Gerald G. Briggs

The final part of this series covers the use of infliximab, anticholinergics/antispasmodics, gastrointestinal stimulants, and anorectal preparations in pregnant and lactating women.

▸ Infliximab (Remicade): Infliximab is a monoclonal antibody used to treat severe Crohn's disease and autoimmune diseases such as ankylosing spondylitis, rheumatoid arthritis, and psoriasis. It binds to and inhibits human tumor necrosis factor-α (TNF-α). Animal reproduction studies have not been conducted with the agent because it does not react with animal TNF-α. Human pregnancy exposure consists of about 30 cases, which are limited to case reports and observational studies. The drug does not appear to represent a significant risk for developmental toxicity. Still, if possible, the best course is to avoid its use in pregnancy. If pregnancy exposure does occur, health care providers are encouraged to register these patients in the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy study by calling the toll-free number, 877-311-8972.

▸ Anticholinergics/antispasmodics: These agents have been used for years for peptic ulcer and functional GI disorders such as diarrhea, hypermotility, neurogenic colon, irritable bowel syndrome, ulcerative colitis, and biliary tract spasm. The agents—available under numerous trade names—include atropine, belladonna, dicyclomine, glycopyrrolate, L-hyoscyamine, mepenzolate, methscopolamine, propantheline, and scopolamine. Only atropine, scopolamine, and dicyclomine have sufficient data in pregnancy. There are no reports suggesting that these agents cause birth defects. However, an excessive dose of scopolamine in labor has been associated with newborn toxicity. The other drugs are also probably low risk, but cannot be classified as such because of the very limited or complete lack of human pregnancy experience. However, anticholinergic combinations formulated with phenobarbital or other sedatives should be avoided in pregnancy and lactation. Although the data are very limited, all anticholinergics, except dicyclomine, appear to be compatible with breast-feeding. Dicyclomine is concentrated in milk and has been associated with apnea in one nursing infant.

▸ GI stimulants: Dexpanthenol (Ilopan) is given by intramuscular injection to prevent paralytic ileus after abdominal surgery. Although the drug has been promoted for constipation in pregnant women, there are no reports of its use or studies in pregnant or lactating animals or humans. Thus, the drug should not be given during pregnancy or breast-feeding.

In contrast, another GI stimulant, metoclopramide (Reglan, Maxolon), has substantial human pregnancy experience, primarily as an antiemetic. Although it is considered compatible with pregnancy, its use during breast-feeding is controversial. It has been successfully used as a lactation stimulant at doses of 20–45 mg/day. The drug is excreted into milk, but the estimated dose ingested by a nursing infant from milk is much lower than the therapeutic infant dose. However, mild intestinal discomfort has been observed in two infants. Because of its dopaminergic blocking action, the American Academy of Pediatrics classifies metoclopramide as a drug of potential concern during breast-feeding.

▸ Anorectal preparations: These include a large group of agents that are available in various topical formulations such as creams, ointments, foams, lotions, tissues and pads, and suppositories. With the exception of the hydrocortisone products, all are available over the counter, so you might not know that your patient is using them unless a careful history is taken. The OTC preparations are formulated with low concentrations of various drug mixtures, such as local anesthetics, vasoconstrictors, astringents, antiseptics, emollients/protectants, counterirritants, keratolytics, and wound healing agents. Only a few of these products and drugs have been studied in human pregnancy or lactation, but these preparations are used for their local effects and clinically significant systemic levels are not expected.

About 26% of the corticosteroid is absorbed from hydrocortisone suppositories, but the maximum strength of these products is only 30 mg, so the amount reaching the circulation is clinically insignificant. Therefore, at recommended doses, the use of anorectal preparations during pregnancy or breast-feeding can be considered low risk.

Of the drugs covered in this series, misoprostol and tetracycline cause structural defects, castor oil can induce labor, and mesalamine-containing agents and dicyclomine have caused toxicity in nursing infants. Most GI agents are safe in pregnancy and lactation, but many have insufficient data to judge their risk.

The final part of this series covers the use of infliximab, anticholinergics/antispasmodics, gastrointestinal stimulants, and anorectal preparations in pregnant and lactating women.

▸ Infliximab (Remicade): Infliximab is a monoclonal antibody used to treat severe Crohn's disease and autoimmune diseases such as ankylosing spondylitis, rheumatoid arthritis, and psoriasis. It binds to and inhibits human tumor necrosis factor-α (TNF-α). Animal reproduction studies have not been conducted with the agent because it does not react with animal TNF-α. Human pregnancy exposure consists of about 30 cases, which are limited to case reports and observational studies. The drug does not appear to represent a significant risk for developmental toxicity. Still, if possible, the best course is to avoid its use in pregnancy. If pregnancy exposure does occur, health care providers are encouraged to register these patients in the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy study by calling the toll-free number, 877-311-8972.

▸ Anticholinergics/antispasmodics: These agents have been used for years for peptic ulcer and functional GI disorders such as diarrhea, hypermotility, neurogenic colon, irritable bowel syndrome, ulcerative colitis, and biliary tract spasm. The agents—available under numerous trade names—include atropine, belladonna, dicyclomine, glycopyrrolate, L-hyoscyamine, mepenzolate, methscopolamine, propantheline, and scopolamine. Only atropine, scopolamine, and dicyclomine have sufficient data in pregnancy. There are no reports suggesting that these agents cause birth defects. However, an excessive dose of scopolamine in labor has been associated with newborn toxicity. The other drugs are also probably low risk, but cannot be classified as such because of the very limited or complete lack of human pregnancy experience. However, anticholinergic combinations formulated with phenobarbital or other sedatives should be avoided in pregnancy and lactation. Although the data are very limited, all anticholinergics, except dicyclomine, appear to be compatible with breast-feeding. Dicyclomine is concentrated in milk and has been associated with apnea in one nursing infant.

▸ GI stimulants: Dexpanthenol (Ilopan) is given by intramuscular injection to prevent paralytic ileus after abdominal surgery. Although the drug has been promoted for constipation in pregnant women, there are no reports of its use or studies in pregnant or lactating animals or humans. Thus, the drug should not be given during pregnancy or breast-feeding.

In contrast, another GI stimulant, metoclopramide (Reglan, Maxolon), has substantial human pregnancy experience, primarily as an antiemetic. Although it is considered compatible with pregnancy, its use during breast-feeding is controversial. It has been successfully used as a lactation stimulant at doses of 20–45 mg/day. The drug is excreted into milk, but the estimated dose ingested by a nursing infant from milk is much lower than the therapeutic infant dose. However, mild intestinal discomfort has been observed in two infants. Because of its dopaminergic blocking action, the American Academy of Pediatrics classifies metoclopramide as a drug of potential concern during breast-feeding.

▸ Anorectal preparations: These include a large group of agents that are available in various topical formulations such as creams, ointments, foams, lotions, tissues and pads, and suppositories. With the exception of the hydrocortisone products, all are available over the counter, so you might not know that your patient is using them unless a careful history is taken. The OTC preparations are formulated with low concentrations of various drug mixtures, such as local anesthetics, vasoconstrictors, astringents, antiseptics, emollients/protectants, counterirritants, keratolytics, and wound healing agents. Only a few of these products and drugs have been studied in human pregnancy or lactation, but these preparations are used for their local effects and clinically significant systemic levels are not expected.

About 26% of the corticosteroid is absorbed from hydrocortisone suppositories, but the maximum strength of these products is only 30 mg, so the amount reaching the circulation is clinically insignificant. Therefore, at recommended doses, the use of anorectal preparations during pregnancy or breast-feeding can be considered low risk.

Of the drugs covered in this series, misoprostol and tetracycline cause structural defects, castor oil can induce labor, and mesalamine-containing agents and dicyclomine have caused toxicity in nursing infants. Most GI agents are safe in pregnancy and lactation, but many have insufficient data to judge their risk.

The final part of this series covers the use of infliximab, anticholinergics/antispasmodics, gastrointestinal stimulants, and anorectal preparations in pregnant and lactating women.

▸ Infliximab (Remicade): Infliximab is a monoclonal antibody used to treat severe Crohn's disease and autoimmune diseases such as ankylosing spondylitis, rheumatoid arthritis, and psoriasis. It binds to and inhibits human tumor necrosis factor-α (TNF-α). Animal reproduction studies have not been conducted with the agent because it does not react with animal TNF-α. Human pregnancy exposure consists of about 30 cases, which are limited to case reports and observational studies. The drug does not appear to represent a significant risk for developmental toxicity. Still, if possible, the best course is to avoid its use in pregnancy. If pregnancy exposure does occur, health care providers are encouraged to register these patients in the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy study by calling the toll-free number, 877-311-8972.

▸ Anticholinergics/antispasmodics: These agents have been used for years for peptic ulcer and functional GI disorders such as diarrhea, hypermotility, neurogenic colon, irritable bowel syndrome, ulcerative colitis, and biliary tract spasm. The agents—available under numerous trade names—include atropine, belladonna, dicyclomine, glycopyrrolate, L-hyoscyamine, mepenzolate, methscopolamine, propantheline, and scopolamine. Only atropine, scopolamine, and dicyclomine have sufficient data in pregnancy. There are no reports suggesting that these agents cause birth defects. However, an excessive dose of scopolamine in labor has been associated with newborn toxicity. The other drugs are also probably low risk, but cannot be classified as such because of the very limited or complete lack of human pregnancy experience. However, anticholinergic combinations formulated with phenobarbital or other sedatives should be avoided in pregnancy and lactation. Although the data are very limited, all anticholinergics, except dicyclomine, appear to be compatible with breast-feeding. Dicyclomine is concentrated in milk and has been associated with apnea in one nursing infant.

▸ GI stimulants: Dexpanthenol (Ilopan) is given by intramuscular injection to prevent paralytic ileus after abdominal surgery. Although the drug has been promoted for constipation in pregnant women, there are no reports of its use or studies in pregnant or lactating animals or humans. Thus, the drug should not be given during pregnancy or breast-feeding.

In contrast, another GI stimulant, metoclopramide (Reglan, Maxolon), has substantial human pregnancy experience, primarily as an antiemetic. Although it is considered compatible with pregnancy, its use during breast-feeding is controversial. It has been successfully used as a lactation stimulant at doses of 20–45 mg/day. The drug is excreted into milk, but the estimated dose ingested by a nursing infant from milk is much lower than the therapeutic infant dose. However, mild intestinal discomfort has been observed in two infants. Because of its dopaminergic blocking action, the American Academy of Pediatrics classifies metoclopramide as a drug of potential concern during breast-feeding.

▸ Anorectal preparations: These include a large group of agents that are available in various topical formulations such as creams, ointments, foams, lotions, tissues and pads, and suppositories. With the exception of the hydrocortisone products, all are available over the counter, so you might not know that your patient is using them unless a careful history is taken. The OTC preparations are formulated with low concentrations of various drug mixtures, such as local anesthetics, vasoconstrictors, astringents, antiseptics, emollients/protectants, counterirritants, keratolytics, and wound healing agents. Only a few of these products and drugs have been studied in human pregnancy or lactation, but these preparations are used for their local effects and clinically significant systemic levels are not expected.

About 26% of the corticosteroid is absorbed from hydrocortisone suppositories, but the maximum strength of these products is only 30 mg, so the amount reaching the circulation is clinically insignificant. Therefore, at recommended doses, the use of anorectal preparations during pregnancy or breast-feeding can be considered low risk.

Of the drugs covered in this series, misoprostol and tetracycline cause structural defects, castor oil can induce labor, and mesalamine-containing agents and dicyclomine have caused toxicity in nursing infants. Most GI agents are safe in pregnancy and lactation, but many have insufficient data to judge their risk.

The second part of this three-part series examines the safety of drugs used to treat several gastrointestinal diseases that cause significant morbidity in pregnant women.

▸ Helicobacter pylori infection: The bacteria H. pylori are associated with chronic active antral gastritis, duodenal ulcer, and gastric ulcer. Although controversial, several studies have associated this infection with severe nausea/vomiting of pregnancy, including hyperemesis gravidarum. Eradication regimens involve dual, triple, or quadruple therapy, typically given for 2 weeks, combining one or two anti-infectives and an antisecretory agent. Bismuth and ranitidine bismuth citrate are sometimes added to the regimen. If clinically acceptable, the wisest course is to delay therapy until after the first trimester. Of the four anti-infectives used in these regimens (amoxicillin, clarithromycin, metronidazole, and tetracycline), only tetracycline clearly causes developmental toxicity, but the carcinogenic potential of metronidazole has not been adequately assessed.

Two proton pump inhibitors, lansoprazole (Prevacid) and omeprazole (Prilosec, Zegerid), are the antisecretory agents of choice in H. pylori eradication regimens because neither appears to represent a significant risk in pregnancy. Although ranitidine (Zantac) is compatible with pregnancy, both the salt form ranitidine bismuth citrate (Tritec) and bismuth alone are best avoided because the limited human data prevents an accurate assessment of bismuth's risk to the embryo or fetus.

Amoxicillin, clarithromycin, and tetracycline are compatible with breast-feeding. All of the other agents used for H. pylori infection are best avoided in lactation because of potential toxicity in the nursing infant.

▸ Cholelithiasis: Only one gallstone-solubilizing agent, ursodiol (Actigall, Urso), is available in the United States. Reports of exposure to this agent early in pregnancy are limited, but there are more data in the second half of pregnancy, which indicates that the drug does not appear to represent a risk in pregnancy or lactation.

▸ Digestive enzymes: Two digestive pancreatic enzymes—pancreatin and pancrelipase—are used for various conditions that result in deficient pancreatic secretions, such as cystic fibrosis and chronic pancreatitis. These enzymes metabolize fats, proteins, and starches in the duodenum and upper jejunum. Only fragments of pancreatin and pancrelipase are absorbed systematically. Although human data are limited, animal data suggest these enzymes are low risk in pregnancy and lactation. Of note, the enteric coating on many of these products is diethyl phthalate, and high doses of some phthalates may cause developmental toxicity. However, the very small quantities that the embryo or fetus may be exposed to from the enteric coating suggest that the risk of reproductive and developmental toxicity is probably minimal to negligible.

