Instructor: Dominic P. Decker, MS, CPhT
Introduction Care of the pregnant woman spans across the disciplines of medicine, pharmacy, mental health and nutrition, all of which serve as resources to patients and their families in this time of life. To help allocate these resources where they are needed most, biostatisticians track and analyze trends in pregnancy statistics. The Centers for Disease Control and Prevention (CDC) estimates that there were a total of 6.4 million pregnancies in the United States in 2009, the most recent year for which data is available. Of those pregnancies, there were 4.1 million live births, 1.2 million induced abortions and 1.1 million fetal losses. The pregnancy rate for women in this country has declined since 2007, now estimated at 102.1 pregnancies per 1,000 women ages 15-44. Of note, between 1990-2009, pregnancy rates for women under 30 declined, while rates for women over 30 increased. These numbers represent the scope and impact of pregnancy on health care delivery. A host of physiologic changes occur in women who are pregnant and lactating, several of which have direct effects on medication use. Pregnancy and lactation can change drug absorption, distribution, metabolism and excretion in significant ways. Women who are contemplating pregnancy or currently pregnant should have their medication list reviewed by their physician and pharmacist to ensure the drugs they are taking are safe for use in the pre- and post-natal periods. Pharmacy technicians serve as an integral link between patient and pharmacist. With an understanding of drug use during pregnancy and lactation, the technician can direct questions to the pharmacist for counseling and support the patient during this profound time of life. Pregnancy Diagnosis When sperm migrate up the cervix, through the uterus and into the fallopian tubes, they may come into contact with an egg that has been released during ovulation. Upon this meeting, a series of chemical reactions takes place allowing the sperm to penetrate the egg, effectively fertilizing it and setting the stage for the first mitotic division of the new zygote. Within four days of this taking place, the developing fetus has undergone several more cell divisions and begins to implant into the uterine lining, called the endometrium. Fetal and endometrial lining merge during this time and maternal and fetal blood begin to exchange gases and nutrients by diffusion in the placenta. Thus the developing fetus is supported as it rapidly grows in the weeks immediately following conception. A woman who is pregnant may initially suspect this because of a missed menstrual period. She can confirm the pregnancy by using a home pregnancy test. This test detects levels of human chorionic gonadotropin (hCG), a hormone produced by the placenta, in the urine. hCG levels rise to measurable levels within nine days of conception, making early detection of pregnancy possible with even the cheapest or most basic of home pregnancy tests. Since fetal growth and organ development is substantial in the first trimester, early detection of pregnancy is necessary so that the mother may avoid behaviors and substances that would compromise fetal viability. Physiologic Changes in Pregnancy The external manifestations of pregnancy are often obvious, particularly in the second and third trimesters. Internally, several changes are occurring during this time that impact both mother and fetus. These changes can be summarized by their effect on drug absorption, distribution, metabolism and excretion: Absorption: The pregnant state significantly alters absorption for medications that are administered via topical, inhalational and oral routes. A pregnant woman has a larger surface area, so dosages of topical creams and ointments have to be adjusted accordingly. Pregnancy increases minute ventilation - that is, the volume of gas exchanged in the lungs per minute - and inhalational medications such as those delivered by inhaler and nebulizer can be impacted. Finally, the gastric pH rises, gastric emptying is delayed and gastrointestinal motility is decreased, all of which change how oral medications are absorbed. Distribution: Within the first three months of pregnancy, plasma volume goes up an average of 30-50% as the mother compensates for the increasing size and metabolic demands of the fetus. Because drugs are either hydrophilic or hydrophobic by nature of their chemical composition, they will tend to distribute in fluid or fat, respectively. Administering a hydrophilic drug with extensive fluid distribution during pregnancy requires consideration of the expanded maternal plasma volume to calculate dosage. Metabolism: As plasma volume increases to compensate for the growing fetus, it does so in part by decreasing the total percentage of blood flow to the liver, where much of drug metabolism takes place. Drugs that undergo hepatic metabolism and do not reach the liver to be