Hydroxyzine 6.0.60/995.

Tripelennamine 6.0.6/100.

Triprolidine 1.4.

9/628.

Second generation Astemizole 1.8.

2/114.

Cetirizine 4.0.38/950.

Loratadine 3.8.

81/2147.

Terfenadine 4.0.88/2195.

n, number of infants with a congenital anomaly who were exposed to antihistamine during the first trimester; N, number of motherinfant pairs exposed to antihistamine during the first trimester.

Compiled from Gilbert et al., 2005. Most of these studies were controlled and only the numbers of exposed are shown here for ill.u.s.trative purposes without odds ratios and comparative data.

ANTIHISTAMINES.

Antihistamines and some popular proprietary preparations are listed in Table 11.2.

These medications act primarily by competing with histamine for H -receptor binding.

1.Chemically they are related to local anesthetics and may be used as such. Other effects of some members of this group include sedation, antiemesis, antimotion sickness, and antidyskinesia.

The primary difference between the first-generation and second-generation antihistamines is the sedative effect. Second-generation antihistamines are also referred to as the nonsedating antihistamines.

The FDA pregnancy risk categories for antihistamines are given in Table 11.3. Adapted from a recent review, the percentage of congenital anomalies shows the generally accepted nonteratogenic nature of antihistamines in human exposure (Gilbert et al et al., 2005). Most authorities consider antihistamines to be safe for use during pregnancy, but it is prudent to rely on research for specific agents rather than blanket statements about drug cla.s.ses. One report suggested that antihistamines as a group may be a.s.sociated with an increased frequency of retrolental fibroplasia in premature infants (Zierler and Purohit, 1986).

Propylamine derivatives Propylamine derivatives include brompheniramine, chlorpheniramine, dexchlorpheniramine, and triprolidine. Of all antihistamines a.n.a.lyzed in the Collaborative Perinatal 210 210 Antihistamines, decongestants, and expectorants during pregnancy Project, only brompheniramine was found to be weakly a.s.sociated with congenital defects in 65 offspring, and it is unlikely that it was causative (Heinonen Project, only brompheniramine was found to be weakly a.s.sociated with congenital defects in 65 offspring, and it is unlikely that it was causative (Heinonen et al et al., 1977). In a larger study of 270 infants born following first-trimester exposure to brompheniramine, there was no increased frequency of congenital anomalies (Aselton et al et al., 1985; Jick et al et al., 1981). Meta-a.n.a.lysis of all available data on brompheniramine indicate it is not a human teratogen (Seto et al et al., 1993) and this finding is supported by a recent review (Gilbert et et al al., 2005) that included more information than the meta-a.n.a.lysis (Table 11.3).

Chlorpheniramine was not a.s.sociated with an increased frequency of congenital anomalies; neither was the closely related agent dexchlorpheniramine (Gilbert et al et al., 2005; Heinonen et al et al., 1977). In one survey of 275 infants exposed to this drug in the first trimester, chlorpheniramine was not a.s.sociated with an increased frequency of malformations (Gilbert et al et al., 2005; Jick et al et al., 1981). According to its manufacturer, this antihistamine was not teratogenic in animal studies, although the study has not been published.

Triprolidine was not a.s.sociated with an increased frequency of malformations in the offspring of 628 women who took this drug in the first trimester (Aselton et al et al., 1985; Gilbert et al et al., 2005; Jick et al et al., 1981). No animal teratology studies have been published regarding this agent.

Ethanolamine/ethylamine derivatives Of 2847 infants exposed to clemastine during the first trimester, there was no increased frequency of congenital anomalies (Table 11.3). No human studies have been published regarding the use of bromodiphenhydramine and carbinoxamine, and neither have animal teratology studies with either drug been published. The frequency of malformations was not increased in one animal study of carbinoxamine (Maruyama and Yoshida, 1968).

In a large casecontrol study (23 757 cases; 39 877 controls), the risk of congenital anomalies was not increased among 2640 infants born to women who used dimenhy-drate during the first trimester (Czeizel and Vargha, 2005). Dimenhydrinate exposure during embryogenesis was not a.s.sociated with an increased frequency of congenital anomalies in one animal study (McColl et al et al., 1965).

Diphenhydramine was not a.s.sociated with an increased frequency of congenital anomalies among 865 pregnancies exposed during the first trimester (Aselton et al et al., 1985; Heinonen et al et al., 1977). No studies regarding the use of bromodiphenhydramine during pregnancy have been published. Ten normal infants whose mothers were exposed to bromodiphenhydramine during gestation were included in the Collaborative Perinatal Project (Heinonen et al et al., 1977), but this number is too small to interpret. Importantly, ethanolaminide derivatives have been reported to have oxytocic-like effects when used parenterally (Hara et al et al., 1980; Klieger and Ma.s.sart, 1965; Rotter et al et al., 1958).