▸ Ulcer prophylaxis: Sucralfate (Carafate) inhibits pepsin activity and protects against ulceration. Only very small amounts of the drug are absorbed systemically, and it is compatible in both pregnancy and lactation. The prostaglandin misoprostol (Cytotec) is also indicated for ulcer prophylaxis, but this use is contraindicated in pregnancy (see GI Agents: Part I, FAMILY PRACTICE NEWS, Dec. 1, 2005, page 47).

▸ Flatulence: Two antiflatulents available over the counter are the silicone product simethicone (multiple trade names) and activated charcoal. They also are combined in a single product (Flatulex). Because neither agent is absorbable, they present no risk to the embryo, fetus, or nursing infant.

▸ Obesity: There is no human pregnancy experience with the lipase inhibitor, orlistat (Xenical). The drug inhibits the absorption of dietary fats. The animal reproduction data and minimal systemic bioavailability suggest that the drug represents a low risk in pregnancy and lactation.

▸ Inflammatory bowel disease (IBD): Mesalamine (5-aminosalicylic acid, 5-ASA) (Asacol, Canasa, Pentasa, Rowasa) is compatible with pregnancy. Reports have described several hundred pregnant women who had received the drug without apparent harm to embryo or fetus. Two other agents in this class, balsalazide (Colazal) and olsalazine (Dipentum), are broken down in the colon to 5-ASA. Both of these agents appear to be compatible with pregnancy.

A third agent, sulfasalazine (Azulfidine), is metabolized to 5-ASA plus sulfapyridine. Sulfapyridine readily crosses the placenta to the fetus. When sulfapyridine is used close to delivery, neonatal jaundice and/or kernicterus secondary to displacement of bilirubin from albumin is a theoretical concern but has not been reported. Although the human experience is limited, sulfasalazine appears to be compatible with pregnancy.

However, all of the IBD agents should be used cautiously during lactation. Multiple episodes of diarrhea were reported in one nursing infant that appeared to be related to the mesalamine rectal suppositories used by the mother. In another case, persistent bloody diarrhea was attributed to the mother's use of sulfasalazine. Because of these cases, close observation of the nursing infant is required if the mother is taking any of these agents.

The second part of this three-part series examines the safety of drugs used to treat several gastrointestinal diseases that cause significant morbidity in pregnant women.

▸ Helicobacter pylori infection: The bacteria H. pylori are associated with chronic active antral gastritis, duodenal ulcer, and gastric ulcer. Although controversial, several studies have associated this infection with severe nausea/vomiting of pregnancy, including hyperemesis gravidarum. Eradication regimens involve dual, triple, or quadruple therapy, typically given for 2 weeks, combining one or two anti-infectives and an antisecretory agent. Bismuth and ranitidine bismuth citrate are sometimes added to the regimen. If clinically acceptable, the wisest course is to delay therapy until after the first trimester. Of the four anti-infectives used in these regimens (amoxicillin, clarithromycin, metronidazole, and tetracycline), only tetracycline clearly causes developmental toxicity, but the carcinogenic potential of metronidazole has not been adequately assessed.

Two proton pump inhibitors, lansoprazole (Prevacid) and omeprazole (Prilosec, Zegerid), are the antisecretory agents of choice in H. pylori eradication regimens because neither appears to represent a significant risk in pregnancy. Although ranitidine (Zantac) is compatible with pregnancy, both the salt form ranitidine bismuth citrate (Tritec) and bismuth alone are best avoided because the limited human data prevents an accurate assessment of bismuth's risk to the embryo or fetus.

Amoxicillin, clarithromycin, and tetracycline are compatible with breast-feeding. All of the other agents used for H. pylori infection are best avoided in lactation because of potential toxicity in the nursing infant.

▸ Cholelithiasis: Only one gallstone-solubilizing agent, ursodiol (Actigall, Urso), is available in the United States. Reports of exposure to this agent early in pregnancy are limited, but there are more data in the second half of pregnancy, which indicates that the drug does not appear to represent a risk in pregnancy or lactation.

▸ Digestive enzymes: Two digestive pancreatic enzymes—pancreatin and pancrelipase—are used for various conditions that result in deficient pancreatic secretions, such as cystic fibrosis and chronic pancreatitis. These enzymes metabolize fats, proteins, and starches in the duodenum and upper jejunum. Only fragments of pancreatin and pancrelipase are absorbed systematically. Although human data are limited, animal data suggest these enzymes are low risk in pregnancy and lactation. Of note, the enteric coating on many of these products is diethyl phthalate, and high doses of some phthalates may cause developmental toxicity. However, the very small quantities that the embryo or fetus may be exposed to from the enteric coating suggest that the risk of reproductive and developmental toxicity is probably minimal to negligible.

▸ Ulcer prophylaxis: Sucralfate (Carafate) inhibits pepsin activity and protects against ulceration. Only very small amounts of the drug are absorbed systemically, and it is compatible in both pregnancy and lactation. The prostaglandin misoprostol (Cytotec) is also indicated for ulcer prophylaxis, but this use is contraindicated in pregnancy (see GI Agents: Part I, FAMILY PRACTICE NEWS, Dec. 1, 2005, page 47).

▸ Flatulence: Two antiflatulents available over the counter are the silicone product simethicone (multiple trade names) and activated charcoal. They also are combined in a single product (Flatulex). Because neither agent is absorbable, they present no risk to the embryo, fetus, or nursing infant.

▸ Obesity: There is no human pregnancy experience with the lipase inhibitor, orlistat (Xenical). The drug inhibits the absorption of dietary fats. The animal reproduction data and minimal systemic bioavailability suggest that the drug represents a low risk in pregnancy and lactation.

▸ Inflammatory bowel disease (IBD): Mesalamine (5-aminosalicylic acid, 5-ASA) (Asacol, Canasa, Pentasa, Rowasa) is compatible with pregnancy. Reports have described several hundred pregnant women who had received the drug without apparent harm to embryo or fetus. Two other agents in this class, balsalazide (Colazal) and olsalazine (Dipentum), are broken down in the colon to 5-ASA. Both of these agents appear to be compatible with pregnancy.

A third agent, sulfasalazine (Azulfidine), is metabolized to 5-ASA plus sulfapyridine. Sulfapyridine readily crosses the placenta to the fetus. When sulfapyridine is used close to delivery, neonatal jaundice and/or kernicterus secondary to displacement of bilirubin from albumin is a theoretical concern but has not been reported. Although the human experience is limited, sulfasalazine appears to be compatible with pregnancy.

However, all of the IBD agents should be used cautiously during lactation. Multiple episodes of diarrhea were reported in one nursing infant that appeared to be related to the mesalamine rectal suppositories used by the mother. In another case, persistent bloody diarrhea was attributed to the mother's use of sulfasalazine. Because of these cases, close observation of the nursing infant is required if the mother is taking any of these agents.

The second part of this three-part series examines the safety of drugs used to treat several gastrointestinal diseases that cause significant morbidity in pregnant women.

▸ Helicobacter pylori infection: The bacteria H. pylori are associated with chronic active antral gastritis, duodenal ulcer, and gastric ulcer. Although controversial, several studies have associated this infection with severe nausea/vomiting of pregnancy, including hyperemesis gravidarum. Eradication regimens involve dual, triple, or quadruple therapy, typically given for 2 weeks, combining one or two anti-infectives and an antisecretory agent. Bismuth and ranitidine bismuth citrate are sometimes added to the regimen. If clinically acceptable, the wisest course is to delay therapy until after the first trimester. Of the four anti-infectives used in these regimens (amoxicillin, clarithromycin, metronidazole, and tetracycline), only tetracycline clearly causes developmental toxicity, but the carcinogenic potential of metronidazole has not been adequately assessed.

Two proton pump inhibitors, lansoprazole (Prevacid) and omeprazole (Prilosec, Zegerid), are the antisecretory agents of choice in H. pylori eradication regimens because neither appears to represent a significant risk in pregnancy. Although ranitidine (Zantac) is compatible with pregnancy, both the salt form ranitidine bismuth citrate (Tritec) and bismuth alone are best avoided because the limited human data prevents an accurate assessment of bismuth's risk to the embryo or fetus.

Amoxicillin, clarithromycin, and tetracycline are compatible with breast-feeding. All of the other agents used for H. pylori infection are best avoided in lactation because of potential toxicity in the nursing infant.

▸ Cholelithiasis: Only one gallstone-solubilizing agent, ursodiol (Actigall, Urso), is available in the United States. Reports of exposure to this agent early in pregnancy are limited, but there are more data in the second half of pregnancy, which indicates that the drug does not appear to represent a risk in pregnancy or lactation.

▸ Digestive enzymes: Two digestive pancreatic enzymes—pancreatin and pancrelipase—are used for various conditions that result in deficient pancreatic secretions, such as cystic fibrosis and chronic pancreatitis. These enzymes metabolize fats, proteins, and starches in the duodenum and upper jejunum. Only fragments of pancreatin and pancrelipase are absorbed systematically. Although human data are limited, animal data suggest these enzymes are low risk in pregnancy and lactation. Of note, the enteric coating on many of these products is diethyl phthalate, and high doses of some phthalates may cause developmental toxicity. However, the very small quantities that the embryo or fetus may be exposed to from the enteric coating suggest that the risk of reproductive and developmental toxicity is probably minimal to negligible.

▸ Ulcer prophylaxis: Sucralfate (Carafate) inhibits pepsin activity and protects against ulceration. Only very small amounts of the drug are absorbed systemically, and it is compatible in both pregnancy and lactation. The prostaglandin misoprostol (Cytotec) is also indicated for ulcer prophylaxis, but this use is contraindicated in pregnancy (see GI Agents: Part I, FAMILY PRACTICE NEWS, Dec. 1, 2005, page 47).

▸ Flatulence: Two antiflatulents available over the counter are the silicone product simethicone (multiple trade names) and activated charcoal. They also are combined in a single product (Flatulex). Because neither agent is absorbable, they present no risk to the embryo, fetus, or nursing infant.

▸ Obesity: There is no human pregnancy experience with the lipase inhibitor, orlistat (Xenical). The drug inhibits the absorption of dietary fats. The animal reproduction data and minimal systemic bioavailability suggest that the drug represents a low risk in pregnancy and lactation.

▸ Inflammatory bowel disease (IBD): Mesalamine (5-aminosalicylic acid, 5-ASA) (Asacol, Canasa, Pentasa, Rowasa) is compatible with pregnancy. Reports have described several hundred pregnant women who had received the drug without apparent harm to embryo or fetus. Two other agents in this class, balsalazide (Colazal) and olsalazine (Dipentum), are broken down in the colon to 5-ASA. Both of these agents appear to be compatible with pregnancy.

A third agent, sulfasalazine (Azulfidine), is metabolized to 5-ASA plus sulfapyridine. Sulfapyridine readily crosses the placenta to the fetus. When sulfapyridine is used close to delivery, neonatal jaundice and/or kernicterus secondary to displacement of bilirubin from albumin is a theoretical concern but has not been reported. Although the human experience is limited, sulfasalazine appears to be compatible with pregnancy.

However, all of the IBD agents should be used cautiously during lactation. Multiple episodes of diarrhea were reported in one nursing infant that appeared to be related to the mesalamine rectal suppositories used by the mother. In another case, persistent bloody diarrhea was attributed to the mother's use of sulfasalazine. Because of these cases, close observation of the nursing infant is required if the mother is taking any of these agents.

Gastrointestinal complaints are common in pregnancy and during the postpartum period. They include conditions such as nausea and vomiting, constipation, diarrhea, heartburn, and erosive gastroesophageal reflux disease.

▸ Antiemetics. Nausea and vomiting is the most frequent GI complaint in pregnancy. Many oral and parenteral antiemetics are available to treat nausea and vomiting of pregnancy (NVP). All are considered low risk for developmental toxicity (growth retardation, structural defects, functional and behavioral deficits, or death).

The most commonly prescribed over-the-counter agent for this condition is doxylamine (Unisom), usually combined with vitamin B6 (pyridoxine). These two drugs were the components of Bendectin, which was removed from the market by its manufacturer in 1983, but classified by the Food and Drug Administration as safe and effective. Other commonly used oral medications for NVP include prochlorperazine (Compazine), metoclopramide (Reglan), trimethobenzamide (Tigan), promethazine (Phenergan), and ondansetron (Zofran).

The most severe form of nausea, hyperemesis gravidarum, occurs in less than 1% of pregnancies and requires hospitalization and intravenous antiemetics, such as droperidol (Inapsine), prochlorperazine, and ondansetron.

▸ Laxatives. Seven types of products act as laxatives: saline (phosphates and magnesium hydroxide and its salts); stimulants/irritants (cascara, bisacodyl, casanthranol, senna, and castor oil); bulking agents (methylcellulose, polycarbophil, and psyllium); emollient (mineral oil); fecal softeners (docusate); hyperosmotics (glycerin, lactulose); and tegaserod (Zelnorm).

With the exception of lactulose and tegaserod, all of these products are available over the counter, and most do not cause direct embryo/fetal toxicity. However, castor oil, which is converted to ricinoleic acid in the gut, is an irritant that may induce premature labor. Improper use of saline laxatives can cause electrolyte imbalances, and mineral oil will prevent absorption of fat-soluble vitamins.

Of the laxatives, bulking agents and fecal softeners are the best choices in pregnancy. Cascara sagrada and senna are excreted into breast milk and are compatible with breast-feeding, although they may cause diarrhea in a nursing infant.

Tesgaserod, a serotonin type-4 receptor agonist, is approved for women with irritable bowel syndrome whose primary bowel symptom is constipation (and for idiopathic constipation in those under age 65). Limited animal and human data suggest a low risk for embryo/fetal toxicity, but the drug is best avoided during lactation because of the absence of any human data.

▸ Antidiarrheal agents. The antidiarrheal agents diphenoxylate and its active metabolite, difenoxin, are meperidine-related narcotics. Available as Lomotil and Motofen when combined with atropine to prevent abuse, they present low risk in pregnancy. Although there is potential for toxicity in a nursing infant, infrequent use is probably compatible with nursing. Loperamide (Imodium) is low risk in pregnancy and lactation. Alosetron (Lotronex), a serotonin antagonist, has both antiemetic and antidiarrheal properties. It is indicated only in women with IBS whose primary symptom is severe, chronic diarrhea. Based only on animal data, it is considered low risk in pregnancy. Because severe GI toxicity (constipation, ischemic colitis) has been reported in adults, it should be avoided during lactation. Bismuth subsalicylate, such as Pepto-Bismol and Kaopectate, should not be used in pregnancy or lactation.

