During the past 20 years, more medications have been made available without a prescription than ever before.1 Despite the large number of patients who self-treat, only a small percentage seek the advice of a health care professional when selecting a product.2,3 This presents a problem, considering the size of this potential patient population. This population includes many patients who have chronic health conditions, which can be worsened by the inappropriate use of OTC medications. Of particular concern is the safe use of nonprescription medications in pregnant women. A recent study showed that during pregnancy, 92.6% and 45.2% of women utilize OTC and herbal medications, respectively. Analgesics and cough and cold preparations are two of the most common categories of OTC products purchased during pregnancy.4
Safety Data and Pregnancy
At this time, there are limited safety data on the use of OTC medications during pregnancy. Due to ethical concerns, most safety data available have been provided by postmarketing surveillance reports and retrospective studies. The FDA has developed pregnancy categories for both OTC and prescription medications. This classification system allows practitioners to make educated decisions about the use of medications during pregnancy. The system is organized into five categories: A, B, C, D, and X. Each letter indicates the level of safety evidence available to support the use of a medication during pregnancy (table 1 ).5,6 The safety of a medication during pregnancy is often dependent on the trimester or stage of fetal embryonic development.
Benefits Versus Risks
In the United States, about 150,000 babies are born each year with birth defects.7 Birth defects can occur due to many nonpharmacologic factors. Some of the most common defects are spina bifida, microtia, hypoplastic left heart, cleft palate, cleft lip, esophageal atresia, anencephaly, omphalocele, and limb reduction.7 Practitioners must weigh the benefits versus the risks when recommending OTC analgesics and cough and cold preparations to pregnant women. Since ailments treated with OTC and herbal products in pregnant women are not usually life-threatening, practitioners should also consider suggesting nonpharmacologic remedies, such as rest and fluids.
This article presents information on some common OTC analgesic and cough and cold preparations available. Each section discusses the product, pregnancy category, information regarding safety data in pregnancy, dosing, side effects, and contraindications. The comparison of risks and benefits must be considered for each individual patient. Information relating to when patients should refer to a physician (Tables 2 and 3) is included to assist with the decision-making process.
Acetaminophen: During pregnancy, acetaminophen is the most widely recommended analgesic medication. Acetaminophen is pregnancy category B during all three trimesters, making it the pain reliever of choice for pregnant patients.8 Acetaminophen does appear to cross the placenta, but three studies that involved over 10,000 newborn infants have shown no increased risk of malformations in newborns exposed to acetaminophen in the first trimester. 9 One small, retrospective study showed a slightly higher incidence of gastroschisis (a birth defect resulting in bowel protrusion near the umbilical cord) in newborns who had been exposed to the drug. The risk of gastroschisis in the infant was higher in mothers who had taken acetaminophen in conjunction with pseudoephedrine.10 Some published case reports have cited acetaminophen exposure as the possible cause for adverse effects, including one case of fatal kidney disease, but these reports are rare.9
Overall, acetaminophen is used
extensively during pregnancy, and few adverse effects have been reported.
Patients can be advised to take 325 to 1,000 mg every four to six hours as
needed (maximum of 4,000 mg/day). Pregnant patients should be instructed to
use the smallest effective dose of the medication. If the medication is
ineffective, or required use is more than 10 days, the patient should be
referred to her physician. Other pregnant women who should consult a physician
before starting self-treatment are those with renal or hepatic dysfunction, a
high-risk pregnancy, a complaint of headache in the third trimester (a
possible sign of increased blood pressure and eclampsia), any pain rated
higher than 6 on a scale of 1 through 10, presence of fever or other signs of
infection, or pain associated with any type of trauma.11
Nonpharmacologic recommendations can be made according to the type of pain.
For example, a patient complaining of headache should try resting and lying
down in a dark, quiet room.
