Cabbage, Lori A. MSN, CNM, FNP; Neal, Jeremy L. PhD, CNM, RN
Pregnancy is accompanied by many physical changes that result in discomforts for women. Common discomforts include nausea, heartburn, congestion, backache, and constipation. In an effort to alleviate pregnancy-related discomforts, over-the-counter (OTC) medications are often selected by pregnant women or recommended by healthcare providers. Despite an -increasing awareness of the need to avoid unnecessary exposure to medications, the vast majority of women consume OTC medications during pregnancy.1–3 Glover et al. report that 92.6% of pregnant women consume OTC medications with more than 20% self--medicating with at least five OTC medications.1 Although the use of particular OTC medications decreases throughout pregnancy, others are used more often as pregnancy progresses.1,3
Unfortunately, there is a paucity of published information -regarding the safety and maternal/fetal effects of OTC medication exposure. In 2003, the National Institute of Child Health and Human Development (NICHD) reported that the study of drugs used in pregnancy is one of the most neglected areas of pharmacologic -research resulting in a lack of FDA obstetric labeling.4 The NICHD affirms that there is a critical need for improved information -regarding medication use in pregnancy. The purpose of this article is to integrate the available research literature and provide clinicians with an up-to-date list of the more commonly used OTC medications in pregnancy. The information regarding these medications and their safety in pregnancy can be used as a guideline when counseling women on relief measures for common pregnancy discomforts.
Risk factor classification of drugs in pregnancy
For more than 20 years, the FDA has used a five-category system to rank the safety of prescription and OTC medications when used during pregnancy (see FDA risk classifications of medications in pregnancy). Many older medications, however, were not given letter rankings by their manufacturer. Coupled with the scarce and often contradictory data regarding the pharmacokinetic alterations of some medications in pregnancy, this makes it more difficult for healthcare providers to counsel women regarding medication use in pregnancy. In May 2008, major revisions to the current classification system were proposed by the FDA.6 The elimination of the pregnancy categories was one such proposed revision. The changes would allow clinicians to make better informed decisions when prescribing medications for women who are of childbearing age, who are pregnant, or who are breastfeeding. In addition, healthcare providers would be able to utilize a risk summary when educating these women. Per the FDA, "as of February 2011, the Final Rule is in the writing and clearance process".6
OTC pain medications are widely available, thereby luring a false sense of security regarding their safety during pregnancy. Pain relievers consistently rank in the top 10 medications consumed during pregnancy.1–3 Kamysheva et al. -reported that more than 76% of pregnant women experience some form of pain such as headache, backache, or groin pain.7 Werler et al. reviewed the findings from two large birth defect studies—the National Birth Defect Prevention Study (NBDPS) and the Boston University Slone Epidemiology Center Birth Defects Study (BDS)—to assess patterns of OTC medication use among pregnant women.3 The NBDPS project is an ongoing, multicenter, population-based, case-control study of birth defects including subjects with major structural malformations, as well as a random sample of healthy infants. Subjects are queried about medications taken for specific illnesses during pregnancy and about certain named products. The BDS investigative team interviewed more than 23,000 mothers of infants with a wide range of birth defects. Both the NBDPS and BDS studies concluded that acetaminophen is the most commonly taken medication, being used by at least 65.5% of women at some point during their pregnancy. In comparison, ibuprofen is used by 15% of pregnant women while aspirin is used by at least 4%.3