▸ Antacids. Antacids available to treat heartburn include calcium carbonate, magnesium hydroxide and oxide, and aluminum hydroxide and carbonate. Systemic absorption of antacids is negligible, so recommended doses are safe in pregnancy and lactation. Sodium bicarbonate should be avoided because it is absorbed systemically and could cause alkalosis.

▸ Antisecretory agents. These agents, used for heartburn and GERD, include the histamine H₂ antagonists cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid), and ranitidine (Zantac) and the proton pump inhibitors esomeprazole (Nexium), lansoprazole (Prevacid), omeprazole (Prilosec), pantoprazole (Protonix), and rabeprazole (Aciphex).

Low strengths of the histamine antagonists are available over the counter, but omeprazole is the only PPI available without a prescription. All of these antisecretory agents are low risk in pregnancy. The histamine antagonists are compatible with breast-feeding. In contrast, the PPIs have carcinogenic and mutagenic properties, so prolonged use while breast-feeding should be avoided.

Misoprostol (Cytotec), another antisecretory agent and a prostaglandin E₁ (PGE₁) analogue, is a proven human teratogen. It should only be used in pregnancy for its off-label indications: uterine stimulation and cervical ripening. Although its use during lactation has not been reported, naturally occurring PGE₁ is excreted into milk and may protect the GI tract in nursing infants.

Gastrointestinal complaints are common in pregnancy and during the postpartum period. They include conditions such as nausea and vomiting, constipation, diarrhea, heartburn, and erosive gastroesophageal reflux disease.

▸ Antiemetics. Nausea and vomiting is the most frequent GI complaint in pregnancy. Many oral and parenteral antiemetics are available to treat nausea and vomiting of pregnancy (NVP). All are considered low risk for developmental toxicity (growth retardation, structural defects, functional and behavioral deficits, or death).

The most commonly prescribed over-the-counter agent for this condition is doxylamine (Unisom), usually combined with vitamin B6 (pyridoxine). These two drugs were the components of Bendectin, which was removed from the market by its manufacturer in 1983, but classified by the Food and Drug Administration as safe and effective. Other commonly used oral medications for NVP include prochlorperazine (Compazine), metoclopramide (Reglan), trimethobenzamide (Tigan), promethazine (Phenergan), and ondansetron (Zofran).

The most severe form of nausea, hyperemesis gravidarum, occurs in less than 1% of pregnancies and requires hospitalization and intravenous antiemetics, such as droperidol (Inapsine), prochlorperazine, and ondansetron.

▸ Laxatives. Seven types of products act as laxatives: saline (phosphates and magnesium hydroxide and its salts); stimulants/irritants (cascara, bisacodyl, casanthranol, senna, and castor oil); bulking agents (methylcellulose, polycarbophil, and psyllium); emollient (mineral oil); fecal softeners (docusate); hyperosmotics (glycerin, lactulose); and tegaserod (Zelnorm).

With the exception of lactulose and tegaserod, all of these products are available over the counter, and most do not cause direct embryo/fetal toxicity. However, castor oil, which is converted to ricinoleic acid in the gut, is an irritant that may induce premature labor. Improper use of saline laxatives can cause electrolyte imbalances, and mineral oil will prevent absorption of fat-soluble vitamins.

Of the laxatives, bulking agents and fecal softeners are the best choices in pregnancy. Cascara sagrada and senna are excreted into breast milk and are compatible with breast-feeding, although they may cause diarrhea in a nursing infant.

Tesgaserod, a serotonin type-4 receptor agonist, is approved for women with irritable bowel syndrome whose primary bowel symptom is constipation (and for idiopathic constipation in those under age 65). Limited animal and human data suggest a low risk for embryo/fetal toxicity, but the drug is best avoided during lactation because of the absence of any human data.

▸ Antidiarrheal agents. The antidiarrheal agents diphenoxylate and its active metabolite, difenoxin, are meperidine-related narcotics. Available as Lomotil and Motofen when combined with atropine to prevent abuse, they present low risk in pregnancy. Although there is potential for toxicity in a nursing infant, infrequent use is probably compatible with nursing. Loperamide (Imodium) is low risk in pregnancy and lactation. Alosetron (Lotronex), a serotonin antagonist, has both antiemetic and antidiarrheal properties. It is indicated only in women with IBS whose primary symptom is severe, chronic diarrhea. Based only on animal data, it is considered low risk in pregnancy. Because severe GI toxicity (constipation, ischemic colitis) has been reported in adults, it should be avoided during lactation. Bismuth subsalicylate, such as Pepto-Bismol and Kaopectate, should not be used in pregnancy or lactation.

▸ Antacids. Antacids available to treat heartburn include calcium carbonate, magnesium hydroxide and oxide, and aluminum hydroxide and carbonate. Systemic absorption of antacids is negligible, so recommended doses are safe in pregnancy and lactation. Sodium bicarbonate should be avoided because it is absorbed systemically and could cause alkalosis.

▸ Antisecretory agents. These agents, used for heartburn and GERD, include the histamine H₂ antagonists cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid), and ranitidine (Zantac) and the proton pump inhibitors esomeprazole (Nexium), lansoprazole (Prevacid), omeprazole (Prilosec), pantoprazole (Protonix), and rabeprazole (Aciphex).

Low strengths of the histamine antagonists are available over the counter, but omeprazole is the only PPI available without a prescription. All of these antisecretory agents are low risk in pregnancy. The histamine antagonists are compatible with breast-feeding. In contrast, the PPIs have carcinogenic and mutagenic properties, so prolonged use while breast-feeding should be avoided.

Misoprostol (Cytotec), another antisecretory agent and a prostaglandin E₁ (PGE₁) analogue, is a proven human teratogen. It should only be used in pregnancy for its off-label indications: uterine stimulation and cervical ripening. Although its use during lactation has not been reported, naturally occurring PGE₁ is excreted into milk and may protect the GI tract in nursing infants.

Gastrointestinal complaints are common in pregnancy and during the postpartum period. They include conditions such as nausea and vomiting, constipation, diarrhea, heartburn, and erosive gastroesophageal reflux disease.

▸ Antiemetics. Nausea and vomiting is the most frequent GI complaint in pregnancy. Many oral and parenteral antiemetics are available to treat nausea and vomiting of pregnancy (NVP). All are considered low risk for developmental toxicity (growth retardation, structural defects, functional and behavioral deficits, or death).

The most commonly prescribed over-the-counter agent for this condition is doxylamine (Unisom), usually combined with vitamin B6 (pyridoxine). These two drugs were the components of Bendectin, which was removed from the market by its manufacturer in 1983, but classified by the Food and Drug Administration as safe and effective. Other commonly used oral medications for NVP include prochlorperazine (Compazine), metoclopramide (Reglan), trimethobenzamide (Tigan), promethazine (Phenergan), and ondansetron (Zofran).

The most severe form of nausea, hyperemesis gravidarum, occurs in less than 1% of pregnancies and requires hospitalization and intravenous antiemetics, such as droperidol (Inapsine), prochlorperazine, and ondansetron.

▸ Laxatives. Seven types of products act as laxatives: saline (phosphates and magnesium hydroxide and its salts); stimulants/irritants (cascara, bisacodyl, casanthranol, senna, and castor oil); bulking agents (methylcellulose, polycarbophil, and psyllium); emollient (mineral oil); fecal softeners (docusate); hyperosmotics (glycerin, lactulose); and tegaserod (Zelnorm).

With the exception of lactulose and tegaserod, all of these products are available over the counter, and most do not cause direct embryo/fetal toxicity. However, castor oil, which is converted to ricinoleic acid in the gut, is an irritant that may induce premature labor. Improper use of saline laxatives can cause electrolyte imbalances, and mineral oil will prevent absorption of fat-soluble vitamins.

Of the laxatives, bulking agents and fecal softeners are the best choices in pregnancy. Cascara sagrada and senna are excreted into breast milk and are compatible with breast-feeding, although they may cause diarrhea in a nursing infant.

Tesgaserod, a serotonin type-4 receptor agonist, is approved for women with irritable bowel syndrome whose primary bowel symptom is constipation (and for idiopathic constipation in those under age 65). Limited animal and human data suggest a low risk for embryo/fetal toxicity, but the drug is best avoided during lactation because of the absence of any human data.

▸ Antidiarrheal agents. The antidiarrheal agents diphenoxylate and its active metabolite, difenoxin, are meperidine-related narcotics. Available as Lomotil and Motofen when combined with atropine to prevent abuse, they present low risk in pregnancy. Although there is potential for toxicity in a nursing infant, infrequent use is probably compatible with nursing. Loperamide (Imodium) is low risk in pregnancy and lactation. Alosetron (Lotronex), a serotonin antagonist, has both antiemetic and antidiarrheal properties. It is indicated only in women with IBS whose primary symptom is severe, chronic diarrhea. Based only on animal data, it is considered low risk in pregnancy. Because severe GI toxicity (constipation, ischemic colitis) has been reported in adults, it should be avoided during lactation. Bismuth subsalicylate, such as Pepto-Bismol and Kaopectate, should not be used in pregnancy or lactation.

▸ Antacids. Antacids available to treat heartburn include calcium carbonate, magnesium hydroxide and oxide, and aluminum hydroxide and carbonate. Systemic absorption of antacids is negligible, so recommended doses are safe in pregnancy and lactation. Sodium bicarbonate should be avoided because it is absorbed systemically and could cause alkalosis.

▸ Antisecretory agents. These agents, used for heartburn and GERD, include the histamine H₂ antagonists cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid), and ranitidine (Zantac) and the proton pump inhibitors esomeprazole (Nexium), lansoprazole (Prevacid), omeprazole (Prilosec), pantoprazole (Protonix), and rabeprazole (Aciphex).

Low strengths of the histamine antagonists are available over the counter, but omeprazole is the only PPI available without a prescription. All of these antisecretory agents are low risk in pregnancy. The histamine antagonists are compatible with breast-feeding. In contrast, the PPIs have carcinogenic and mutagenic properties, so prolonged use while breast-feeding should be avoided.

Misoprostol (Cytotec), another antisecretory agent and a prostaglandin E₁ (PGE₁) analogue, is a proven human teratogen. It should only be used in pregnancy for its off-label indications: uterine stimulation and cervical ripening. Although its use during lactation has not been reported, naturally occurring PGE₁ is excreted into milk and may protect the GI tract in nursing infants.

Gastrointestinal complaints are common in pregnancy and the postpartum period. They include conditions such as nausea and vomiting, constipation, diarrhea, heartburn, and erosive gastroesophageal reflux disease, which may be treated with the following products:

▸ Antiemetics. Nausea and vomiting is the most frequent GI complaint in pregnancy. A wide range of oral and parenteral antiemetics is available to treat nausea and vomiting of pregnancy (NVP). All are considered low risk for developmental toxicity (growth retardation, structural defects, functional and behavioral deficits, or death). The most commonly prescribed over-the-counter agent for this condition is doxylamine (Unisom), usually combined with vitamin B₆ (pyridoxine). These two drugs were the components of Bendectin, which was removed from the market by its manufacturer in 1983, but classified by the Food and Drug Administration as safe and effective. Other common oral medications for NVP include prochlorperazine (Compazine), metoclopramide (Reglan), trimethobenzamide (Tigan), promethazine (Phenergan), and ondansetron (Zofran).

Hyperemesis gravidarum, requires intravenous antiemetics, such as droperidol (Inapsine), prochlorperazine, and ondansetron.

▸ Laxatives. There are seven types of products that act as laxatives: saline (phosphates and magnesium hydroxide and its salts), stimulants/irritants (cascara, bisacodyl, casanthranol, senna, and castor oil), bulking agents (methylcellulose, polycarbophil, and psyllium), emollient (mineral oil), fecal softeners (docusate), hyperosmotics (glycerin, lactulose), and tegaserod (Zelnorm).

With the exception of lactulose and tegaserod, these products are available over the counter. Most do not cause direct embryo/fetal toxicity. However, castor oil, which is converted to ricinoleic acid in the gut, is an irritant that may induce premature labor. Improper use of saline laxatives can cause electrolyte imbalances, and mineral oil will prevent absorption of fat-soluble vitamins.

Of the laxatives, bulking agents and fecal softeners are the best in pregnancy. Cascara sagrada and senna are excreted into breast milk and are compatible with breast-feeding, although they may cause diarrhea in a nursing infant.

Tesgaserod, a serotonin type-4 receptor agonist, is approved for women with irritable bowel syndrome whose primary bowel symptom is constipation (and for idiopathic constipation in those under age 65). Limited animal and human data suggest a low risk for embryo/fetal toxicity.

▸ Antidiarrheal agents. The antidiarrheal agents diphenoxylate and its active metabolite, difenoxin, are meperidine-related narcotics. Available as Lomotil and Motofen when combined with atropine to prevent abuse, they present low risk in pregnancy. Although there is potential for toxicity in a nursing infant, infrequent use is probably compatible with nursing. Loperamide (Imodium) is low risk in pregnancy and lactation. Alosetron (Lotronex), a serotonin antagonist, has both antiemetic and antidiarrheal properties. It is indicated only in women with IBS whose primary symptom is severe, chronic diarrhea. Based only on animal data, it is considered low risk in pregnancy. Because severe GI toxicity has been reported in adults, it should be avoided during lactation. Bismuth subsalicylate, such as Pepto-Bismol and Kaopectate, should not be used in pregnancy or lactation since metabolism releases salicylate.

▸ Antacids. Types to treat heartburn include calcium carbonate, magnesium hydroxide and oxide, and aluminum hydroxide and carbonate. Since systemic absorption of antacids is negligible, recommended doses are safe in pregnancy and lactation. Sodium bicarbonate should be avoided because it is absorbed systemically and could cause alkalosis.

▸ Antisecretory agents. These agents, used for heartburn and GERD, include the histamine H₂ antagonists cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid), and ranitidine (Zantac) and the proton pump inhibitors esomeprazole (Nexium), lansoprazole (Prevacid), omeprazole (Prilosec), pantoprazole (Protonix), and rabeprazole (Aciphex).