NSAIDs: Nonsteroidal anti-inflammatory drugs (NSAIDs) that are available without a prescription include ibuprofen, naproxen, and ketoprofen. All three are pregnancy category B in the first and second trimester, and category D in the third trimester. The most studied NSAID in pregnancy is the prescription product indomethacin. Similar to the OTC products, indomethacin is also a pregnancy category B in the first trimester and D in the third trimester. The data for indomethacin could be applied to the entire class of NSAIDs, as studies for other drugs in this class are lacking.8 Compared to acetaminophen, NSAIDs have been linked with an increased risk of gastroschisis at a slightly higher rate.10 In addition, all NSAIDs used near term are associated with oligohydramnios (a low level of amniotic fluid), a premature closure of the ductus arteriosus, and inhibition of labor.9 Unfortunately, complications can also result in the newborn, such as pulmonary hypertension, fetal nephrotoxicity, and periventricular hemorrhage. 8
Generally, NSAIDs should not be used during pregnancy without approval from the patient's physician. However, when patients require self-treatment with NSAIDs, appropriate doses can be recommended: 200 to 400 mg of ibuprofen every four to six hours (maximum 1,200 mg/day); 220 mg of naproxen every eight to 12 hours (maximum 660 mg/day); and 12.5 mg of ketoprofen every six to eight hours, repeating the initial dose after one hour if no effect (maximum 75 mg/day).11
Whenever possible, the smallest effective dose should be used. The patient should be screened and referred to her physician when appropriate. Appropriate referrals include, but are not limited to, the criteria mentioned for acetaminophen, a history of gastrointestinal ulceration, blood pressure problems, and a history of NSAID-sensitive asthma. Pregnant patients should not take NSAIDs for longer than 48 hours without contacting their physician.
Aspirin is a pregnancy category C in doses less than 150 mg daily and a category D in standard doses in all three trimesters.9 Salicylates have been associated with increased mortality, neonatal hemorrhage, decreased birth weight, prolonged gestation and labor, and possible birth defects. A pregnant patient should never take aspirin without the approval and guidance of her physician.
Oral: Pseudoephedrine and phenyl ephrine are the only oral OTC decongestants available in the U.S. These oral decongestants are available as monotherapy and in combination products. Cough and cold combination products frequently contain an analgesic, antihistamine, cough modulator, and/or decongestant. These combination products are often more convenient to the patient due to a decreased pill burden and cost. However, similar to nonpregnant patients, pregnant patients should use only the analgesic and cough and cold products that address their symptoms. This will help minimize potential risks from the use of unnecessary medications.
Pseudoephedrine and phenylephrine are pregnancy category C in all three trimesters of pregnancy. 12 The American College of Obstetricians and Gynecologists (ACOG) and the American College of Allergy, Asthma and Immunology (ACAAI) recommend using pseudoephedrine during pregnancy. However, they advise against the use of oral decongestants during the first trimester because of the potential increased risk of gastroschisis (an abdominal wall defect).12 Retrospective studies have shown an increased risk of gastroschisis with pseudoephedrine. 10,13,14 However, gastroschisis is a relatively rare condition, and a higher risk does not guarantee that the adverse event will occur. One prospective study of 453 women using decongestants in their first trimester showed no elevated risk for malformations.14 Unfortunately, the study population may not have been large enough to eliminate the risk of gastroschisis.
Oral decongestants may also result in vasoconstriction, which can induce maternal hypertension and lead to impaired blood flow to the fetus. Since impaired blood flow can hinder fetal growth, the risks of taking oral decongestants in the first trimester may outweigh the benefits.