Acetaminophen, a category B medication in pregnancy, may be used for its analgesic and/or antipyretic properties. Despite its frequent use in pregnancy, there remains a limited amount of data regarding associated birth defects.8 In a retrospective study, Werler et al. reported a significant risk of fetal gastroschisis with ingestion of acetaminophen (odds ratio [OR] 1.5, 95% confidence interval: 1.1, 2.2)8; however, these findings must be interpreted cautiously considering that selection bias and confounding variables may have influenced the results.8 Countering these findings, Feldkamp et al., in a more recent trial reported that first trimester use of acetaminophen is not associated with an increased risk of any birth defect, including gastroschisis (adjusted OR 1.03, 95% confidence interval 0.83–1.28).9 Moreover, when used in the first trimester of pregnancy to treat febrile illness, acetaminophen was found to reduce the risk of gastroschisis and multiple other birth defects such as anencephaly, encephalocele, and oral facial clefts when compared with no antipyretic use at all.9 Some data indicates other potential adverse effects may be associated with acetaminophen use during pregnancy. For example, older studies regarding acetaminophen overdose during pregnancy revealed an association with fetal hepatic necrosis, although no recent studies determining the effect of maternal acetaminophen use on the fetal liver could be identified.10 In a recent systematic review and meta-analysis, Eyers et al. reported that use of acetaminophen during pregnancy increases the odds of respiratory wheezing in the exposed offspring (pooled random effects OR 1.21, 95% CI: 1.02, 1.44).11 The authors urge more research in this area so -appropriate recommendations regarding this association can be made.11 In summary, acetaminophen crosses the placental barrier but, when used in therapeutic doses and short term, appears to be safe.12
Although investigators have found that many pregnant women consume ibuprofen and aspirin, Glover et al. revealed that consumption of nonsteroidal anti-inflammatory drugs (NSAIDs) decreases as pregnancy progresses.1–3 This may be due to healthcare provider knowledge that these medications may be dangerous when used during later pregnancy. Ibuprofen is a category B medication in pregnancy and is not known to be teratogenic. Studies reveal that there is no increase in renal anomalies or congenital heart defects; however, there is evidence of increased risk of gastroschisis if ibuprofen is taken in early pregnancy.8,13,14
NSAIDs inhibit prostaglandin synthesis, which may have several effects on both mother and baby. When used in the first trimester, ibuprofen may interfere with implantation and placental circulation, increasing the risk of miscarriage. Comparatively, aspirin does not appear to increase miscarriage risk.14 When used near-term gestation, NSAIDs may prolong pregnancy, decrease the amount of amniotic fluid, and increase maternal postpartum blood loss. In addition, fetal effects may include premature closure of the fetal ductus arteriosus, pulmonary hypertension, and impaired renal function.
Aspirin is listed as a category D medication when used in full dose in the third trimester. This medication reportedly increases the risk of gastroschisis by two- to three-fold.8,15 Some evidence suggests that aspirin may be associated with premature closure of the fetal ductus arteriosus.16 Low-dose aspirin therapy (60–100 mg/day), however, is considered to be safe throughout pregnancy and has not been shown to increase maternal or neonatal morbidity or mortality.14,15,17,18
Because of the potential for adverse effects, ibuprofen and aspirin should be used sparingly, taking extra note of the effects after 36 weeks' gestation. Evidence suggests that low-dose aspirin is safe during pregnancy; however, some controversy remains whether it should be discontinued near the expected time of delivery. Acetaminophen appears to be the best choice for both pain and fever reduction in pregnant women.