Low strengths of the histamine antagonists are available over the counter, but omeprazole is the only PPI that is available without a prescription. All of these antisecretory agents are low risk in pregnancy. The histamine antagonists are also compatible with breast-feeding. In contrast, the PPIs have carcinogenic and mutagenic properties, so prolonged use during lactation should be avoided.

Misoprostol (Cytotec), another antisecretory agent and a prostaglandin E₁ (PGE₁) analogue, is a proven human teratogen. It should only be used in pregnancy for its off-label indications: uterine stimulation and cervical ripening.

Gastrointestinal complaints are common in pregnancy and the postpartum period. They include conditions such as nausea and vomiting, constipation, diarrhea, heartburn, and erosive gastroesophageal reflux disease, which may be treated with the following products:

▸ Antiemetics. Nausea and vomiting is the most frequent GI complaint in pregnancy. A wide range of oral and parenteral antiemetics is available to treat nausea and vomiting of pregnancy (NVP). All are considered low risk for developmental toxicity (growth retardation, structural defects, functional and behavioral deficits, or death). The most commonly prescribed over-the-counter agent for this condition is doxylamine (Unisom), usually combined with vitamin B₆ (pyridoxine). These two drugs were the components of Bendectin, which was removed from the market by its manufacturer in 1983, but classified by the Food and Drug Administration as safe and effective. Other common oral medications for NVP include prochlorperazine (Compazine), metoclopramide (Reglan), trimethobenzamide (Tigan), promethazine (Phenergan), and ondansetron (Zofran).

Hyperemesis gravidarum, requires intravenous antiemetics, such as droperidol (Inapsine), prochlorperazine, and ondansetron.

▸ Laxatives. There are seven types of products that act as laxatives: saline (phosphates and magnesium hydroxide and its salts), stimulants/irritants (cascara, bisacodyl, casanthranol, senna, and castor oil), bulking agents (methylcellulose, polycarbophil, and psyllium), emollient (mineral oil), fecal softeners (docusate), hyperosmotics (glycerin, lactulose), and tegaserod (Zelnorm).

With the exception of lactulose and tegaserod, these products are available over the counter. Most do not cause direct embryo/fetal toxicity. However, castor oil, which is converted to ricinoleic acid in the gut, is an irritant that may induce premature labor. Improper use of saline laxatives can cause electrolyte imbalances, and mineral oil will prevent absorption of fat-soluble vitamins.

Of the laxatives, bulking agents and fecal softeners are the best in pregnancy. Cascara sagrada and senna are excreted into breast milk and are compatible with breast-feeding, although they may cause diarrhea in a nursing infant.

Tesgaserod, a serotonin type-4 receptor agonist, is approved for women with irritable bowel syndrome whose primary bowel symptom is constipation (and for idiopathic constipation in those under age 65). Limited animal and human data suggest a low risk for embryo/fetal toxicity.

▸ Antidiarrheal agents. The antidiarrheal agents diphenoxylate and its active metabolite, difenoxin, are meperidine-related narcotics. Available as Lomotil and Motofen when combined with atropine to prevent abuse, they present low risk in pregnancy. Although there is potential for toxicity in a nursing infant, infrequent use is probably compatible with nursing. Loperamide (Imodium) is low risk in pregnancy and lactation. Alosetron (Lotronex), a serotonin antagonist, has both antiemetic and antidiarrheal properties. It is indicated only in women with IBS whose primary symptom is severe, chronic diarrhea. Based only on animal data, it is considered low risk in pregnancy. Because severe GI toxicity has been reported in adults, it should be avoided during lactation. Bismuth subsalicylate, such as Pepto-Bismol and Kaopectate, should not be used in pregnancy or lactation since metabolism releases salicylate.

▸ Antacids. Types to treat heartburn include calcium carbonate, magnesium hydroxide and oxide, and aluminum hydroxide and carbonate. Since systemic absorption of antacids is negligible, recommended doses are safe in pregnancy and lactation. Sodium bicarbonate should be avoided because it is absorbed systemically and could cause alkalosis.

▸ Antisecretory agents. These agents, used for heartburn and GERD, include the histamine H₂ antagonists cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid), and ranitidine (Zantac) and the proton pump inhibitors esomeprazole (Nexium), lansoprazole (Prevacid), omeprazole (Prilosec), pantoprazole (Protonix), and rabeprazole (Aciphex).

Low strengths of the histamine antagonists are available over the counter, but omeprazole is the only PPI that is available without a prescription. All of these antisecretory agents are low risk in pregnancy. The histamine antagonists are also compatible with breast-feeding. In contrast, the PPIs have carcinogenic and mutagenic properties, so prolonged use during lactation should be avoided.

Misoprostol (Cytotec), another antisecretory agent and a prostaglandin E₁ (PGE₁) analogue, is a proven human teratogen. It should only be used in pregnancy for its off-label indications: uterine stimulation and cervical ripening.

Gastrointestinal complaints are common in pregnancy and the postpartum period. They include conditions such as nausea and vomiting, constipation, diarrhea, heartburn, and erosive gastroesophageal reflux disease, which may be treated with the following products:

▸ Antiemetics. Nausea and vomiting is the most frequent GI complaint in pregnancy. A wide range of oral and parenteral antiemetics is available to treat nausea and vomiting of pregnancy (NVP). All are considered low risk for developmental toxicity (growth retardation, structural defects, functional and behavioral deficits, or death). The most commonly prescribed over-the-counter agent for this condition is doxylamine (Unisom), usually combined with vitamin B₆ (pyridoxine). These two drugs were the components of Bendectin, which was removed from the market by its manufacturer in 1983, but classified by the Food and Drug Administration as safe and effective. Other common oral medications for NVP include prochlorperazine (Compazine), metoclopramide (Reglan), trimethobenzamide (Tigan), promethazine (Phenergan), and ondansetron (Zofran).

Hyperemesis gravidarum, requires intravenous antiemetics, such as droperidol (Inapsine), prochlorperazine, and ondansetron.

▸ Laxatives. There are seven types of products that act as laxatives: saline (phosphates and magnesium hydroxide and its salts), stimulants/irritants (cascara, bisacodyl, casanthranol, senna, and castor oil), bulking agents (methylcellulose, polycarbophil, and psyllium), emollient (mineral oil), fecal softeners (docusate), hyperosmotics (glycerin, lactulose), and tegaserod (Zelnorm).

With the exception of lactulose and tegaserod, these products are available over the counter. Most do not cause direct embryo/fetal toxicity. However, castor oil, which is converted to ricinoleic acid in the gut, is an irritant that may induce premature labor. Improper use of saline laxatives can cause electrolyte imbalances, and mineral oil will prevent absorption of fat-soluble vitamins.

Of the laxatives, bulking agents and fecal softeners are the best in pregnancy. Cascara sagrada and senna are excreted into breast milk and are compatible with breast-feeding, although they may cause diarrhea in a nursing infant.

Tesgaserod, a serotonin type-4 receptor agonist, is approved for women with irritable bowel syndrome whose primary bowel symptom is constipation (and for idiopathic constipation in those under age 65). Limited animal and human data suggest a low risk for embryo/fetal toxicity.

▸ Antidiarrheal agents. The antidiarrheal agents diphenoxylate and its active metabolite, difenoxin, are meperidine-related narcotics. Available as Lomotil and Motofen when combined with atropine to prevent abuse, they present low risk in pregnancy. Although there is potential for toxicity in a nursing infant, infrequent use is probably compatible with nursing. Loperamide (Imodium) is low risk in pregnancy and lactation. Alosetron (Lotronex), a serotonin antagonist, has both antiemetic and antidiarrheal properties. It is indicated only in women with IBS whose primary symptom is severe, chronic diarrhea. Based only on animal data, it is considered low risk in pregnancy. Because severe GI toxicity has been reported in adults, it should be avoided during lactation. Bismuth subsalicylate, such as Pepto-Bismol and Kaopectate, should not be used in pregnancy or lactation since metabolism releases salicylate.

▸ Antacids. Types to treat heartburn include calcium carbonate, magnesium hydroxide and oxide, and aluminum hydroxide and carbonate. Since systemic absorption of antacids is negligible, recommended doses are safe in pregnancy and lactation. Sodium bicarbonate should be avoided because it is absorbed systemically and could cause alkalosis.

▸ Antisecretory agents. These agents, used for heartburn and GERD, include the histamine H₂ antagonists cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid), and ranitidine (Zantac) and the proton pump inhibitors esomeprazole (Nexium), lansoprazole (Prevacid), omeprazole (Prilosec), pantoprazole (Protonix), and rabeprazole (Aciphex).

Low strengths of the histamine antagonists are available over the counter, but omeprazole is the only PPI that is available without a prescription. All of these antisecretory agents are low risk in pregnancy. The histamine antagonists are also compatible with breast-feeding. In contrast, the PPIs have carcinogenic and mutagenic properties, so prolonged use during lactation should be avoided.

Misoprostol (Cytotec), another antisecretory agent and a prostaglandin E₁ (PGE₁) analogue, is a proven human teratogen. It should only be used in pregnancy for its off-label indications: uterine stimulation and cervical ripening.

The large antihyperlipidemic class of drugs can be subdivided into bile acid sequestrants, HMG-CoA reductase inhibitors, fibric acid derivatives, ezetimibe, and niacin. With the possible exception of familial hypercholesterolemia, there appears to be no maternal benefit for the treatment of hyperlipidemia during gestation. Nearly all reported pregnancy exposures have occurred accidentally. If treatment is required, only bile acid sequestrants are considered compatible in pregnancy and lactation.

Ezetimibe (Zetia) also appears to be low risk in gestation, but not in lactation. Because most drug-induced adverse effects (about two-thirds) in nursing infants have been reported during the first month after birth, delaying treatment of a nursing mother until after this period appears to be the best course.

Cholesterol is the precursor of bile acids that are excreted from the liver and gallbladder into the intestine to aid in the digestion of fat in food. Bile acid sequestrants—cholestyramine (Questran and various other names), colestipol (Colestid), and colesevelam (WelChol)—are anion exchange resins that form insoluble complexes with bile acids in the intestine. The complexes are then excreted in the feces, removing cholesterol from the system.

Cholestyramine has been used as a treatment for intrahepatic cholestasis of pregnancy and as an antidote for some types of diarrhea, chlordecone pesticide poisoning, and digitalis toxicity. Because bile acid sequestrants are not absorbed into the systemic circulation, they do not represent a direct risk to the embryo or fetus and are considered compatible with pregnancy (all are rated risk factor B) and lactation. However, the resins also bind fat-soluble vitamins (vitamins A, D, E, and K) in the gut, and deficiencies of these vitamins may result.

The six HMG-CoA reductase inhibitors (statins) are atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor). All are contraindicated in pregnancy (risk factor X). Case reports and surveillance studies have described healthy outcomes from a number of pregnancies inadvertently exposed in the first trimester and later. The largest number of cases (187) were reported with simvastatin, with 86 cases that could be evaluated: 74% had normal outcomes, 15% resulted in spontaneous abortion, 6% of cases demonstrated congenital anomalies, 4% of cases had effects related to prematurity, and 1% resulted in fetal death. Three of the five birth defect cases were not related to simvastatin because of the timing of exposure or the outcome was a known chromosome defect. The remaining two cases involved unilateral cleft lip and a clubfoot, neither of which appear to be attributable to simvastatin.

In contrast, a 2004 reference described 178 cases of first-trimester exposure to statins reported to the Food and Drug Administration. Among the 52 cases suitable for evaluation, there were 20 major malformations, some thought to be consistent with inhibition of cholesterol biosynthesis. All 20 defects involved a lipophilic statin (atorvastatin), cerivastatin (Baycol), lovastatin, or simvastatin. No defects were reported with pravastatin, a hydrophilic agent with low tissue penetration that is not associated with animal developmental toxicity. These results are controversial, and controlled studies are needed to determine if there is a causal relationship. Because all statins are probably excreted into milk, women taking these drugs should not breast-feed.

Among the fibric acid derivatives, only gemfibrozil (Lopid) has some human data. The other agent, fenofibrate (TriCor), has no human data. The animal data (developmental toxicity in two animal species at doses up to 10 times the human dose) for each drug suggest there may be a risk to the human embryo or fetus. Thus, the safest course is to avoid these drugs in pregnancy (both are risk factor C). Although there are no data, the drugs are probably excreted into milk, and women on these agents should not breast-feed because of the potential toxicity, such as tumors, in their infants.

Ezetimibe (risk factor C) selectively inhibits the intestinal absorption of cholesterol and related phytosterols. At doses up to 10 times the human dose, the drug is teratogenic in rats but not in rabbits. Human pregnancy exposures have not been reported. If therapy during pregnancy is mandated, ezetimibe appears to be a better choice than statins. There are no data on use during lactation, but the drug is probably excreted into milk. Toxicity is a potential concern, and nursing infants should be monitored for headache, diarrhea, arthralgia, pharyngitis, sinusitis, and other adverse effects observed in adults.

The large antihyperlipidemic class of drugs can be subdivided into bile acid sequestrants, HMG-CoA reductase inhibitors, fibric acid derivatives, ezetimibe, and niacin. With the possible exception of familial hypercholesterolemia, there appears to be no maternal benefit for the treatment of hyperlipidemia during gestation. Nearly all reported pregnancy exposures have occurred accidentally. If treatment is required, only bile acid sequestrants are considered compatible in pregnancy and lactation.

Ezetimibe (Zetia) also appears to be low risk in gestation, but not in lactation. Because most drug-induced adverse effects (about two-thirds) in nursing infants have been reported during the first month after birth, delaying treatment of a nursing mother until after this period appears to be the best course.

Cholesterol is the precursor of bile acids that are excreted from the liver and gallbladder into the intestine to aid in the digestion of fat in food. Bile acid sequestrants—cholestyramine (Questran and various other names), colestipol (Colestid), and colesevelam (WelChol)—are anion exchange resins that form insoluble complexes with bile acids in the intestine. The complexes are then excreted in the feces, removing cholesterol from the system.