metabolized may have increased circulating levels, putting both mother and fetus at risk for adverse effects if these levels become too high. Excretion: Along with a 30-50% increase in plasma volume, the pregnant state is characterized by an increase in glomerular filtration rate (GFR), or the volume that is filtered by the kidney for excretion in the urine, on the same order of magnitude. Drugs that undergo renal excretion may thus be excreted in higher amounts, leading to decreased circulating levels in the blood. GFR in pregnant and non-pregnant patients is calculated by measuring the amount of serum creatinine, a protein byproduct of muscle breakdown that is excreted by the kidneys at a constant rate. Medication Use in Pregnancy Given the complexity of physiologic changes that occur during pregnancy and directly impact drug absorption, distribution, metabolism and excretion, it is important to weigh the risks and benefits of medications to both mother and fetus. The Food and Drug Administration (FDA) has provided guidance on medication use in pregnancy by establishing five pregnancy categories: A, B, C, D and X (Table 1). In considering these, it is important to understand that the majority of currently prescribed medications falls into category C, representing that an insufficient number of well-controlled studies has been performed to be either in favor or opposed to use of the drug during pregnancy. The reason for this is that clinical trials of medications are generally not conducted on pregnant women because of the potential risk to the developing fetus. Use of medications in pregnancy category C are left up to the discretion of the physician and pharmacist in accordance with the patient's wishes after they have carefully weighed the potential benefit to the mother against the risk to the fetus. Recognizing the limitations of the current pregnancy categories, the FDA proposed revising how information about medication use in pregnancy is presented with the goal of simplifying it for both health care providers and patients. According to the organization, FDA proposed that both the pregnancy and lactation subsections of labeling include a risk summary, clinical considerations to support patient care decisions and counseling and a data section that includes more detailed information. The proposed regulations eliminate the current pregnancy categories A, B, C, D and X due to limitations in their ability to accurately and consistently convey risk and benefit (Pregnancy and Lactation Labeling, Table 2). These revisions were first offered in 2008, opened for a comment period after that, but have not yet taken effect. Embryogenesis As will be made clear in the discussion of known teratogens, the timing of exposure to a drug or toxin primarily determines the extent of fetal damage that occurs. With that, an outline of embryogenesis - the development of the embryo and fetus during gestation - is necessary to understand why drug exposure at various points of development can produce markedly different outcomes. The first two weeks of embryogenesis are characterized by a rapid series of divisions to increase cell number. Following these first two weeks, the embryo enters weeks 3-8, called the embryonic period. It is during this time that organogenesis takes place and it is for this reason that the fetus is most susceptible to drug exposure in the first trimester. Beyond week 8, the fetus is in the fetal period, a time of growth and maturation of the organs that have already formed. In general, early exposure results in changes of form: organs affected during this time can be formed incorrectly. For example, limb abnormalities may arise. Later exposure results in changes of function: the organs have formed correctly, but their function may be impaired. For example, an intellectual disability may arise due to fetal brain damage. Teratogens A teratogen is an agent that acts during embryonic or fetal development to cause a permanent change to the fetus. While more than half of congenital malformations have unknown causes, around 5% are due to drug exposure. The limited amount of studies available on which drugs act as teratogens, reflected in the preponderance of medications in pregnancy category C, shows that there is still much to be learned on how a drug alters fetal development. However, there are several known teratogens, some of which will be explained in greater detail here (Table 3). Our focus will be on thalidomide, phenytoin, carbamazepine, valproate, warfarin and isotretinoin. In addition to these prescription medications, alcohol, smoking and cocaine will also be covered. One of the most publicized teratogens in the history of the FDA is thalidomide. In 1962, a case report in the British Medical Journal described a 35-year-old woman who took thalidomide as prescribed for sedation before conception and during the first three weeks of pregnancy and subsequently gave birth to a child