Doxylamine was one of the main components of the popular antinausea drug, Bendectin (along with pyridoxine and dicyclomine). Some investigators reported an a.s.sociation of Bendectin use in pregnancy and diaphragmatic hernias (Bracken and Berg, 1983), congenital heart disease, and pyloric stenosis (Aselton et al et al., 1985; Esken.a.z.i et et al al., 1982). Other researchers found no such a.s.sociation with congenital anomalies following exposure during embryogenesis (Mitch.e.l.l et al et al., 1981, 1983; Zierler and Rothman, 1985). The frequency of congenital anomalies was not increased among more than 1100 infants exposed to doxylamine (an antihistamine component of Bendectin) Second-generation antihistamines Second-generation antihistamines 211.

during the first trimester of pregnancy (Heinonen et al et al., 1977). No a.s.sociation was found between doxylamine and congenital heart disease in a case-controlled study (Zierler and Rothman, 1985), nor were malformations found to be increased in frequency in one animal teratology study of doxylamine (Gibson et al et al., 1968). Considering the millions of women who have used Bendectin during the first trimester of pregnancy without scientific evidence of adverse fetal effects, it is extremely unlikely that doxylamine or the components of Bendectin are human teratogens. Drugs such as Bendectin that do not cause birth defects, but are a.s.sociated with lawsuits are called 'litogens,' i.e., lawsuit-inducing (Brent, 1983).

In summary, doxylamine is a safe drug for use during pregnancy.

Piperadine derivatives The frequency of congenital anomalies was not increased among 127 infants whose mothers took azatadine during the first trimester. Similarly, among 285 infants whose mothers took cyproheptadine during the first trimester, the frequency of congenital anomalies was not increased (see Table 11.3). There are no epidemiological studies of adverse fetal effects, including congenital malformations, in the offspring of mothers who took diphenylpyraline during pregnancy. Animal teratology studies of cyproheptadine are not consistent (de la Fuente and Alia, 1982; Rodriguez-Gonzalez et al et al., 1983; Weinstein et al et al., 1975). No animal teratology studies of azatadine have been published.

Ethylenediamine derivatives In a survey of 100 and 112 offspring exposed to tripelennamine and pyrilamine, respectively, during the first trimester, the frequency of congenital anomalies was not increased (Heinonen et al et al., 1977). Pyrilamine was a.s.sociated with an increased rate of fetal loss in animal studies (Bovet-Nitti et al et al., 1963; Naranjo and de Naranjo, 1968). No animal teratology studies on tripelennamine have been published.

SECOND-GENERATION ANTIHISTAMINES.

Butyrophenone derivatives The only member in this group is terfenadine (Seldane). Among 134 infants born to women who used terfenadine during the first trimester, there was no increased frequency of congenital anomalies (Schick et al et al., 1994). In a recent review, the frequency of congenital anomalies among 2194 infants whose mothers took terfenadine during the first trimester was not increased (see Table 11.3). Terfenadine is not recommended for nursing mothers as it has been a.s.sociated with decreased pup weight in rat studies (data from the manufacturer).

Other second-generation antihistamines Among 950 infants whose mothers took cetirizine during the first trimester the frequency of congenital anomalies was not increased. Similarly, astemizole exposure during the first trimester was not a.s.sociated with an increased frequency of congenital 212 212 Antihistamines, decongestants, and expectorants during pregnancy anomalies among 114 infants. Loratidine, an FDA category B drug, exposure during the first trimester was not a.s.sociated with a higher than expected frequency of congenital anomalies (see Table 11.3). These drugs seem safe for use during pregnancy, with greater confidence a.s.signed to those drugs whose studies have the larger denominators (e.g., loratidine) (Gilbert anomalies among 114 infants. Loratidine, an FDA category B drug, exposure during the first trimester was not a.s.sociated with a higher than expected frequency of congenital anomalies (see Table 11.3). These drugs seem safe for use during pregnancy, with greater confidence a.s.signed to those drugs whose studies have the larger denominators (e.g., loratidine) (Gilbert et al et al., 2005).

Piperazine derivatives Cyclizine, buclizine, and meclizine are used primarily as antiemetics, although they also have antihistamine action. Among over 1000 infants who were exposed to meclizine in the first trimester, the frequency of congenital anomalies was not increased (Heinonen et al et al., 1977). In addition, the risk of congenital anomalies was not increased by first-trimester exposure to meclizine in one cohort and three casecontrol studies (Greenberg et al et al., 1977; Mellin, 1964; Milkovich and van den Berg, 1976; Nelson and Forfar, 1971). First-trimester exposure to cyclizine among 111 infants was not a.s.sociated with an increased frequency of congenital anomalies (Milkovich and van den Berg, 1976). No studies have been published on the use of buclizine during pregnancy.