Cholestyramine has been used as a treatment for intrahepatic cholestasis of pregnancy and as an antidote for some types of diarrhea, chlordecone pesticide poisoning, and digitalis toxicity. Because bile acid sequestrants are not absorbed into the systemic circulation, they do not represent a direct risk to the embryo or fetus and are considered compatible with pregnancy (all are rated risk factor B) and lactation. However, the resins also bind fat-soluble vitamins (vitamins A, D, E, and K) in the gut, and deficiencies of these vitamins may result.

The six HMG-CoA reductase inhibitors (statins) are atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor). All are contraindicated in pregnancy (risk factor X). Case reports and surveillance studies have described healthy outcomes from a number of pregnancies inadvertently exposed in the first trimester and later. The largest number of cases (187) were reported with simvastatin, with 86 cases that could be evaluated: 74% had normal outcomes, 15% resulted in spontaneous abortion, 6% of cases demonstrated congenital anomalies, 4% of cases had effects related to prematurity, and 1% resulted in fetal death. Three of the five birth defect cases were not related to simvastatin because of the timing of exposure or the outcome was a known chromosome defect. The remaining two cases involved unilateral cleft lip and a clubfoot, neither of which appear to be attributable to simvastatin.

In contrast, a 2004 reference described 178 cases of first-trimester exposure to statins reported to the Food and Drug Administration. Among the 52 cases suitable for evaluation, there were 20 major malformations, some thought to be consistent with inhibition of cholesterol biosynthesis. All 20 defects involved a lipophilic statin (atorvastatin), cerivastatin (Baycol), lovastatin, or simvastatin. No defects were reported with pravastatin, a hydrophilic agent with low tissue penetration that is not associated with animal developmental toxicity. These results are controversial, and controlled studies are needed to determine if there is a causal relationship. Because all statins are probably excreted into milk, women taking these drugs should not breast-feed.

Among the fibric acid derivatives, only gemfibrozil (Lopid) has some human data. The other agent, fenofibrate (TriCor), has no human data. The animal data (developmental toxicity in two animal species at doses up to 10 times the human dose) for each drug suggest there may be a risk to the human embryo or fetus. Thus, the safest course is to avoid these drugs in pregnancy (both are risk factor C). Although there are no data, the drugs are probably excreted into milk, and women on these agents should not breast-feed because of the potential toxicity, such as tumors, in their infants.

Ezetimibe (risk factor C) selectively inhibits the intestinal absorption of cholesterol and related phytosterols. At doses up to 10 times the human dose, the drug is teratogenic in rats but not in rabbits. Human pregnancy exposures have not been reported. If therapy during pregnancy is mandated, ezetimibe appears to be a better choice than statins. There are no data on use during lactation, but the drug is probably excreted into milk. Toxicity is a potential concern, and nursing infants should be monitored for headache, diarrhea, arthralgia, pharyngitis, sinusitis, and other adverse effects observed in adults.

The large antihyperlipidemic class of drugs can be subdivided into bile acid sequestrants, HMG-CoA reductase inhibitors, fibric acid derivatives, ezetimibe, and niacin. With the possible exception of familial hypercholesterolemia, there appears to be no maternal benefit for the treatment of hyperlipidemia during gestation. Nearly all reported pregnancy exposures have occurred accidentally. If treatment is required, only bile acid sequestrants are considered compatible in pregnancy and lactation.

Ezetimibe (Zetia) also appears to be low risk in gestation, but not in lactation. Because most drug-induced adverse effects (about two-thirds) in nursing infants have been reported during the first month after birth, delaying treatment of a nursing mother until after this period appears to be the best course.

Cholesterol is the precursor of bile acids that are excreted from the liver and gallbladder into the intestine to aid in the digestion of fat in food. Bile acid sequestrants—cholestyramine (Questran and various other names), colestipol (Colestid), and colesevelam (WelChol)—are anion exchange resins that form insoluble complexes with bile acids in the intestine. The complexes are then excreted in the feces, removing cholesterol from the system.

Cholestyramine has been used as a treatment for intrahepatic cholestasis of pregnancy and as an antidote for some types of diarrhea, chlordecone pesticide poisoning, and digitalis toxicity. Because bile acid sequestrants are not absorbed into the systemic circulation, they do not represent a direct risk to the embryo or fetus and are considered compatible with pregnancy (all are rated risk factor B) and lactation. However, the resins also bind fat-soluble vitamins (vitamins A, D, E, and K) in the gut, and deficiencies of these vitamins may result.

The six HMG-CoA reductase inhibitors (statins) are atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor). All are contraindicated in pregnancy (risk factor X). Case reports and surveillance studies have described healthy outcomes from a number of pregnancies inadvertently exposed in the first trimester and later. The largest number of cases (187) were reported with simvastatin, with 86 cases that could be evaluated: 74% had normal outcomes, 15% resulted in spontaneous abortion, 6% of cases demonstrated congenital anomalies, 4% of cases had effects related to prematurity, and 1% resulted in fetal death. Three of the five birth defect cases were not related to simvastatin because of the timing of exposure or the outcome was a known chromosome defect. The remaining two cases involved unilateral cleft lip and a clubfoot, neither of which appear to be attributable to simvastatin.

In contrast, a 2004 reference described 178 cases of first-trimester exposure to statins reported to the Food and Drug Administration. Among the 52 cases suitable for evaluation, there were 20 major malformations, some thought to be consistent with inhibition of cholesterol biosynthesis. All 20 defects involved a lipophilic statin (atorvastatin), cerivastatin (Baycol), lovastatin, or simvastatin. No defects were reported with pravastatin, a hydrophilic agent with low tissue penetration that is not associated with animal developmental toxicity. These results are controversial, and controlled studies are needed to determine if there is a causal relationship. Because all statins are probably excreted into milk, women taking these drugs should not breast-feed.

Among the fibric acid derivatives, only gemfibrozil (Lopid) has some human data. The other agent, fenofibrate (TriCor), has no human data. The animal data (developmental toxicity in two animal species at doses up to 10 times the human dose) for each drug suggest there may be a risk to the human embryo or fetus. Thus, the safest course is to avoid these drugs in pregnancy (both are risk factor C). Although there are no data, the drugs are probably excreted into milk, and women on these agents should not breast-feed because of the potential toxicity, such as tumors, in their infants.

Ezetimibe (risk factor C) selectively inhibits the intestinal absorption of cholesterol and related phytosterols. At doses up to 10 times the human dose, the drug is teratogenic in rats but not in rabbits. Human pregnancy exposures have not been reported. If therapy during pregnancy is mandated, ezetimibe appears to be a better choice than statins. There are no data on use during lactation, but the drug is probably excreted into milk. Toxicity is a potential concern, and nursing infants should be monitored for headache, diarrhea, arthralgia, pharyngitis, sinusitis, and other adverse effects observed in adults.

The autoimmune disorder rheumatoid arthritis occurs in about 1%–2% of the population. The disease is more prevalent in women than men by about a 3:1 ratio, but in the reproductive years, the ratio may be as high as 6:1. During pregnancy, the incidence is about 1 in 1,000.

RA is characterized by production of cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1 in the synovial cavity, and irreversible damage to soft tissues and bones. Drug therapy of RA involves using disease-modifying antirheumatic drugs (DMARDs) to prevent or lessen this damage. The therapy can be categorized as biologic DMARDs, synthetic DMARDs, and anti-inflammatory agents.

Biologic DMARDs include three agents that inhibit TNF-α—adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade)—and one interleukin-1 receptor antagonist, anakinra (Kineret). Although the human pregnancy data for these four drugs are lacking, animal reproduction data suggest they pose a low risk for developmental toxicity (growth retardation, structural defects, functional/behavioral defects, or death).

The safest course is to avoid these agents during the first trimester, but with their long elimination half-lives, inadvertent exposures during organogenesis of unplanned pregnancies is likely.

Synthetic DMARDs include azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), gold compounds, hydroxychloroquine (Plaquenil), leflunomide (Arava), methotrexate, penicillamine, and sulfasalazine (Azulfidine).

The two immunosuppressants, azathioprine and cyclosporine, do not appear to cause congenital defects, but they may be associated with growth retardation. There is limited human pregnancy experience with the gold compounds—auranofin (Ridaura), aurothioglucose (Solganal), and gold sodium thiomalate (Aurolate)—but the animal data suggest the risk for developmental toxicity is low.

Hydroxychloroquine is probably compatible in pregnancy, but there is limited pregnancy experience with the high doses commonly used in RA. The drug has a very long elimination half-life from maternal tissues (weeks to months), so stopping the drug when pregnancy is confirmed will not prevent embryo/fetal exposure.

Leflunomide, a pyrimidine synthesis inhibitor, causes dose-related teratogenicity and toxicity in animals at doses much lower than those used in humans. Human pregnancy experience is too limited to determine the risk to the embryo or fetus, and the drug is contraindicated in pregnancy. Exposure of unplanned pregnancies will probably occur because the drug and its active metabolite may take up to 2 years to reach nondetectable plasma levels.

The folic acid antagonist methotrexate is contraindicated during pregnancy. The drug is associated with spontaneous abortions and a spectrum of congenital defects collectively termed methotrexate embryopathy. The critical exposure period for structural defects is 8–10 weeks after the first day of the last menstrual period. Exposure after this period is associated with fetal toxicity and mortality. The critical dose is thought to be 10 mg or more per week.

Another folate antagonist, sulfasalazine, does not seem to cause developmental toxicity, but supplemental folic acid (1 mg/day) should be used if there is a risk of unplanned pregnancy or if pregnancy occurs. The drug has caused bloody diarrhea in a nursing infant, so breast-feeding should be done with caution. Penicillamine, a chelating agent associated with a risk of fetal connective tissue defects (cutis laxa), should be avoided during pregnancy.

The NSAIDs, which include aspirin, have considerable potential for embryo/fetal toxicity: spontaneous abortions when used around the time of conception, fetal renal toxicity, and premature closure of the ductus arteriosus in the third trimester. Aspirin use near term may increase the risk of bleeding in the mother and the infant. The use of prednisone during organogenesis carries a low risk for oral clefts and prolonged use in pregnancy has been associated with growth retardation.

The biologic DMARDs, gold compounds, hydroxychloroquine, NSAIDs (except high-dose aspirin), and prednisone are probably compatible with breast-feeding. The other agents are either contraindicated (methotrexate) or should be avoided because of potential toxicity. High-dose aspirin and sulfasalazine have been associated with toxicity in nursing infants.

The Organization of Teratology Information Services is conducting a study of pregnancy exposure to rheumatoid arthritis drugs. Health care professionals can call the toll-free number (877-311-8972) for information about enrolling patients in this study.

The autoimmune disorder rheumatoid arthritis occurs in about 1%–2% of the population. The disease is more prevalent in women than men by about a 3:1 ratio, but in the reproductive years, the ratio may be as high as 6:1. During pregnancy, the incidence is about 1 in 1,000.

RA is characterized by production of cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1 in the synovial cavity, and irreversible damage to soft tissues and bones. Drug therapy of RA involves using disease-modifying antirheumatic drugs (DMARDs) to prevent or lessen this damage. The therapy can be categorized as biologic DMARDs, synthetic DMARDs, and anti-inflammatory agents.

Biologic DMARDs include three agents that inhibit TNF-α—adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade)—and one interleukin-1 receptor antagonist, anakinra (Kineret). Although the human pregnancy data for these four drugs are lacking, animal reproduction data suggest they pose a low risk for developmental toxicity (growth retardation, structural defects, functional/behavioral defects, or death).

The safest course is to avoid these agents during the first trimester, but with their long elimination half-lives, inadvertent exposures during organogenesis of unplanned pregnancies is likely.

Synthetic DMARDs include azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), gold compounds, hydroxychloroquine (Plaquenil), leflunomide (Arava), methotrexate, penicillamine, and sulfasalazine (Azulfidine).

The two immunosuppressants, azathioprine and cyclosporine, do not appear to cause congenital defects, but they may be associated with growth retardation. There is limited human pregnancy experience with the gold compounds—auranofin (Ridaura), aurothioglucose (Solganal), and gold sodium thiomalate (Aurolate)—but the animal data suggest the risk for developmental toxicity is low.

Hydroxychloroquine is probably compatible in pregnancy, but there is limited pregnancy experience with the high doses commonly used in RA. The drug has a very long elimination half-life from maternal tissues (weeks to months), so stopping the drug when pregnancy is confirmed will not prevent embryo/fetal exposure.

Leflunomide, a pyrimidine synthesis inhibitor, causes dose-related teratogenicity and toxicity in animals at doses much lower than those used in humans. Human pregnancy experience is too limited to determine the risk to the embryo or fetus, and the drug is contraindicated in pregnancy. Exposure of unplanned pregnancies will probably occur because the drug and its active metabolite may take up to 2 years to reach nondetectable plasma levels.

The folic acid antagonist methotrexate is contraindicated during pregnancy. The drug is associated with spontaneous abortions and a spectrum of congenital defects collectively termed methotrexate embryopathy. The critical exposure period for structural defects is 8–10 weeks after the first day of the last menstrual period. Exposure after this period is associated with fetal toxicity and mortality. The critical dose is thought to be 10 mg or more per week.

Another folate antagonist, sulfasalazine, does not seem to cause developmental toxicity, but supplemental folic acid (1 mg/day) should be used if there is a risk of unplanned pregnancy or if pregnancy occurs. The drug has caused bloody diarrhea in a nursing infant, so breast-feeding should be done with caution. Penicillamine, a chelating agent associated with a risk of fetal connective tissue defects (cutis laxa), should be avoided during pregnancy.

The NSAIDs, which include aspirin, have considerable potential for embryo/fetal toxicity: spontaneous abortions when used around the time of conception, fetal renal toxicity, and premature closure of the ductus arteriosus in the third trimester. Aspirin use near term may increase the risk of bleeding in the mother and the infant. The use of prednisone during organogenesis carries a low risk for oral clefts and prolonged use in pregnancy has been associated with growth retardation.

The biologic DMARDs, gold compounds, hydroxychloroquine, NSAIDs (except high-dose aspirin), and prednisone are probably compatible with breast-feeding. The other agents are either contraindicated (methotrexate) or should be avoided because of potential toxicity. High-dose aspirin and sulfasalazine have been associated with toxicity in nursing infants.

