Principles of Pharmacotherapy in Pregnancy and Lactation
Andrew M. Peterson
Lauren M. Czosnowski
Although very little is known about the effects of medications on the fetus, many women ingest drugs during their pregnancy. The World Health Organization states “there can be no doubt that at present some drugs are more widely used in pregnancy than is justified by the knowledge available” (Collaborative Group on Drug Use in Pregnancy, 1991). Although considerable attention has been given recently to complementary and alternative medicine use during pregnancy, the use of these ubiquitous substances continues and poses significant challenges to today’s health care practitioner (Briggs et al., 2014).
ISSUES IN MEDICATION USE DURING PREGNANCY
Studies have determined that about 90% of women will use one medication during pregnancy, and about 70% will use one or more prescription medications (CDC, 2014). As the number of medications being prescribed during pregnancy increases, the practitioner needs a solid understanding of the physiologic changes that occur during pregnancy and the effects that these changes have on medication use. The practitioner must also balance the need to treat the mother against the potential risk to the fetus. Because there are few studies available discussing the pharmacokinetic changes that occur during pregnancy, appropriate dosing of medications may be difficult. Understanding these changes will assist the practitioner in making recommendations during drug therapy. The maternal and fetal response to medications ingested during pregnancy may be influenced by two factors:
Changes in the absorption, distribution, and elimination of the drug in the mother, which are altered by physiologic changes.
The placental-fetal unit, which affects the amount of drug that crosses the placental membrane, the amount of drug metabolized by the placenta, and the distribution and elimination of the drug by the fetus.
Pregnancy-Induced Maternal Physiologic Changes
Women undergo many physiologic changes during pregnancy (Table 5.1). These changes affect the way a medication exerts its effects on both the mother and fetus.
Absorption
Drug absorption into the maternal bloodstream can occur by different processes, including the gastrointestinal (GI) tract, skin, or lungs, or the drug may be directly placed into the bloodstream via intravenous administration.
Gastrointestinal Absorption
Pregnancy-induced maternal physiologic changes may affect GI function, and therefore, the absorption of some drugs may be altered. Of the many factors that can affect GI absorption of drugs, one is the decrease in GI tract motility, especially during labor. It is believed that an increase in plasma progesterone levels causes this decrease in motility, which may delay the absorption of orally administered drugs.
In addition, pregnant women experience a reduction in gastric acid secretions (up to 40% less than in nonpregnant women) as well as an increase in gastric mucus secretion (Fredericksen, 2001; Loebstein et al., 1997). Together, this may lead to an increase in gastric pH and a decrease in the absorption of medications that need an acidic pH for appropriate absorption.
TABLE 5.1 Physiologic Changes in Pregnancy | ||||||||||||||||||||||||||||
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Another reason for decreased GI absorption may be the nausea and vomiting that is common during the first trimester of pregnancy and that is thought to be associated with increased progesterone levels. Therefore, pregnant women may be well advised to take their medications at times when nausea is minimal.
Lung Absorption
Physiologic changes in pregnancy favor the absorption of medications administered through the inhalation route. Both cardiac and tidal volumes are increased by approximately 50% in pregnancy; this results in hyperventilation and increased pulmonary blood flow (Loebstein et al., 1997). These alterations aid in the transfer of medications through the alveoli into the maternal bloodstream (Loebstein et al., 1997).
Transdermal Absorption
An increase in the absorption of medications through the skin is evident during pregnancy. The increase in peripheral vasodilation and increase in blood flow to the skin (Kraemer et al., 1997) enhance this increase in absorption. Because of an increase in total body water, there is increased water content in the skin, therefore favoring an increased rate and extent of absorption to water-soluble medications like lidocaine, which is used as a topical anesthetic during pregnancy (Yankowitz & Niebyl, 2001).
Distribution
Maternal blood volume increases significantly during pregnancy. The 30% to 50% increase in blood volume (Guyton & Hall, 1996; Loebstein et al., 1997) is characteristically distributed to various organ systems serving the needs of the growing fetus. The full increase in total body water during pregnancy is 8 L, with 60% distributed to the placenta, fetus, and amniotic fluid and 40% going to maternal tissues (Loebstein et al., 1997). It is these increases that cause the volume of distribution of medications to increase, resulting in a decrease (dilutional effect) in drug concentrations. Studies show that serum levels of water-soluble drugs decrease because of the increased volume of distribution (Simone et al., 1994). Conversely, drug distribution is affected by an increase in maternal fat deposits. Medications that are highly lipophilic distribute to maternal fat deposits, also resulting in decreased serum drug levels. Body fat increases during pregnancy by 3 to 4 kg and may act as a reservoir for medications that favor a fat-soluble environment (Yankowitz & Niebyl, 2001). Another factor that may affect medication distribution is the concentration of albumin in the maternal blood. The concentration of plasma albumin decreases during pregnancy. This decrease is believed to be caused by a reduction in the rate of albumin in synthesis or an increase in its rate of catabolism (Fredericksen, 2001). Medications that are highly bound to plasma albumin (e.g., anticonvulsants) may have an increased free drug concentration due to decreased albumin binding.
Elimination
Hormonal changes that normally occur during pregnancy can affect the elimination of various medications. The normal increase in progesterone levels can stimulate hepatic microsomal enzyme systems, thereby increasing the elimination of some hepatically eliminated medications (e.g., phenytoin [Dilantin]). Progesterone may also decrease the elimination of some medications (e.g., theophylline [Theo-Dur]) by inhibiting specific microsomal enzyme systems. Therefore, depending on the elimination pathway of a specific medication, the elimination rate may not be predictable. The extent of these physiologic changes is difficult to quantify, and it is unknown whether changes in dosages are required.
As plasma volumes increase, so does renal blood flow (Fredericksen, 2001; Guyton & Hall, 1996; Loebstein et al., 1997). With the increase in renal blood flow by 50% (Loebstein et al., 1997) and increased glomerular filtration rate, drugs excreted primarily by the kidney show increased elimination. Again, the magnitude of these increases in elimination is not known, and therefore, dosage adjustment may not be required.
Factors in Placental-Fetal Physiology
Until the 1960s, it was widely believed that the uterus provided a secure and protected environment for the developing fetus. Very little thought was given to the potential harm posed to the fetus from maternal drug use. After the thalidomide tragedy in the 1960s, the government required testing of drugs before human use. It is now known that by the fifth week of fetal development, virtually every drug has the ability to cross the placenta (Kraemer et al., 1997).
The treatment of medical conditions is complicated during pregnancy by various factors that must be considered before initiating drug therapy. A key factor is whether the drug will cross the placenta and potentially cause fetal harm.
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