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