The Organization of Teratology Information Services is conducting a study of pregnancy exposure to rheumatoid arthritis drugs. Health care professionals can call the toll-free number (877-311-8972) for information about enrolling patients in this study.

The autoimmune disorder rheumatoid arthritis occurs in about 1%–2% of the population. The disease is more prevalent in women than men by about a 3:1 ratio, but in the reproductive years, the ratio may be as high as 6:1. During pregnancy, the incidence is about 1 in 1,000.

RA is characterized by production of cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1 in the synovial cavity, and irreversible damage to soft tissues and bones. Drug therapy of RA involves using disease-modifying antirheumatic drugs (DMARDs) to prevent or lessen this damage. The therapy can be categorized as biologic DMARDs, synthetic DMARDs, and anti-inflammatory agents.

Biologic DMARDs include three agents that inhibit TNF-α—adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade)—and one interleukin-1 receptor antagonist, anakinra (Kineret). Although the human pregnancy data for these four drugs are lacking, animal reproduction data suggest they pose a low risk for developmental toxicity (growth retardation, structural defects, functional/behavioral defects, or death).

The safest course is to avoid these agents during the first trimester, but with their long elimination half-lives, inadvertent exposures during organogenesis of unplanned pregnancies is likely.

Synthetic DMARDs include azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), gold compounds, hydroxychloroquine (Plaquenil), leflunomide (Arava), methotrexate, penicillamine, and sulfasalazine (Azulfidine).

The two immunosuppressants, azathioprine and cyclosporine, do not appear to cause congenital defects, but they may be associated with growth retardation. There is limited human pregnancy experience with the gold compounds—auranofin (Ridaura), aurothioglucose (Solganal), and gold sodium thiomalate (Aurolate)—but the animal data suggest the risk for developmental toxicity is low.

Hydroxychloroquine is probably compatible in pregnancy, but there is limited pregnancy experience with the high doses commonly used in RA. The drug has a very long elimination half-life from maternal tissues (weeks to months), so stopping the drug when pregnancy is confirmed will not prevent embryo/fetal exposure.

Leflunomide, a pyrimidine synthesis inhibitor, causes dose-related teratogenicity and toxicity in animals at doses much lower than those used in humans. Human pregnancy experience is too limited to determine the risk to the embryo or fetus, and the drug is contraindicated in pregnancy. Exposure of unplanned pregnancies will probably occur because the drug and its active metabolite may take up to 2 years to reach nondetectable plasma levels.

The folic acid antagonist methotrexate is contraindicated during pregnancy. The drug is associated with spontaneous abortions and a spectrum of congenital defects collectively termed methotrexate embryopathy. The critical exposure period for structural defects is 8–10 weeks after the first day of the last menstrual period. Exposure after this period is associated with fetal toxicity and mortality. The critical dose is thought to be 10 mg or more per week.

Another folate antagonist, sulfasalazine, does not seem to cause developmental toxicity, but supplemental folic acid (1 mg/day) should be used if there is a risk of unplanned pregnancy or if pregnancy occurs. The drug has caused bloody diarrhea in a nursing infant, so breast-feeding should be done with caution. Penicillamine, a chelating agent associated with a risk of fetal connective tissue defects (cutis laxa), should be avoided during pregnancy.

The NSAIDs, which include aspirin, have considerable potential for embryo/fetal toxicity: spontaneous abortions when used around the time of conception, fetal renal toxicity, and premature closure of the ductus arteriosus in the third trimester. Aspirin use near term may increase the risk of bleeding in the mother and the infant. The use of prednisone during organogenesis carries a low risk for oral clefts and prolonged use in pregnancy has been associated with growth retardation.

The biologic DMARDs, gold compounds, hydroxychloroquine, NSAIDs (except high-dose aspirin), and prednisone are probably compatible with breast-feeding. The other agents are either contraindicated (methotrexate) or should be avoided because of potential toxicity. High-dose aspirin and sulfasalazine have been associated with toxicity in nursing infants.

The Organization of Teratology Information Services is conducting a study of pregnancy exposure to rheumatoid arthritis drugs. Health care professionals can call the toll-free number (877-311-8972) for information about enrolling patients in this study.

The large antihyperlipidemic class of drugs can be subdivided into bile acid sequestrants, HMG-CoA reductase inhibitors, fibric acid derivatives, ezetimibe, and niacin. With the possible exception of familial hypercholesterolemia, there appears to be no maternal benefit for the treatment of hyperlipidemia during gestation. Nearly all reported pregnancy exposures have occurred accidentally. If treatment is required, only bile acid sequestrants are considered compatible in pregnancy and lactation.

Ezetimibe (Zetia) also appears to be low risk in gestation, but not in lactation. Because most drug-induced adverse effects (about two-thirds) in nursing infants have been reported during the first month after birth, delaying treatment of a nursing mother until after this period appears to be best.

Cholestyramine has been used as a treatment for intrahepatic cholestasis of pregnancy and as an antidote for some types of diarrhea, chlordecone pesticide poisoning, and digitalis toxicity. Because bile acid sequestrants are not absorbed into the systemic circulation, they do not represent a direct risk to the embryo or fetus and are considered compatible with pregnancy (all are rated risk factor B) and lactation. However, the resins also bind fat-soluble vitamins in the gut, and deficiencies of these vitamins may result.

The six HMG-CoA reductase inhibitors (statins) are atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor). All are contraindicated in pregnancy (risk factor X). Case reports and surveillance studies have described healthy outcomes from a number of pregnancies inadvertently exposed in the first trimester and later. The largest number of cases (187) were reported with simvastatin, with 86 cases that could be evaluated: 74% had normal outcomes, 15% resulted in spontaneous abortion, 6% of cases demonstrated congenital anomalies, 4% of cases had effects related to prematurity, and 1% resulted in fetal death. Three of the five birth defect cases were not related to simvastatin because of the timing of exposure or the outcome was a known chromosome defect. The remaining two cases involved unilateral cleft lip and a clubfoot, neither of which appear to be attributable to simvastatin.

In contrast, a 2004 reference described 178 cases of first-trimester exposure to statins reported to the Food and Drug Administration. Among the 52 cases suitable for evaluation, there were 20 major malformations, some thought to be consistent with inhibition of cholesterol biosynthesis. All 20 defects involved a lipophilic statin (atorvastatin, cerivastatin (Baycol), lovastatin, or simvastatin). No defects were reported with pravastatin, a hydrophilic agent with low tissue penetration that is not associated with animal developmental toxicity. These results are controversial, and controlled studies are needed to determine if there is a causal relationship. Because all statins are probably excreted into milk, women taking these drugs should not breast-feed.

Among the fibric acid derivatives, only gemfibrozil (Lopid) has some human data. The other agent, fenofibrate (TriCor), has no human data. The animal data (developmental toxicity in two animal species at doses up to 10 times the human dose) for each drug suggest there may be a risk to the human embryo or fetus. Thus, the safest course is to avoid these drugs in pregnancy (both are risk factor C). Although there are no data, the drugs are probably excreted into milk, and women on these agents should not breast-feed because of the potential toxicity, such as tumors, in their infants.

Ezetimibe (risk factor C) selectively inhibits the intestinal absorption of cholesterol and related phytosterols. At doses up to 10 times the human dose, the drug is teratogenic in rats but not in rabbits. Human pregnancy exposures have not been reported. If therapy during pregnancy is mandated, ezetimibe appears to be a better choice than statins. There are no data on use during lactation, but the drug is probably excreted into milk. Toxicity is a potential concern; nursing infants should be monitored for headache, diarrhea, arthralgia, pharyngitis, sinusitis, and other adverse effects observed in adults.

Niacin (nicotinic acid) is converted in vivo to niacinamide, the active form of vitamin B₃, an essential nutrient. But high doses (up to 2,000 mg/day) used for hyperlipidemia have not been studied in pregnancy. Because niacinamide is actively transported to the fetus, producing higher concentrations in the fetus and newborn than in the mother, niacin is best avoided during pregnancy and lactation.

The large antihyperlipidemic class of drugs can be subdivided into bile acid sequestrants, HMG-CoA reductase inhibitors, fibric acid derivatives, ezetimibe, and niacin. With the possible exception of familial hypercholesterolemia, there appears to be no maternal benefit for the treatment of hyperlipidemia during gestation. Nearly all reported pregnancy exposures have occurred accidentally. If treatment is required, only bile acid sequestrants are considered compatible in pregnancy and lactation.

Ezetimibe (Zetia) also appears to be low risk in gestation, but not in lactation. Because most drug-induced adverse effects (about two-thirds) in nursing infants have been reported during the first month after birth, delaying treatment of a nursing mother until after this period appears to be best.

Cholestyramine has been used as a treatment for intrahepatic cholestasis of pregnancy and as an antidote for some types of diarrhea, chlordecone pesticide poisoning, and digitalis toxicity. Because bile acid sequestrants are not absorbed into the systemic circulation, they do not represent a direct risk to the embryo or fetus and are considered compatible with pregnancy (all are rated risk factor B) and lactation. However, the resins also bind fat-soluble vitamins in the gut, and deficiencies of these vitamins may result.

The six HMG-CoA reductase inhibitors (statins) are atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor). All are contraindicated in pregnancy (risk factor X). Case reports and surveillance studies have described healthy outcomes from a number of pregnancies inadvertently exposed in the first trimester and later. The largest number of cases (187) were reported with simvastatin, with 86 cases that could be evaluated: 74% had normal outcomes, 15% resulted in spontaneous abortion, 6% of cases demonstrated congenital anomalies, 4% of cases had effects related to prematurity, and 1% resulted in fetal death. Three of the five birth defect cases were not related to simvastatin because of the timing of exposure or the outcome was a known chromosome defect. The remaining two cases involved unilateral cleft lip and a clubfoot, neither of which appear to be attributable to simvastatin.

In contrast, a 2004 reference described 178 cases of first-trimester exposure to statins reported to the Food and Drug Administration. Among the 52 cases suitable for evaluation, there were 20 major malformations, some thought to be consistent with inhibition of cholesterol biosynthesis. All 20 defects involved a lipophilic statin (atorvastatin, cerivastatin (Baycol), lovastatin, or simvastatin). No defects were reported with pravastatin, a hydrophilic agent with low tissue penetration that is not associated with animal developmental toxicity. These results are controversial, and controlled studies are needed to determine if there is a causal relationship. Because all statins are probably excreted into milk, women taking these drugs should not breast-feed.

Among the fibric acid derivatives, only gemfibrozil (Lopid) has some human data. The other agent, fenofibrate (TriCor), has no human data. The animal data (developmental toxicity in two animal species at doses up to 10 times the human dose) for each drug suggest there may be a risk to the human embryo or fetus. Thus, the safest course is to avoid these drugs in pregnancy (both are risk factor C). Although there are no data, the drugs are probably excreted into milk, and women on these agents should not breast-feed because of the potential toxicity, such as tumors, in their infants.

Ezetimibe (risk factor C) selectively inhibits the intestinal absorption of cholesterol and related phytosterols. At doses up to 10 times the human dose, the drug is teratogenic in rats but not in rabbits. Human pregnancy exposures have not been reported. If therapy during pregnancy is mandated, ezetimibe appears to be a better choice than statins. There are no data on use during lactation, but the drug is probably excreted into milk. Toxicity is a potential concern; nursing infants should be monitored for headache, diarrhea, arthralgia, pharyngitis, sinusitis, and other adverse effects observed in adults.

Niacin (nicotinic acid) is converted in vivo to niacinamide, the active form of vitamin B₃, an essential nutrient. But high doses (up to 2,000 mg/day) used for hyperlipidemia have not been studied in pregnancy. Because niacinamide is actively transported to the fetus, producing higher concentrations in the fetus and newborn than in the mother, niacin is best avoided during pregnancy and lactation.

The large antihyperlipidemic class of drugs can be subdivided into bile acid sequestrants, HMG-CoA reductase inhibitors, fibric acid derivatives, ezetimibe, and niacin. With the possible exception of familial hypercholesterolemia, there appears to be no maternal benefit for the treatment of hyperlipidemia during gestation. Nearly all reported pregnancy exposures have occurred accidentally. If treatment is required, only bile acid sequestrants are considered compatible in pregnancy and lactation.

Ezetimibe (Zetia) also appears to be low risk in gestation, but not in lactation. Because most drug-induced adverse effects (about two-thirds) in nursing infants have been reported during the first month after birth, delaying treatment of a nursing mother until after this period appears to be best.

Cholestyramine has been used as a treatment for intrahepatic cholestasis of pregnancy and as an antidote for some types of diarrhea, chlordecone pesticide poisoning, and digitalis toxicity. Because bile acid sequestrants are not absorbed into the systemic circulation, they do not represent a direct risk to the embryo or fetus and are considered compatible with pregnancy (all are rated risk factor B) and lactation. However, the resins also bind fat-soluble vitamins in the gut, and deficiencies of these vitamins may result.

The six HMG-CoA reductase inhibitors (statins) are atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor). All are contraindicated in pregnancy (risk factor X). Case reports and surveillance studies have described healthy outcomes from a number of pregnancies inadvertently exposed in the first trimester and later. The largest number of cases (187) were reported with simvastatin, with 86 cases that could be evaluated: 74% had normal outcomes, 15% resulted in spontaneous abortion, 6% of cases demonstrated congenital anomalies, 4% of cases had effects related to prematurity, and 1% resulted in fetal death. Three of the five birth defect cases were not related to simvastatin because of the timing of exposure or the outcome was a known chromosome defect. The remaining two cases involved unilateral cleft lip and a clubfoot, neither of which appear to be attributable to simvastatin.

In contrast, a 2004 reference described 178 cases of first-trimester exposure to statins reported to the Food and Drug Administration. Among the 52 cases suitable for evaluation, there were 20 major malformations, some thought to be consistent with inhibition of cholesterol biosynthesis. All 20 defects involved a lipophilic statin (atorvastatin, cerivastatin (Baycol), lovastatin, or simvastatin). No defects were reported with pravastatin, a hydrophilic agent with low tissue penetration that is not associated with animal developmental toxicity. These results are controversial, and controlled studies are needed to determine if there is a causal relationship. Because all statins are probably excreted into milk, women taking these drugs should not breast-feed.