with severe malformations of the arms and legs. Other cases were made known and the connection between thalidomide use and congenital malformations was established, eventually leading the FDA to place this drug in pregnancy category X. This case report and the ones that followed underscore that the fetus is most at risk for adverse effects due to drug exposure in the first trimester of pregnancy, during which organ formation takes place. Of note, thalidomide has recently reemerged as a treatment for myeloma and its use needs to be carefully considered in women of childbearing age. Due to its pregnancy categorization and limited scope of use, thalidomide no longer presents as significant of a threat as it once did. Drugs more often used that are also known teratogens include several medications indicated for the treatment of epilepsy, including phenytoin, carbamazepine and valproate. The latter two are known to cause neural tube defects. In embryogenesis, the neural tube - a precursor to the central nervous system - must close by the fourth week of development. Failure of this tube to close at either the rostral (head) or caudal (feet) end can lead to severe congenital malformations. If the tube does not close at the rostral end, anencephaly results: the fetus lacks and brain and dies in utero or shortly after birth. If the tube does not close at the caudal end, spina bifida results: the fetus lacks normal vertebral structure and the spinal cord can be displaced outside of the vertebrae. Anencephaly is uniformly fatal, while spina bifida is not. However, both represent significant malformations that can result from drug use. Anticonvulsant use presents a particular challenge in pregnant women. A woman who is well-controlled on phenytoin, carbamazepine or valproate may have to remain on these medications into pregnancy as withdrawing them could precipitate seizures that are potentially fatal to the mother or fetus. As always, the benefit to the mother needs to be weighed against the risk to the fetus when considering use of these drugs. Warfarin is another medication in common use, with indications from atrial fibrillation to prophylaxis for deep venous thromboembolism (DVT) and pulmonary embolism (PE). Pregnancy is a procoagulant state, meaning that blood clots are more likely to develop in a pregnant than in a non-pregnant woman. The reason for this partly lies in the effect estrogen has on the liver, where clotting factors are made. Estrogen, which is present in high levels during pregnancy, increases clotting factor production by the liver and can lead to clots. Clot formation can be prevented in the general population with the use of warfarin, but this is not appropriate in pregnant women due to the risk of adverse effects in the fetus, including bone and eye deformities, fetal bleeding and even spontaneous abortion. Instead, low molecular weight heparin (LMWH), such as enoxaparin sodium (Lovenox ) is used because it does not cross and placenta. Antibiotic use in pregnancy should also be carefully considered, with medications from the aminoglycoside and tetracycline classes of drugs avoided due to their potential teratogenic effects. Both of these classes target the 30S ribosomal subunit used by the bacterial cell for protein production and thus propagation of the infection. Aminoglycosides include gentamicin, neomycin, and tobramycin, among others. They are known to be ototoxic, that is, they affect the vestibulocochlear nerve that carries sound information to the brain and can result in congenital deafness if fetal exposure occurs. Tetracyclines, which include tetracycline, doxycycline, and minocycline, do not have an impact on hearing, but rather alter bone development and have been known to cause teeth discoloration in infants. Perhaps the most recognizable teratogen in the pharmacy is isotretinoin (Accutane , Clavaris ), indicated for the treatment of cystic acne and often used in adolescents and young adults. The medication acts as a vitamin A derivative at retinoic acid receptors, causing cell death and leading to severe congenital abnormalities in a developing fetus such as cardiac abnormalities, cleft palate and spontaneous abortion. As a result, patients (both male and female), physicians, pharmacies and wholesalers must enroll in the iPLEDGE program, which has stated goals of ensuring that no female patient starts isotretinoin if pregnant or becomes pregnant while on isotretinoin. According to the program, This program is designed to create a verifiable link between the negative pregnancy test and the dispensing of the isotretinoin prescription to the female patient of childbearing potential. The iPLEDGE program requires that all patients meet qualification criteria and monthly program requirements. Before the patient receives his/her isotretinoin prescription each month, the prescriber must counsel the patient and document in the iPLEDGE system that the patient has