In a rat study, the frequency of craniofacial and skeletal malformations was increased among fetuses exposed to meclizine during embryogenesis (King, 1963). No birth defects were found in the offspring of monkeys who received 10 times the usual human dose of meclizine during embryogenesis (Courtney and Valerio, 1968; Wilson and Gavan, 1967).

Phenindamine No animal or human studies regarding congenital anomalies and the use of phenindamine in pregnant women have been published. However, it is closely related to chlorpheniramine which has been studied during pregnancy and found not to increase the risk for birth defects (Table 11.4).

EXPECTORANTS AND ANt.i.tUSSIVES.

Expectorants Guaifenesin is the major expectorant used currently, and is a major component of most cough mixtures. There are no animal teratology studies available. Guaifenesin use during the first trimester in more than 1000 human pregnancies was not a.s.sociated with an increased risk of congenital anomalies (Aselton, 1985; Heinonen et al et al., 1977; Jick et al et al., 1981). Other mucolytic agents or drugs that act as an expectorant include pota.s.sium iodide or iodinated glycerol. It is well known that iodine-containing agents cross the placenta freely and may result in fetal goiter. Therefore, iodide-containing agents are contraindicated for use during pregnancy.

Ant.i.tussives Dextromethorphan is commonly used as an ant.i.tussive. It was used by 300 pregnant women during the first trimester and the frequency of congenital anomalies was not Expectorants and ant.i.tussives Expectorants and ant.i.tussives 213.

Table 11.4 Teratogen Information System (TERIS) risk for congenital anomaly and Food and Drug Administration (FDA) pregnancy risk category Drugs Teratogen Information System (TERIS) risk for congenital anomaly and Food and Drug Administration (FDA) pregnancy risk category Drugs TERIS risk FDA risk rating Astemizole Unlikely Cm Azatadine Undetermined Bm Bendectin None NA.

Benzonatate Undetermined NA.

Bromodiphenhydramine Undetermined C.

Brompheniramine None Cm Buclizine Undetermined C.

Carbinoxamine Undetermined C.

Chlorpheniramine Unlikely B.

Chlorphenirmine Unlikely B.

Clemastine Undetermined Bm Cyclizine Unlikely B.

Cyproheptadine Undetermined Bm Dextromethorphan None C.

Dicyclomine None Bm Dimenhydrinate Unlikely Bm Diphenhydramine Unlikely Bm Diphenylpyraline Undetermined NA.

Doxylamine None A.

Guaifenesin None C.

Hydroxyzine Unlikely C.

Iodinated glycerol Undetermined Xm Meclizine Unlikely Bm Naphazoline Undetermined NA.

Oxymetazoline Unlikely C.

Phenindamine Undetermined C.

Phenylephrine None to minimal C.

Pseudoephedrine None to minimal C.

Pyridoxine None NA.

Pyrilamine None C.

Terfenadine Unlikely Cm Triprolidine Unlikely Cm Xylometazoline Unlikely NA.

NA, not available.

Compiled from: Friedman et al., Obstet Gynecol 1990; 75 75: 594; Briggs et al., 2005; Friedman and Polifka, 2006.

increased (Heinonen et al et al., 1977). Numerous narcotics are used in cough preparations, including codeine, hydrocodone, and hydromorphone. Chronic use of narcotic agents may result in neonatal addiction, withdrawal, and respiratory depression. However, narcotics are not a.s.sociated with an increased frequency of congenital anomalies. Also, acute use of narcotic ant.i.tussives is not a.s.sociated with neonatal addiction or congenital anomalies.

Benzonatate (Tessalon) is a local anesthetic-like compound and acts as an ant.i.tussive by anesthetizing the stretch receptors in the respiratory pa.s.sage. No human studies are available on which to base an evaluation of adverse fetal effects.

214.

Antihistamines, decongestants, and expectorants during pregnancy Note Note: Many cough preparations contain ethyl alcohol and may cause adverse fetal effects if used chronically. Case reports of fetal alcohol syndrome have been published in which the mother abused cough preparations during pregnancy. However, it is unlikely that short-term use carries significant risk. Alcohol is discussed in further detail in Chapter 16.

SPECIAL CONSIDERATIONS.

Viral upper respiratory infections (the common cold) Pregnant women with colds usually do not require specific therapy, especially in the first trimester. If symptomatic therapy is indicated, pregnant women with the common cold can be treated with acetaminophen, in combination with a decongestant and an antihistamine, and a combination of an ant.i.tussive and expectorant. Pseudoephedrine and chlorpheniramine are the preferred treatments (Hornby and Abrahams, 1996). If a nasal spray is deemed necessary, agents containing oxymetazoline, xylometazoline, or naphazoline are reasonable, since minimal systemic absorption occurs. Ant.i.tussive/expectorant compounds containing iodide are contraindicated. Other, noniodinated preparations offer equally effective alternative medication (Tables 11.1 and 11.2).