Among the fibric acid derivatives, only gemfibrozil (Lopid) has some human data. The other agent, fenofibrate (TriCor), has no human data. The animal data (developmental toxicity in two animal species at doses up to 10 times the human dose) for each drug suggest there may be a risk to the human embryo or fetus. Thus, the safest course is to avoid these drugs in pregnancy (both are risk factor C). Although there are no data, the drugs are probably excreted into milk, and women on these agents should not breast-feed because of the potential toxicity, such as tumors, in their infants.

Ezetimibe (risk factor C) selectively inhibits the intestinal absorption of cholesterol and related phytosterols. At doses up to 10 times the human dose, the drug is teratogenic in rats but not in rabbits. Human pregnancy exposures have not been reported. If therapy during pregnancy is mandated, ezetimibe appears to be a better choice than statins. There are no data on use during lactation, but the drug is probably excreted into milk. Toxicity is a potential concern; nursing infants should be monitored for headache, diarrhea, arthralgia, pharyngitis, sinusitis, and other adverse effects observed in adults.

Niacin (nicotinic acid) is converted in vivo to niacinamide, the active form of vitamin B₃, an essential nutrient. But high doses (up to 2,000 mg/day) used for hyperlipidemia have not been studied in pregnancy. Because niacinamide is actively transported to the fetus, producing higher concentrations in the fetus and newborn than in the mother, niacin is best avoided during pregnancy and lactation.

Migraine symptoms improve in up to 70% of women during pregnancy, usually during the second and third trimesters. But in 4%–8% of women, migraines worsen, and as many as 16% of all migraine cases during pregnancy may be new onset.

A 2002 review identified drugs or drug classes used for preventing migraine attacks (N. Engl. J. Med. 2002;346:257–70), including four drugs available in the United States that were considered well-accepted treatments or had proved to be effective: metoprolol, propranolol, amitriptyline, and valproate. Verapamil (Calan, Isoptin) and selective serotonin-reuptake inhibitors (SSRIs) also were widely used, but the reviewers concluded that there was poor evidence of benefit. Gabapentin (Neurontin) and topiramate (Topamax), were considered promising for migraine prophylaxis.

Only amitriptyline, verapamil, and low-dose propranolol (30–40 mg/day) have sufficient data to be classified as low risk throughout pregnancy. But higher doses of propranolol may cause intrauterine growth retardation (IUGR) and other fetal/neonatal toxicity. Based on the drug class (antihistamine and calcium channel blocker), flunarizine is probably compatible with pregnancy. Gabapentin and topiramate should be avoided in the first trimester because of inadequate human data to assess their risk. Valproate is known to cause neural tube defects and other structural anomalies if used in the first trimester, and use of metoprolol during the second and third trimesters is associated with an increased risk of IUGR. Use of the SSRIs in the third trimester may cause newborn toxicity, and methysergide and other ergot alkaloids are contraindicated in pregnancy.

Many other drugs have been used in treating migraines, including: acetaminophen (alone, or in combination with caffeine and butalbital, aspirin and caffeine, or isometheptene and dichloralphenazone); NSAIDs, including aspirin; chlorpromazine (Thorazine); dimenhydrinate (Dramamine); diphenhydramine (Benadryl); morphine; meperidine; intranasal butorphanol (Stadol); and corticosteroids.

Combination products with butalbital are not recommended because in studies, the butalbital component did not increase efficacy. Acetaminophen, caffeine, dimenhydrinate, diphenhydramine, narcotic analgesics, lidocaine, and butorphanol are compatible (i.e., very low risk) in pregnancy. However, frequent, prolonged use of narcotic analgesics may result in maternal and fetal addiction.

NSAIDs, including aspirin, have been associated with miscarriage when used around the time of conception, and exposure in the third trimester is associated with premature closure of the ductus arteriosus with the risk of persistent pulmonary hypertension of the newborn.

Since aspirin causes irreversible inhibition of platelet function and other clotting disorders, its use near term may enhance maternal blood loss at delivery and increase the incidence of intracranial hemorrhage in premature infants. Use of corticosteroids in the first trimester is associated with a low risk of oral clefts. Ergot alkaloid preparations are contraindicated in pregnancy because of dose-related developmental toxicity and oxytocic properties.

In the United States, seven triptans indicated for the short-term treatment of migraine with or without aura are available: sumatriptan (Imitrex), almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), and zolmitriptan (Zomig). Triptans do not appear to be major teratogens in humans, but more data are needed to adequately assess this risk.

In animal studies at doses or systemic exposures 10 times the human dose, triptans caused developmental toxicity. Human data, primarily from pregnancy registries, are available only for naratriptan, sumatriptan, and rizatriptan. As of early 2004, about 500 women had been prospectively enrolled, about 90% with first-trimester exposure. Except for a small cluster of five ventricular septal defects, a common heart condition, there was no consistent pattern of defects to suggest a common cause.

Other than ergot drugs (contraindicated) and amitriptyline (concern for long-term neurotoxicity), all antimigraine agents appear to be compatible with breast-feeding. However, there are few or no data available for gabapentin and topiramate. Ergot alkaloids may inhibit lactation, and high doses have been associated with toxicity in nursing infants. The effect of triptans on a nursing infant is unknown, but the small amount of drug found in milk does not appear to represent a risk and it is probable that they are all compatible with breast-feeding.

Migraine symptoms improve in up to 70% of women during pregnancy, usually during the second and third trimesters. But in 4%–8% of women, migraines worsen, and as many as 16% of all migraine cases during pregnancy may be new onset.

A 2002 review identified drugs or drug classes used for preventing migraine attacks (N. Engl. J. Med. 2002;346:257–70), including four drugs available in the United States that were considered well-accepted treatments or had proved to be effective: metoprolol, propranolol, amitriptyline, and valproate. Verapamil (Calan, Isoptin) and selective serotonin-reuptake inhibitors (SSRIs) also were widely used, but the reviewers concluded that there was poor evidence of benefit. Gabapentin (Neurontin) and topiramate (Topamax), were considered promising for migraine prophylaxis.

Only amitriptyline, verapamil, and low-dose propranolol (30–40 mg/day) have sufficient data to be classified as low risk throughout pregnancy. But higher doses of propranolol may cause intrauterine growth retardation (IUGR) and other fetal/neonatal toxicity. Based on the drug class (antihistamine and calcium channel blocker), flunarizine is probably compatible with pregnancy. Gabapentin and topiramate should be avoided in the first trimester because of inadequate human data to assess their risk. Valproate is known to cause neural tube defects and other structural anomalies if used in the first trimester, and use of metoprolol during the second and third trimesters is associated with an increased risk of IUGR. Use of the SSRIs in the third trimester may cause newborn toxicity, and methysergide and other ergot alkaloids are contraindicated in pregnancy.

Many other drugs have been used in treating migraines, including: acetaminophen (alone, or in combination with caffeine and butalbital, aspirin and caffeine, or isometheptene and dichloralphenazone); NSAIDs, including aspirin; chlorpromazine (Thorazine); dimenhydrinate (Dramamine); diphenhydramine (Benadryl); morphine; meperidine; intranasal butorphanol (Stadol); and corticosteroids.

Combination products with butalbital are not recommended because in studies, the butalbital component did not increase efficacy. Acetaminophen, caffeine, dimenhydrinate, diphenhydramine, narcotic analgesics, lidocaine, and butorphanol are compatible (i.e., very low risk) in pregnancy. However, frequent, prolonged use of narcotic analgesics may result in maternal and fetal addiction.

NSAIDs, including aspirin, have been associated with miscarriage when used around the time of conception, and exposure in the third trimester is associated with premature closure of the ductus arteriosus with the risk of persistent pulmonary hypertension of the newborn.

Since aspirin causes irreversible inhibition of platelet function and other clotting disorders, its use near term may enhance maternal blood loss at delivery and increase the incidence of intracranial hemorrhage in premature infants. Use of corticosteroids in the first trimester is associated with a low risk of oral clefts. Ergot alkaloid preparations are contraindicated in pregnancy because of dose-related developmental toxicity and oxytocic properties.

In the United States, seven triptans indicated for the short-term treatment of migraine with or without aura are available: sumatriptan (Imitrex), almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), and zolmitriptan (Zomig). Triptans do not appear to be major teratogens in humans, but more data are needed to adequately assess this risk.

In animal studies at doses or systemic exposures 10 times the human dose, triptans caused developmental toxicity. Human data, primarily from pregnancy registries, are available only for naratriptan, sumatriptan, and rizatriptan. As of early 2004, about 500 women had been prospectively enrolled, about 90% with first-trimester exposure. Except for a small cluster of five ventricular septal defects, a common heart condition, there was no consistent pattern of defects to suggest a common cause.

Other than ergot drugs (contraindicated) and amitriptyline (concern for long-term neurotoxicity), all antimigraine agents appear to be compatible with breast-feeding. However, there are few or no data available for gabapentin and topiramate. Ergot alkaloids may inhibit lactation, and high doses have been associated with toxicity in nursing infants. The effect of triptans on a nursing infant is unknown, but the small amount of drug found in milk does not appear to represent a risk and it is probable that they are all compatible with breast-feeding.

Migraine symptoms improve in up to 70% of women during pregnancy, usually during the second and third trimesters. But in 4%–8% of women, migraines worsen, and as many as 16% of all migraine cases during pregnancy may be new onset.

A 2002 review identified drugs or drug classes used for preventing migraine attacks (N. Engl. J. Med. 2002;346:257–70), including four drugs available in the United States that were considered well-accepted treatments or had proved to be effective: metoprolol, propranolol, amitriptyline, and valproate. Verapamil (Calan, Isoptin) and selective serotonin-reuptake inhibitors (SSRIs) also were widely used, but the reviewers concluded that there was poor evidence of benefit. Gabapentin (Neurontin) and topiramate (Topamax), were considered promising for migraine prophylaxis.

Only amitriptyline, verapamil, and low-dose propranolol (30–40 mg/day) have sufficient data to be classified as low risk throughout pregnancy. But higher doses of propranolol may cause intrauterine growth retardation (IUGR) and other fetal/neonatal toxicity. Based on the drug class (antihistamine and calcium channel blocker), flunarizine is probably compatible with pregnancy. Gabapentin and topiramate should be avoided in the first trimester because of inadequate human data to assess their risk. Valproate is known to cause neural tube defects and other structural anomalies if used in the first trimester, and use of metoprolol during the second and third trimesters is associated with an increased risk of IUGR. Use of the SSRIs in the third trimester may cause newborn toxicity, and methysergide and other ergot alkaloids are contraindicated in pregnancy.

Many other drugs have been used in treating migraines, including: acetaminophen (alone, or in combination with caffeine and butalbital, aspirin and caffeine, or isometheptene and dichloralphenazone); NSAIDs, including aspirin; chlorpromazine (Thorazine); dimenhydrinate (Dramamine); diphenhydramine (Benadryl); morphine; meperidine; intranasal butorphanol (Stadol); and corticosteroids.

Combination products with butalbital are not recommended because in studies, the butalbital component did not increase efficacy. Acetaminophen, caffeine, dimenhydrinate, diphenhydramine, narcotic analgesics, lidocaine, and butorphanol are compatible (i.e., very low risk) in pregnancy. However, frequent, prolonged use of narcotic analgesics may result in maternal and fetal addiction.

NSAIDs, including aspirin, have been associated with miscarriage when used around the time of conception, and exposure in the third trimester is associated with premature closure of the ductus arteriosus with the risk of persistent pulmonary hypertension of the newborn.

Since aspirin causes irreversible inhibition of platelet function and other clotting disorders, its use near term may enhance maternal blood loss at delivery and increase the incidence of intracranial hemorrhage in premature infants. Use of corticosteroids in the first trimester is associated with a low risk of oral clefts. Ergot alkaloid preparations are contraindicated in pregnancy because of dose-related developmental toxicity and oxytocic properties.

In the United States, seven triptans indicated for the short-term treatment of migraine with or without aura are available: sumatriptan (Imitrex), almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), and zolmitriptan (Zomig). Triptans do not appear to be major teratogens in humans, but more data are needed to adequately assess this risk.

In animal studies at doses or systemic exposures 10 times the human dose, triptans caused developmental toxicity. Human data, primarily from pregnancy registries, are available only for naratriptan, sumatriptan, and rizatriptan. As of early 2004, about 500 women had been prospectively enrolled, about 90% with first-trimester exposure. Except for a small cluster of five ventricular septal defects, a common heart condition, there was no consistent pattern of defects to suggest a common cause.

Other than ergot drugs (contraindicated) and amitriptyline (concern for long-term neurotoxicity), all antimigraine agents appear to be compatible with breast-feeding. However, there are few or no data available for gabapentin and topiramate. Ergot alkaloids may inhibit lactation, and high doses have been associated with toxicity in nursing infants. The effect of triptans on a nursing infant is unknown, but the small amount of drug found in milk does not appear to represent a risk and it is probable that they are all compatible with breast-feeding.

MR. BRIGGS is pharmacist clinical specialist, Women's Pavilion at Miller Children's Hospital, Long Beach, Calif.; clinical professor of pharmacy, University of California, San Francisco; and adjunct professor of pharmacy, University of Southern California, Los Angeles. He also is coauthor of the reference book, “Drugs in Pregnancy and Lactation.”

The autoimmune disorder rheumatoid arthritis occurs in about 1%-2% of the population. The disease is more prevalent in women than men by about a 3:1 ratio, but in the reproductive years, the ratio may be as high as 6:1. During pregnancy, the incidence is about 1:1,000.

RA is characterized by the production of cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1 in the synovial cavity, and irreversible damage to soft tissues and bones. Drug therapy of RA involves the use of disease-modifying antirheumatic drugs (DMARDs) to prevent or lessen this damage. The therapy can be categorized as biologic DMARDs, synthetic DMARDs, and anti-inflammatory agents.

Biologic DMARDs include three agents that inhibit TNF-α—adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade)—and one interleukin-1 receptor antagonist, anakinra (Kineret). Although the human pregnancy data for these four drugs are very limited or completely absent, animal reproduction data suggest they pose a low risk for developmental toxicity (growth retardation, structural defects, functional/behavioral defects, or death).