been counseled about the risks of isotretinoin (About iPLEDGE). Additional requirements of a female patient on isotretinoin include the following: Using two forms of contraception one month before, during and one month after isotretinoin therapy Having two negative pregnancy tests before starting isotretinoin therapy Having her physician document pregnancy test results and contraception forms each month in the iPLEDGE system Using the iPLEDGE system may be seem cumbersome to those participating in it, but the effects of isotretinoin on a fetus can be devastating and must be prevented whenever possible. In addition to these prescription medications, alcohol, smoking and cocaine, are also known teratogens and cause adverse effects on the fetus ranging from intrauterine growth restriction (low birth weight) to fetal alcohol syndrome, the leading cause of intellectual disability in the US. Like the teratogens listed above, alcohol has teratogenic effects based on the timing of exposure. Early exposure to alcohol during pregnancy results in a pattern of facial findings, heart defects, growth restriction, and cognitive disability. Later exposure results in all of these except the facial findings. These characteristic facial findings are part of the diagnostic criteria for fetal alcohol syndrome, the name of the condition given to those children who had been exposed to alcohol during fetal development. They include small eye openings, short nose, flat philtrum (area between upper lip and nose), and a thin upper lip. It must be noted that not every fetus exposed to alcohol during pregnancy will develop these features. In fact, the proportion of fetuses affected by alcohol exposure ranges from 30-60%. Because of this uncertainty, and because caring for infants exposed to alcohol during fetal development accounts for billions of dollars in health care costs every year, there is no known safe amount of alcohol during pregnancy. Access to alcohol and smoking remains widespread, increasing the chance that a woman may be using one or both during pregnancy. Alcohol exposure causes the distinctive features of fetal alcohol syndrome listed above. Smoking during pregnancy, on the other hand, can have more subtle effects. Most notable among these is intrauterine growth restriction, also known as low birth weight. Inhaling cigarette smoke causes physiologic changes in the mother due to hypoxia, a state of low oxygen. Lack of oxygen delivery to both maternal and fetal tissues delays growth of the fetus, potentially leading to impaired development. In addition to putting the fetus at risk for low birth weight, smoking also increases the incidence of preterm labor and placental problems. An infant delivered prematurely to a mother who smoked during pregnancy may not have sufficient lung development to breathe normally and often requires intensive interventions in the post-partum period to support life. Placental problems include placenta previa, in which the placenta is at the base of the uterus and blocking the cervical opening, and placental abruption, in which it prematurely separates from the uterine lining. The latter puts both mother and fetus at significant risk for complications including blood loss and death and needs to be emergently addressed. While less available than alcohol and smoking, cocaine still presents a risk to fetal development, but it is more poorly understood. The US Substance Abuse and Mental Health Services Administration (SAMHSA) conducted the National Survey on Drug Use and Abuse in 2002, which revealed that 2 million Americans over the age of 12 used cocaine or crack. By comparison, 14.6 million used marijuana and 6.2 million used prescription drugs, like oxycodone, illicitly. Like smoking, cocaine can result in low birth weight and placental abruption. Perhaps of more immediate importance in the post-partum period is treatment of a cocaine-exposed infant. Withdrawal symptoms at birth include diarrhea, vomiting, irritability, lethargy, or excitation. Together with the Center for Substance Abuse Treatment, SAMHSA released the following guidelines for addressing infant cocaine exposure in their publication Treatment Improvement Protocols, which are summarized here: Optimal nursery environment: To facilitate and promote optimal infant growth and development, nursery personnel should carefully monitor feeds, initiate strategies to facilitate intake for those infants experiencing feeding difficulties, observe for feeding intolerance or necrotizing enterocolitis, provide opportunities to interact with parents and environment as the infant is able to tolerate them, and provide primary nursing to facilitate parent-infant interactions. Brazelton Neonatal Behavioral Assessment Scale: This scale has been used extensively to evaluate newborn behavior such as habituation and responsivity to stimuli (faces, voices, light, bell, rattle, etc.); state (sleeping, alertness); characteristics