Cold and allergy medications
Cold and allergy medications are not well studied in pregnancy, yet many women take these medications while pregnant. Commonly used medications include guaifenesin, dextromethorphan, pseudoephedrine, diphenhydramine, and chlorpheniramine. Werler et al. reported that pseudoephedrine and guaifenesin use increased from prepregnancy through the second trimester but then decreased in the third trimester.3 Chlorpheniramine and dextromethorphan use decreased across the trimesters while diphenhydramine use increased in the third trimester. Diphenhydramine and chlorpheniramine are older antihistamines that are category B during pregnancy. These medications are used for the control of allergy symptoms but also have a well-known sedating effect. Several large studies have identified these medications to be safe when used in pregnancy with neither having any clear teratogenic effects.12,19 When used in high doses (such as 50 mg I.V.), diphenhydramine may produce oxytocin-like -effects.12 Loratadine, also category B in pregnancy, is a -second-generation antihistamine and generally regarded as nonsedating. Kallen and Olausson reviewed the Swedish Medical Birth Register from 1995 to 2001 and again from 2001 to 2004 and reported no evidence of an association between maternal loratadine use in early pregnancy and the incidence of offspring hypospadias.20 More studies regarding the use of loratadine during pregnancy are needed. The American College of Obstetricians and Gynecologists (ACOG) and the American College of Allergy, Asthma, and Immunology (ACAAI) published a position paper in 2000, declaring chlorpheniramine as one of the antihistamines of choice in pregnancy.21
Pseudoephedrine, a category C medication in pregnancy, is used by as many as 25% of pregnant women.3 As an alpha-adrenergic receptor agonist, pseudoephedrine causes vasoconstriction that may lead to increased maternal BP and decreased uterine blood flow, which is of particular concern in the pregnant patient.12,22 Effects on placental-fetal circulation are not known. Pseudoephedrine alone does not appear to increase the risk of birth defects overall.8,22 In a retrospective study by Werler et al., pseudoephedrine use alone was not shown to increase the risk of gastroschisis; however, multicomponent products containing both pseudoephedrine and acetaminophen reportedly increase risk of gastroschisis by 4.2-fold.8
The Boston University Slone Epidemiology Center Birth Defects Study revealed that more than 12% of women take some sort of cough medication while pregnant. A study by Glover et al. found that 14% of women took guaifenesin alone or in combination with dextromethorphan during pregnancy.1,3 Both dextromethorphan and guaifenesin are category C medications in pregnancy. Although dextromethorphan use during pregnancy has not been associated with -adverse fetal effects to date, one study reported that guaifenesin is associated with an increased risk of neural tube defects when used during the first trimester of pregnancy in the presence of a febrile illness.23 It remains unclear if the increase in neural tube defects was associated with guaifenesin use, febrile illness, or both.24 Other sources, however, do not support this finding, indicating that the frequency of malformations was not increased in fetuses exposed to guaifenesin in the first trimester.12
Although medications should be used judiciously in pregnancy, women suffering from the signs and symptoms of the common cold or seasonal allergies can be reassured that there are particular medications that can be safely consumed while pregnant. Providers should educate pregnant women about the possible risks associated with certain medications commonly used to alleviate cold and allergy symptoms.
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Gastrointestinal complaints such as flatulence, heartburn, and constipation are among the most common complaints in pregnancy, experienced by as many as 75% of pregnant women.7 There are a plethora of medications that are reportedly safe in pregnancy for the reduction of these gastrointestinal complaints.
Bismuth subsalicylate, kaolin/pectin, and loperamide are antidiarrheal medications that can are available OTC. Glover et al. found that approximately 5% of pregnant women take bismuth subsalicylate, which has no association with congenital anomalies.1 Concern remains, however, about exposure to salicylates in pregnancy. Therefore, bismuth subsalicylate should be reserved for the first half of pregnancy and used in only manufacturer recommended doses.12
Loperamide and kaolin/pectin are other category B medications used for treatment of diarrhea. Neither has been linked to adverse fetal outcomes. Kaolin, however, may interfere with iron absorption predisposing women to iron deficiency anemia.12
Simethicone, a category C medication, is an antiflatulent that is not associated with congenital defects. It is not absorbed systemically and is therefore considered safe in pregnancy.12,25 Docusate sodium, a category C medication, is a commonly used laxative in pregnancy. No studies link the use of this medication with any congenital defects.12
More than 50% of women experience heartburn during pregnancy.7 Although this symptom is not life-threatening, it can be very disruptive to a woman's daily life. Diet and lifestyle changes are the interventions of choice; however, if these changes prove ineffective in treating heartburn, antacids may be beneficial. Refuerzo et al. found that antacids are consumed by approximately one-fourth of pregnant women.2 A variety of antacids are available OTC (see Examples of active ingredients in common antacids), containing aluminum, magnesium, and calcium carbonate. Reinke et al. found that, in animal studies, aluminum crosses the placenta impairing skeletal growth and neurologic function.26 A position statement by the American Gastroenterological Association Ins-titute (AGAI),27 however, states that these antacids are safe and effective in human pregnancy. The first-line drug choice should be calcium-based antacids; however, excessive use of calcium carbonate can lead to milk-alkali syndrome.