In the second and third trimesters, pseudoephedrine can be recommended to pregnant patients in appropriate doses. To minimize exposure to the fetus, pregnant patients should take the immediate-release dosage form (instead of the extended-release) and take the minimum effective dose for the shortest duration possible. An appropriate dose is 30 to 60 mg every four to six hours as needed (maximum 240 mg/day).11
Oral decongestants are vasoconstrictors and should not be used in patients with certain cardiac diseases, such as uncontrolled hypertension and acute myocardial infarction. They also have sympathomimetic properties and may aggravate some medical conditions, such as diabetes mellitus and hyperthyroidism. The patient should contact her physician if she has a high-risk pregnancy, a fever, or other signs of infection, if the congestion lasts longer than seven days, or if the medication does not relieve symptoms.11
Nasal: Oxymetazoline, phenylephrine, naphazoline, and xylometazoline are commonly available nasal decongestants in the U.S. All these nasal sprays/drops are pregnancy category C. The amount of fetal exposure is minimal due to the small amount of medication absorbed systemically. Few studies are available for any of the nasal preparations. However, one prospective study of 197 and 56 women exposed to intranasal oxymetazoline and phenylephrine, respectively, did not show an increased risk for malformations.14
The American Pharmacists Association's Handbook of Non-Prescription Drugs recommends using oxymetazoline as the preferred nasal decongestant during pregnancy.11 Appropriate doses of oxymetazoline can be advised for patients during pregnancy provided that the patient does not have any contraindications to the drug. Contraindications include a high-risk pregnancy, fever or any other sign of infection, and congestion longer than seven days. These products should be used cautiously, if at all, in patients who cannot take oral decongestants. The presence of underlying conditions (e.g., diabetes mellitus) and the level of control of those disease states should be assessed before recommending the nasal sprays or drops. An appropriate dose of oxymetazoline is two to three sprays per nostril every 10 to 12 hours (maximum two doses per day). It is important that patients be instructed not to use the medication more often than recommended or longer than three days, due to the risk of rebound congestion. If the medication is not effective, the patient should refer to her physician.11
Expectorants and Antitussives
Guaifenesin: Coughing is a protective reflex. Guaifenesin works to break up the mucus in the patient's chest to make the cough more productive. If the patient is able to cough up more of the mucus, the cough will likely decrease in frequency as the mucus is cleared. However, guaifenesin has not been proven effective against cough in patients with common cold symptoms.11,15,16 Appropriate alternative recommendations include a humidifier or vaporizer, hydration, and hard candy.
Guaifenesin is considered pregnancy category C. Guaifenesin has not been studied as extensively as other OTC products. In one study of 197 pregnant women, there was an association between guaifenesin exposure in the first trimester and an increased incidence of inguinal hernias.17 This inguinal hernia association was not found in other guaifenesin studies.6
Guaifenesin is contraindicated in patients who have a chronic cough due to asthma, cigarette smoking, emphysema, chronic bronchitis, heart failure, or angiotensin-converting enzyme (ACE) inhibitor use. Fortunately, emphysema, chronic bronchitis, and heart failure are relatively rare in women who are of childbearing age. Furthermore, ACE inhibitor use is also traditionally avoided in this patient subset. Other types of cough that should not be self-medicated include coughs longer than seven days in duration, coughs that decrease/disappear and return, and coughs in combination with symptoms of infection, such as fever. Similar to other OTC cough and cold products, the longer-acting, extended-release, and/or alcohol-containing preparations should be avoided to minimize exposure to the fetus. An appropriate dose is 200 to 400 mg every four hours as needed (maximum 2,400 mg/day). See table 3 for specific circumstances when patients should not be self-treated for a cough and should be referred to a physician.
Dextromethorphan: Since coughing may be protective, it should generally not be suppressed except in certain situations. If the cough is not productive and interferes with sleep, or it is severe in nature, it can be suppressed.
Similar to guaifenesin, dextromethorphan has not been shown to be effective in patients with common cold symptoms.11,16,18 Nonpharmacologic treatment similar to that of guaifenesin can be recommended. Dextromethorphan is equipotent to codeine as an antitussive and is a pregnancy category C medication. Dextromethorphan exposure in the first trimester has been studied, and no increased risk of malformations was detected.6 However, one study showed teratogenicity when dextromethorphan was injected into avian embryos.19 Whether the data from avian embryos can be extrapolated to humans was questioned and studied. In 128 women with a first-trimester exposure to dextromethorphan, there were three major and seven minor malformations (versus five major and eight minor malformations in the control group).20 This study demonstrated that the risk of malformations with dextromethorphan was similar to the baseline rate of malformations. However, there is still theoretical concern that an antagonist at the N-methyl-d-aspartate receptor might affect fetal brain growth. To date, this adverse effect has not been studied in humans.