of changes in state (irritability, inconsolability); and neurological and motor development. Pharmacotherapy: If irritability persists in an infant, a short course of phenobarbital is recommended. Central nervous system imaging: Special consideration should be given to specific neuroimaging of cocaine-exposed preterm infants, infants whose head circumference falls below the 10th percentile on standardized fetal growth curves, and infants with abnormal neurologic signs, neurobehavioral dysfunction, or seizure activity. Assessment for congenital malformations/vascular disruptions: Clinicians should have a heightened awareness of the possibility of uncommon but significant congenital malformations or vascular disruptions reported in cocaine-exposed neonates. Systems that may be affected include the genitourinary tract, cardiovascular system (congenital heart malformations), gastrointestinal tract, and skeletal system. Sudden Infant Death Syndrome (SIDS): There is some controversy over the incidence of SIDS in cocaine-exposed infants, but crack cocaine does appear to raise the risk slightly over controls. Data also suggest that cocaine-exposed infants may exhibit respiratory dysfunction. Lactation Concerns about medication exposure between mother and fetus do not end after delivery. If the mother chooses to breastfeed, her physician and pharmacist must consider the possibility of drug transfer to the baby through breast milk. The Toxicology Data Network (TOXNET), a service of the National Library of Medicine, provides a peer-reviewed database on medication use during lactation called LactMed. This is a useful resource for health care providers to look up data on drug concentrations in breast milk and consider alternatives for women who are breastfeeding. Several factors influence the concentration of drugs in breast milk, including milk pH, drug lipid solubility and drug protein binding, but in general the concentration of the medication in the maternal blood matches the concentration in her breast milk. Examples of drugs contraindicated in lactation include chemotherapeutic agents, amiodarone, aspirin, retinoids (such as isotretinoin), alcohol, cocaine and others. Of particular concern during lactation is the use of aspirin, the total dose of which has been estimated to be 4-8% in breast milk. Aspirin use in children under the age of two, and in older children following viral illnesses such as chickenpox and influenza, is contraindicated because of the possibility of developing Reye's syndrome, a rare but life-threatening condition. In this syndrome, aspirin ingestion induces hypoglycemia (low blood sugar) and hyperammonemia (high blood ammonia), leading to swelling in the liver and brain. Symptoms present in Reye's syndrome in patients under the age of two include rapid breathing and diarrhea. Since permanent brain damage may result, rapid intervention and treatment is needed. Although this syndrome is rare - and happens more often in children ages 4-12 - it can still occur in infants ingesting aspirin via breast milk and this should thus be avoided (National Reye's Syndrome Foundation). To minimize the passage of medication into breast milk, the following steps can be taken: Breastfeed immediately prior to drug administration to allow for elimination before next feeding Administer drugs at night, as the infant is likely to nurse less at night than during daytime Use lowest appropriate dose of drug Choose drug with shorter half life Express and discard milk (pump and dump) if drug use is short-term (Walseth) Conclusion Use of medications in women of childbearing age needs special consideration by health care providers. Several drugs are known teratogens, that is, they have the ability to act on the fetus during development and cause permanent changes in form or function. Several others pass through the breast milk and continue to present risk to the infant during lactation. The FDA, NIH and National Library of Medicine maintain pregnancy categories (recently the subject of revision) and databases that assist physicians, pharmacists and patients in understanding drug efficacy and safety during pregnancy and lactation. These classifications are, however, subject to the discretion of the health care provider according to the patient's wishes. The benefit to the mother must always be considered against the risk to the fetus. In many cases, this risk is minimal, as drugs account for approximately 5% of congenital malformations. However, in situations where drug use does result in adverse effects to the fetus, the results can be devastating. Pregnant women are provided with a host of resources to prevent these adverse effects from happening. Individuals from the fields of medicine, pharmacy, mental health and nutrition can advocate on behalf of these women for a healthy and safe pregnancy. As the link between patients and medication use, pharmacy technicians and pharmacists are central to