Allergic rhinitis/sinusitis Chlorpheniramine compounds are preferable for first-line use in pregnant women because they are better studied. The histamine H -receptor antagonist astemizole 1 (Hisma.n.a.l) and terfenadine (Seldane) have been studied in the first trimester in pregnant women (Table 11.3), and are probably safe.

Pruritis/urticaria Diphenhydramine is well studied during pregnancy and is a safe agent to use (Table 11.3).

Its oxytocic effects do not appear to be as p.r.o.nounced as dimenhydrinate (Hara et al et al., 1980).

Other medications found to be safe and effective in the treatment of pruritus are hydroxyzine or dexchlorpheniramine (Drugs and Pregnancy Study Group, 1994) (Table 11.3).

Motion sickness/vertigo Dimenhydrinate is a commonly used agent, although it may have some oxytocic properties. It has been studied during the first trimester of human pregnancy and was not a.s.sociated with an increased frequency of congenital anomalies (Czeizel and Vargha, 2005).

Drug-induced dyskinesia The antimuscarinic and sedative effects of diphenhydramine make it the ideal agent for the treatment of drug-induced dyskinesia in the pregnant patient. Its use during pregnancy has been studied extensively, and there were no apparent untoward effects (Table 11.3).

Key references 215.

Key references Czeizel AE, Vargha AEP. A casecontrol study of congenital abnormality and dimenhydrinate usage during pregnancy. Arch Gynecol Obstet 2005; 271 271: 113.

Gilbert C, Mazzotta P, Loebstein R, Koren G. Fetal safety of drugs used in the treatment of allergic rhinitis. A critical review. Drug Safety 2005; 28 28: 707.

Hornby PJ, Abrahams TP. Pulmonary pharmacology. Clin Obstet Gynecol 1996; 39 39: 17.

Further references are available on the book's website at http://www.drugsandpregnancy.com 12.Nutritional and dietary supplementation during pregnancy Protein-calorie requirements and Antiflatulents, laxatives, and supplements 216.

antidiarrheals 231.

Vitamins 217.

Special considerations 235.

Other essential nutrients 220.

Key references 239.

Gastrointestinal medications during pregnancy 223.

A balanced 'nonfad' diet should provide pregnant women with an adequate complement of nutrients during pregnancy. Prenatal vitamin supplements are usually given, but there is no clear consensus that they are needed. Under the Hippocratic dictum of 'do no harm,' prenatal vitamin supplements are not harmful in recommended daily allowance (RDA) doses. Vitamin supplements for pregnant women should, along with dietary intake, approximate the RDA set by the Food and Drug Administration (FDA) (Table 12.1). Iron is the only nutrient for which supplementation during pregnancy is invariably required.

PROTEIN-CALORIE REQUIREMENTS AND SUPPLEMENTS.

During a normal pregnancy, women should gain between 22 and 27 lbs. Calories required during pregnancy increase (approximately 300500 calories per day) only mar-ginally above the needs of nonpregnant women (2100 calories daily). Composition of the 2400 to 2600 calories should be comprised of 74 g of protein. A reasonably balanced diet provides adequate protein and calories during pregnancy (ACOG, 1993). Under special circ.u.mstances, protein-calorie supplementation is warranted. Gravidas who follow a vegetarian diet or are otherwise nutritionally restricted (e.g., gluten intolerant), may require supplementation. When considering the gravid vegetarian, it is extremely important to distinguish between the strictly vegetarian (e.g., Buddhist) and the lacto-ovo vegetarian (e.g., Seventh Day Adventists). Lacto-ovo vegetarians do not consume animal flesh-derived foods (i.e., meat and fish) from their diets, but do consume animal products (i.e., eggs and dairy products). Nonlacto-ovo vegetarians eat only plant-derived foods and are Vitamins Vitamins 217.

Table 12.1 National Research Council recommended daily dietary allowances for women before and during pregnancy and lactation National Research Council recommended daily dietary allowances for women before and during pregnancy and lactation Nutrient Nonpregnanta Pregnant Lactating Kilocalories 2200.

2500.

2600.

Protein (g) 55.60.65.Fat-soluble vitamins A (g RE)b 800.

800.

1300.

D (g) 10.10.12.E (mg TE)c 8.10.12.K (g) 55.65.65.Water-soluble vitamins C (mg) 60.70.95.Cobalamin, B (g) 2.0.2.2.

2.6.

12.Folate (g) 180.

400.

280.

Niacin (mg) 15.17.20.Pyridoxine, B (mg) 1.6.

2.2.