For some women, especially in later pregnancy, heartburn and indigestion symptoms increase and cannot be controlled with lifestyle changes and antacids. In these cases, an H2 receptor antagonist use may be appropriate. Several OTC options are available, including cimetidine, ranitidine, nizatidine, and famotidine. They are all category B medications in pregnancy despite their ability to readily crosses the placenta. In a large prospective by Garbis et al., 553 pregnant women who used an H2 receptor antagonist during pregnancy were evaluated, with 91% of these women first using these drugs in the first trimester.29 Most women took the recommended dose for a duration of 2 to 4 weeks. These investigators found that H2 receptor antagonist use during pregnancy does not increase the risk of major congenital malformations or other pregnancy complications. The AGAI supports cimetidine and ranitidine as the preferred medications because famotidine and nizatidine have limited safety data.27
Some pregnant women experience more severe gastrointestinal symptoms, causing the clinician to look beyond antacids and H2 receptor antagonists to proton pump inhibitors (PPIs). Omeprazole, a category C medication, is a PPI that can be purchased OTC. Using data from 134,940 pregnant patients, including 1,530 of whom were exposed to PPIs, Gill et al. found no increased risk for major congenital malformations, spontaneous abortion, or preterm delivery with PPI use.30 Until more research is done, omeprazole should be reserved for those ailments refractory to antacids and H2 receptor antagonists.
Implications for practice
Many pregnant women take OTC medications during pregnancy but may not volunteer this information during their prenatal visit. ACOG recommends that women inform their healthcare provider of their OTC medication use during a preconceptual or prenatal visit. In addition, ACOG recommends that healthcare providers educate all women of reproductive age about the importance of discussing the use of OTC medications.31 Despite these recommendations, Morgan et al. found that they are not consistently being followed.32 Although many more obstetricians were likely to ask patients about OTC medication use during obstetric care visits than during routine care visits (86% versus 52%, respectively), 14% did not ask pregnant women about OTC medication use at all. Complete omission of provider--patient discussions regarding OTC medication use is inexcusable, but even delaying these discussions until after pregnancy occurs may be too late in the event that the woman was taking medications known to be harmful to the maternal-fetal unit. In short, discussions about OTC medication use should be ongoing between providers and all women of reproductive age under their care. NPs and nurse-midwives treating women of reproductive age in primary care settings can play a key role in providing education about the proper use of OTC medications.
NPs should familiarize themselves with the most commonly used OTC medications. Pregnant women should be counseled regarding any potential risks involved with taking OTC medications. If a woman chooses to take an OTC medication during pregnancy, she should be encouraged to take a single ingredient medication at the lowest dose possible. In addition, the NP should recommend only those OTC medications considered relatively safe in pregnancy. Usage of newer medications or those without human pregnancy experience should be considered only after careful review of the potential risks and benefits.33
FDA risk classifications of medications in pregnancy
Category A—Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote.
Category B—Either animal reproduction studies have not demonstrated fetal risk but no controlled studies in pregnant women have been reported, or animal reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of risk in later trimesters).
Category C—Either studies in animals have revealed adverse effects on the fetus (teratogenic, embryocidal, or other) but no controlled studies in women have been reported, or studies in women and animals are not available. Drugs should be given only if potential benefit justifies the potential risk to the fetus.
Category D—Positive evidence of human fetal risk exists, but the benefits from use in pregnant women may be acceptable despite the risk. (For example, if the drug is needed for a life-threatening condition or for a serious disease for which safer drugs cannot be used or are ineffective.)
Category X—Studies in animals or human beings have demonstrated fetal abnormalities, or evidence exists of fetal risk based on human experience, or both, and the risk in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.
Source: Federal Register, 19805
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drug safety; over-the-counter medications; pregnancy
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