Concurrent use of dextromethorphan with central nervous system (CNS) depressants and monoamine oxidase (MAO) inhibitors (within 14 days) should be avoided. It has the same contraindications as guaifenesin therapy. An appropriate dose of dextromethorphan is 10 to 20 mg every four hours as needed (maximum 120 mg/day).
In 2006, the American College of Chest Physicians (ACCP) issued new guidelines addressing the appropriate management of cough. Since the available OTC cough products do not relieve the underlying cause, ACCP advises against the use of cough suppressants and expectorants for cough due to postnasal drip. For the postnasal drip cough, an antihistamine or decongestant is recommended. Given that guaifenesin and dextromethorphan have questionable efficacy for cough related to the common cold, they should be used sparingly at most in pregnant patients. Nonpharmacologic measures for cough may prove more effective with less risk to the patient.21
Antihistamines may decrease rhinorrhea and sneezing but do not affect other common cold symptoms.11 The key OTC exception is loratadine, which does not possess potent anticholinergic activity. Thus, loratadine does not treat either rhinorrhea or sneezing from a nonallergic source. According to the position statement issued by ACAAI and ACOG, chlorpheniramine was selected as one of two recommended antihistamines in pregnancy (the other is not available in the U.S.).12
Chlorpheniramine, clemastine, diphenhydramine, and loratadine are considered pregnancy category B. Brompheniramine and triprolidine are pregnancy category C. The most common concerns about antihistamine use in pregnancy are cleft palate (loratadine and diphenhydramine), polydactyly (diphenhydramine), retrolental fibroplasias, and uterine contractions (diphenhydramine).22 A cause-and-effect relationship for cleft palate and polydactyly could not be established due to small sample sizes. An association was found between antihistamine use in the last two weeks of pregnancy and an increased risk of retrolental fibroplasia. 23 When used in the third trimester, high-dose diphenhydramine may have oxytocic properties. This may cause uterine contractions. Due to lack of information and some theoretical risk, antihistamines should be avoided in the late stages of pregnancy.
Several studies have examined antihistamine use in the first trimester and have not shown an increased risk of major malformations over those expected at baseline. Two possible exceptions are brompheniramine and clemastine (limb reduction defects). However, a cause-and-effect relationship has yet to be found. Chlorphen iramine and diphenhydramine have not been associated with major malformations in either the first trimester or at any time in pregnancy. Triprolidine (plus pseudoephedrine) exposure in the first trimester has been studied in 628 women.6 Of those studied, nine had a major congenital abnormality. Whether this was caused by triprolidine or pseudoephedrine could not be determined due to concurrent use.
Antihistamines should be used with caution with CNS depressants, MAO inhibitors, and phenytoin. Caution is also advised regarding antihistamine use if the patient has concurrent narrow-angle glaucoma, peptic ulcer disease, asthma, emphysema, or chronic bronchitis. Patients should be warned that they may have motor impairment even if they do not feel drowsy. Other anticholinergic side effects are also possible. Adult doses are as follows (as needed): 4 mg of brompheniramine every four to six hours (maximum 24 mg/day), 4 mg of chlorpheniramine every four to six hours (maximum 24 mg/day), 1.34 mg of clemastine every 12 hours (maximum 2.68 mg/day), 2.5 mg of triproline every four to six hours (maximum 10 mg/day), and 25 to 50 mg of diphenhydramine every four to six hours (maximum 300 mg/day)
Menthol and Camphor: Menthol and camphor have not been well studied in pregnancy. Menthol is a common ingredient of many throat lozenges, sprays, and topical ointments. There are no human studies on the use of menthol during pregnancy; thus, its risk is undetermined. The concentration of menthol in these products is low, and the risk of malformations is therefore believed to be small. Retrospective studies with a camphor-based product (Vicks VapoRub) have not shown any developmental toxicity associated with exposures during pregnancy.6 This product should not be ingested orally. However, the American Pharmacist's Association's Handbook on Non-Prescription Drugs recommends patients consult their physician before using these medications.