ensuring the safe use of medications during this time of life. Table 1: FDA Pregnancy Categories (Current) Category Description Examples A Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters). Folic acid, vitamin B6, levothyroxine B Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women. Penicillin, metformin, regular insulin, ondansetron C Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Albuterol, sertraline, fluoxetine, along with most drugs used during pregnancy D There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Anticonvulsants (including carbamazepine, phenytoin), paroxetine, lithium X Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits. Isotretinoin, thalidomide, statins, warfarin, NSAIDs (in third trimester) Source: National Institutes of Health; Tim Walseth Table 2: FDA Pregnancy Labeling (Proposed) Heading Description General information General statement about background risk, pregnancy registry contact information Fetal risk summary Characterization of likelihood that drug increases the risk of development abnormalities in humans and other relevant risks, more than one risk conclusion may be needed Clinical considerations Information about inadvertent exposure (including known or predicted risk to fetus from inadvertent exposure to drug early in pregnancy) and prescribing decisions for pregnant women (including risks to the woman or fetus from the disease or condition the drug is intended to treat, information about dosing adjustments in pregnancy, maternal adverse reactions and neonatal complications and needed interventions) Data Human and animal data describing study type, exposure information and any identified fetal developmental abnormality or other adverse effects Source: Sandra Kweder, Birth Defects Research Table 3: Teratogens ACE inhibitors (benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, quinapril, ramipril, trandolapril) Aminopterin Androgenic hormones Busulfan Chlorobiphenyls Cigarette Smoking Cocaine Coumarin anticoagulants Cyclophosphamide Diethylstilbestrol Etretinate Fluconazole (high doses) Iodides Isotretinoin (Accutane) Lithium Mercury, organic Methimazole Methotrexate (methylaminopterin) Methylene blue (via intraamniotic injection) Misoprostol Penicillamine Phenytoin Tetracyclines Thalidomide Toluene (abuse) Trimethadione Valproic acid Source: University of Washington Drug Information Center Idea in Brief There were an estimated 6.4 million pregnancies in the United States in 2009, with an increasing number of those occurring in women over the age of 30. Women of childbearing potential are a population that requires special consideration when initiating or continuing medication therapy because of potential adverse effects during pregnancy and lactation. Idea in Practice Pregnancy induces a host of external and internal physiologic changes that directly impact drug absorption, distribution, metabolism and excretion. Medication dosage should be adjusted accordingly to prevent inappropriately high or low drug concentrations. Even at low concentrations, several known teratogens exist that can cause harm to the fetus and infant during pregnancy and lactation and should thus be avoided when and if possible. Author Biography Dominic P. Decker is a third year medical student at the University of Minnesota in Minneapolis. He holds a Master of Science degree in Narrative Medicine from Columbia University. He has eight years of experience working as a certified pharmacy technician in community pharmacy settings and has authored numerous articles for Today's Technician with a special interest in the interstices between communication, pharmacy and medical practice. Resources Centers for Disease Control and Prevention. NCHS Data Brief. http://www.cdc.gov/nchs/data/databriefs/db136.htm Food and Drug Administration. Pregnancy and Lactation Labeling. http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/labeling/ucm093307.htm iPLEDGE Program. About iPLEDGE. https://www.ipledgeprogram.com/AboutiPLEDGE.aspx Kweder, S.L. Birth Defects Research (Part A) 82:605-609 (2008) National Reye's Syndrome Foundation. Aspirin and breast feeding. http://www.reyessyndrome.org/pdfs/Aspirin_BreastFeeding.pdf Schimmenti, Lisa. Class Lecture. Science of Medical Practice, Session 110. University of Minnesota Medical School, Minnesota. 7 Dec. 2012. Substance Abuse and Mental Health Services Administration. Treatment Improvement Protocol Series, number 5. Center for Substance Abuse Treatment, Rockville MD: 1993. TOXNET, National Library of Medicine. http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT University of Washington Drug Information Center. http://depts.washington.edu/druginfo/Formulary/Pregnancy.pdf US Department of Health and Human Services. FDA Pregnancy Categories. http://chemm.nlm.nih.gov/pregnancycategories.htm Walseth, Tim. Class Lecture. Human Disease 3, Session 67. University of Minnesota Medical School, Minnesota. 10 Feb. 2014.