Echinacea: Echinacea is a common herbal medication used to stimulate the immune system. The evidence available to support the use of echinacea for decreasing the severity and duration of cold symptoms is controversial. The lack of standardization in the product, differing preparations used, problems with study design, and conflicting results make efficacy interpretation difficult. 24 One small study showed that the use of echinacea in the first trimester did not increase the risk of major malformations. The results of the study proved that echinacea was safe as short-term treatment (five to seven days).25 Due to questionable efficacy and limited safety data, echinacea should be avoided in pregnant women.
Zinc: Zinc is commonly used to reduce the signs and symptoms of the common cold when administered within 24 hours of symptom onset.26 Zinc lozenges have been shown to be effective in reducing the duration of cold symptoms by a modest amount.27 Trials involving zinc nasal sprays have not been as promising.28,29
However, due to the unpleasant taste of zinc lozenges, they are not easy to take. For the treatment of cold symptoms, these lozenges, often unpalatable, must be administered every two hours to be efficacious. The most common adverse effect reported with zinc lozenges is nausea, which may be a preexisting problem in this patient population.30 The zinc nasal gel may reduce the likelihood of these side effects but lacks additional safety and efficacy data. 31
Only limited safety data are available to support the use of zinc lozenges. However, several studies have indicated that zinc supplementation in vitamins during pregnancy may improve fetal development.32,33 Zinc has been proven safe in appropriate doses during pregnancy. Doses for pregnant women older than 19 years should not exceed 40 mg per day (34 mg/day for patients ages 14 to 18). Six drops per day is recommended for some OTC zinc lozenges, which is equivalent to 79.9 mg per day. If larger doses are taken, especially during the third trimester, the patient's risk for complications, e.g., premature birth, is increased. 34 Pregnant women should be counseled on the importance of proper dosing from all sources, including prenatal vitamins.
Evidence supporting the use of vitamin C to reduce the severity and duration of common cold symptoms is debatable. In the studies that support vitamin C use for this indication, the effects are modest (a decrease in symptoms by less than 24 hours). To achieve this outcome, the patient needs to take 1 to 3 g of vitamin C per day. Doses larger than 1 g have been associated with an increase in side effects, including nausea and diarrhea.35,36 Many pregnant patients may find that the burden associated with high doses of vitamin C administration may not be worth the potential benefit.
There is a limited amount of safety data available to support vitamin C in pregnancy. However, at appropriate doses, vitamin C appears to be safe during pregnancy.37 It is recommended that pregnant women older than 19 years do not take more than 2 g of vitamin C per day (and less than 1,800 mg/day for pregnant patients between ages 14 and 18).38 Practitioners and patients must weigh the benefits against the risks when considering vitamin C during pregnancy.
Role of the Pharmacist
Given that the common cold is a self-limiting, non–life-threatening condition, and there is some risk involved with any medication use in pregnancy, nonpharmacologic treatment should be recommended before OTC medications. Hydration, rest, vaporizers or humidifiers, nasal irrigation, and saline nasal sprays all help symptom relief. Refer to tables 2 and 3 for conditions when the patient should be referred to a physician and not self-medicated.
If a patient is an appropriate candidate for self-treatment, see tables 4 and 5 for suitable product choices. Pharmacists can help patients avoid combination therapy by recommending medications that will directly address the symptoms that the patient is experiencing. The pharmacist can advise the patient to avoid products that may not work or that could be harmful. By cautioning the patient against long-acting, alcohol-containing products, and encouraging dosage on an as-needed basis, the pharmacist can help the patient minimize drug exposure to the developing fetus. Thus, pharmacists have a vital role in guiding pregnant women through the maze of OTC cough and cold products.
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