The safest course is to avoid these agents in the first trimester, but with their long elimination half-lives, inadvertent exposures during organogenesis of unplanned pregnancies is likely.

The synthetic DMARDs include azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), gold compounds, hydroxychloroquine (Plaquenil), leflunomide (Arava), methotrexate, penicillamine, and sulfasalazine (Azulfidine).

The two immunosuppressants, azathioprine and cyclosporine, do not appear to cause congenital defects, but may be associated with growth retardation. There is limited human pregnancy experience with the gold compounds—auranofin (Ridaura), aurothioglucose (Solganal), and gold sodium thiomalate (Aurolate)—but animal data suggest the risk for developmental toxicity is low.

Hydroxychloroquine is probably compatible in pregnancy. But there is limited pregnancy experience with the high doses used in RA. The drug has a long elimination half-life from maternal tissues (weeks to months) so stopping the drug when pregnancy is confirmed will not prevent embryo/fetal exposure.

Leflunomide, a pyrimidine synthesis inhibitor, causes dose-related teratogenicity and toxicity in animals at doses much lower than those used in humans. Human pregnancy experience is too limited to determine the risk to the embryo or fetus, and the drug is contraindicated in pregnancy. Exposure of unplanned pregnancies will probably occur because the drug and its active metabolite may take up to 2 years to reach nondetectable plasma levels.

The folic acid antagonist methotrexate is contraindicated during pregnancy. The drug is associated with spontaneous abortions and a spectrum of congenital defects collectively termed methotrexate embryopathy. The critical exposure period for structural defects is 8-10 weeks after the first day of the last menstrual period. Exposure after this period is associated with fetal toxicity and mortality. The critical dose is thought to be 10 mg or more per week.

Another folate antagonist, sulfasalazine, does not appear to cause developmental toxicity, but supplemental folic acid (1 mg/day) should be used if there is a risk of unplanned pregnancy or if pregnancy occurs. The drug has caused bloody diarrhea in a nursing infant, so breast-feeding should be undertaken cautiously. Penicillamine, a chelating agent, is associated with a risk of fetal connective tissue defects (cutis laxa) and should be avoided during pregnancy.

The anti-inflammatory agents include prednisone and the NSAIDs, which include aspirin. There is considerable potential for embryo/fetal toxicity from NSAIDs: spontaneous abortions when used around the time of conception, fetal renal toxicity, and premature closure of the ductus arteriosus in the third trimester. Aspirin use near term may increase the risk of bleeding in the mother and the infant. The use of prednisone during organogenesis carries a low risk for oral clefts and prolonged use in pregnancy has been associated with growth retardation.

The biologic DMARDs, gold compounds, hydroxychloroquine, NSAIDs (except high-dose aspirin), and prednisone are probably compatible with breast-feeding. The other agents are either contraindicated (methotrexate) or should be avoided because of potential toxicity. High-dose aspirin and sulfasalazine have been associated with toxicity in nursing infants.

The Organization of Teratology Information Services is conducting a study of pregnancy exposure to RA drugs. Call the toll-free number (877-311-8972) for information about enrolling patients in the study.

MR. BRIGGS is pharmacist clinical specialist, Women's Pavilion at Miller Children's Hospital, Long Beach, Calif.; clinical professor of pharmacy, University of California, San Francisco; and adjunct professor of pharmacy, University of Southern California, Los Angeles. He also is coauthor of the reference book, “Drugs in Pregnancy and Lactation.”

The autoimmune disorder rheumatoid arthritis occurs in about 1%-2% of the population. The disease is more prevalent in women than men by about a 3:1 ratio, but in the reproductive years, the ratio may be as high as 6:1. During pregnancy, the incidence is about 1:1,000.

RA is characterized by the production of cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1 in the synovial cavity, and irreversible damage to soft tissues and bones. Drug therapy of RA involves the use of disease-modifying antirheumatic drugs (DMARDs) to prevent or lessen this damage. The therapy can be categorized as biologic DMARDs, synthetic DMARDs, and anti-inflammatory agents.

Biologic DMARDs include three agents that inhibit TNF-α—adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade)—and one interleukin-1 receptor antagonist, anakinra (Kineret). Although the human pregnancy data for these four drugs are very limited or completely absent, animal reproduction data suggest they pose a low risk for developmental toxicity (growth retardation, structural defects, functional/behavioral defects, or death).

The safest course is to avoid these agents in the first trimester, but with their long elimination half-lives, inadvertent exposures during organogenesis of unplanned pregnancies is likely.

The synthetic DMARDs include azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), gold compounds, hydroxychloroquine (Plaquenil), leflunomide (Arava), methotrexate, penicillamine, and sulfasalazine (Azulfidine).

The two immunosuppressants, azathioprine and cyclosporine, do not appear to cause congenital defects, but may be associated with growth retardation. There is limited human pregnancy experience with the gold compounds—auranofin (Ridaura), aurothioglucose (Solganal), and gold sodium thiomalate (Aurolate)—but animal data suggest the risk for developmental toxicity is low.

Hydroxychloroquine is probably compatible in pregnancy. But there is limited pregnancy experience with the high doses used in RA. The drug has a long elimination half-life from maternal tissues (weeks to months) so stopping the drug when pregnancy is confirmed will not prevent embryo/fetal exposure.

Leflunomide, a pyrimidine synthesis inhibitor, causes dose-related teratogenicity and toxicity in animals at doses much lower than those used in humans. Human pregnancy experience is too limited to determine the risk to the embryo or fetus, and the drug is contraindicated in pregnancy. Exposure of unplanned pregnancies will probably occur because the drug and its active metabolite may take up to 2 years to reach nondetectable plasma levels.

The folic acid antagonist methotrexate is contraindicated during pregnancy. The drug is associated with spontaneous abortions and a spectrum of congenital defects collectively termed methotrexate embryopathy. The critical exposure period for structural defects is 8-10 weeks after the first day of the last menstrual period. Exposure after this period is associated with fetal toxicity and mortality. The critical dose is thought to be 10 mg or more per week.

Another folate antagonist, sulfasalazine, does not appear to cause developmental toxicity, but supplemental folic acid (1 mg/day) should be used if there is a risk of unplanned pregnancy or if pregnancy occurs. The drug has caused bloody diarrhea in a nursing infant, so breast-feeding should be undertaken cautiously. Penicillamine, a chelating agent, is associated with a risk of fetal connective tissue defects (cutis laxa) and should be avoided during pregnancy.

The anti-inflammatory agents include prednisone and the NSAIDs, which include aspirin. There is considerable potential for embryo/fetal toxicity from NSAIDs: spontaneous abortions when used around the time of conception, fetal renal toxicity, and premature closure of the ductus arteriosus in the third trimester. Aspirin use near term may increase the risk of bleeding in the mother and the infant. The use of prednisone during organogenesis carries a low risk for oral clefts and prolonged use in pregnancy has been associated with growth retardation.

The biologic DMARDs, gold compounds, hydroxychloroquine, NSAIDs (except high-dose aspirin), and prednisone are probably compatible with breast-feeding. The other agents are either contraindicated (methotrexate) or should be avoided because of potential toxicity. High-dose aspirin and sulfasalazine have been associated with toxicity in nursing infants.

The Organization of Teratology Information Services is conducting a study of pregnancy exposure to RA drugs. Call the toll-free number (877-311-8972) for information about enrolling patients in the study.

MR. BRIGGS is pharmacist clinical specialist, Women's Pavilion at Miller Children's Hospital, Long Beach, Calif.; clinical professor of pharmacy, University of California, San Francisco; and adjunct professor of pharmacy, University of Southern California, Los Angeles. He also is coauthor of the reference book, “Drugs in Pregnancy and Lactation.”

The autoimmune disorder rheumatoid arthritis occurs in about 1%-2% of the population. The disease is more prevalent in women than men by about a 3:1 ratio, but in the reproductive years, the ratio may be as high as 6:1. During pregnancy, the incidence is about 1:1,000.

RA is characterized by the production of cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1 in the synovial cavity, and irreversible damage to soft tissues and bones. Drug therapy of RA involves the use of disease-modifying antirheumatic drugs (DMARDs) to prevent or lessen this damage. The therapy can be categorized as biologic DMARDs, synthetic DMARDs, and anti-inflammatory agents.

Biologic DMARDs include three agents that inhibit TNF-α—adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade)—and one interleukin-1 receptor antagonist, anakinra (Kineret). Although the human pregnancy data for these four drugs are very limited or completely absent, animal reproduction data suggest they pose a low risk for developmental toxicity (growth retardation, structural defects, functional/behavioral defects, or death).

The safest course is to avoid these agents in the first trimester, but with their long elimination half-lives, inadvertent exposures during organogenesis of unplanned pregnancies is likely.

The synthetic DMARDs include azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), gold compounds, hydroxychloroquine (Plaquenil), leflunomide (Arava), methotrexate, penicillamine, and sulfasalazine (Azulfidine).

The two immunosuppressants, azathioprine and cyclosporine, do not appear to cause congenital defects, but may be associated with growth retardation. There is limited human pregnancy experience with the gold compounds—auranofin (Ridaura), aurothioglucose (Solganal), and gold sodium thiomalate (Aurolate)—but animal data suggest the risk for developmental toxicity is low.

Hydroxychloroquine is probably compatible in pregnancy. But there is limited pregnancy experience with the high doses used in RA. The drug has a long elimination half-life from maternal tissues (weeks to months) so stopping the drug when pregnancy is confirmed will not prevent embryo/fetal exposure.

Leflunomide, a pyrimidine synthesis inhibitor, causes dose-related teratogenicity and toxicity in animals at doses much lower than those used in humans. Human pregnancy experience is too limited to determine the risk to the embryo or fetus, and the drug is contraindicated in pregnancy. Exposure of unplanned pregnancies will probably occur because the drug and its active metabolite may take up to 2 years to reach nondetectable plasma levels.

The folic acid antagonist methotrexate is contraindicated during pregnancy. The drug is associated with spontaneous abortions and a spectrum of congenital defects collectively termed methotrexate embryopathy. The critical exposure period for structural defects is 8-10 weeks after the first day of the last menstrual period. Exposure after this period is associated with fetal toxicity and mortality. The critical dose is thought to be 10 mg or more per week.

Another folate antagonist, sulfasalazine, does not appear to cause developmental toxicity, but supplemental folic acid (1 mg/day) should be used if there is a risk of unplanned pregnancy or if pregnancy occurs. The drug has caused bloody diarrhea in a nursing infant, so breast-feeding should be undertaken cautiously. Penicillamine, a chelating agent, is associated with a risk of fetal connective tissue defects (cutis laxa) and should be avoided during pregnancy.

The anti-inflammatory agents include prednisone and the NSAIDs, which include aspirin. There is considerable potential for embryo/fetal toxicity from NSAIDs: spontaneous abortions when used around the time of conception, fetal renal toxicity, and premature closure of the ductus arteriosus in the third trimester. Aspirin use near term may increase the risk of bleeding in the mother and the infant. The use of prednisone during organogenesis carries a low risk for oral clefts and prolonged use in pregnancy has been associated with growth retardation.

The biologic DMARDs, gold compounds, hydroxychloroquine, NSAIDs (except high-dose aspirin), and prednisone are probably compatible with breast-feeding. The other agents are either contraindicated (methotrexate) or should be avoided because of potential toxicity. High-dose aspirin and sulfasalazine have been associated with toxicity in nursing infants.

The Organization of Teratology Information Services is conducting a study of pregnancy exposure to RA drugs. Call the toll-free number (877-311-8972) for information about enrolling patients in the study.

Migraine symptoms improve in up to 70% of women during pregnancy, usually during the second and third trimesters. But in 4%-8% of women, migraines worsen, and as many as 16% of all migraine cases during pregnancy may be new onset.

A 2002 review identified drugs or drug classes used for preventing migraine attacks (N. Engl. J. Med. 2002;346:257–70), including four drugs available in the United States that were considered well-accepted treatments or had proved to be effective: metoprolol, propranolol, amitriptyline, and valproate. Verapamil (Calan, Isoptin) and selective serotonin-reuptake inhibitors (SSRIs) were also widely used, but the reviewers concluded that there was poor evidence of benefit. Gabapentin (Neurontin) and topiramate (Topamax) were considered promising for migraine prophylaxis.

Of all these agents, only amitriptyline, verapamil, and low-dose propranolol (30–40 mg/day) have sufficient data to be classified as low risk throughout pregnancy. However, higher doses of propranolol may cause intrauterine growth retardation (IUGR) and other fetal/neonatal toxicity. Based on the drug class (antihistamine and calcium channel blocker), flunarizine is probably compatible with pregnancy. Gabapentin and topiramate should be avoided in the first trimester because of inadequate human data to assess their risk. Valproate is known to cause neural tube defects and other structural anomalies if used in the first trimester, and use of metoprolol during the second and third trimesters is associated with an increased risk of IUGR. Use of the SSRIs in the third trimester may cause newborn toxicity, and methysergide and other ergot alkaloids are contraindicated in pregnancy.

Numerous other drugs have been used in treating migraines, including acetaminophen (alone, or in combination with caffeine and butalbital, aspirin and caffeine, or isometheptene and dichloralphenazone); NSAIDs, including aspirin; chlorpromazine (Thorazine); dimenhydrinate (Dramamine); diphenhydramine (Benadryl); morphine; and meperidine. Others are dihydroergotamine (Migranal, D.H.E. 45), ergotamine (Ergomar) (alone or in combination with caffeine, or caffeine-belladonna-pentobarbital), intranasal lidocaine, and selective serotonin receptor agonists, also called triptans.

Combination products with butalbital are not recommended because in studies, the butalbital component did not increase efficacy. Acetaminophen, caffeine, dimenhydrinate, diphenhydramine, narcotic analgesics, and lidocaine are compatible in pregnancy. However, frequent, prolonged use of narcotic analgesics may result in maternal and fetal addiction.

Depending upon the gestational stage of exposure, several therapeutic agents can cause developmental toxicity in humans. NSAIDs, including aspirin, have been associated with miscarriage when used around the time of conception, and exposure in the third trimester is associated with premature closure of the ductus arteriosus with the risk of persistent pulmonary hypertension of the newborn.

Since aspirin causes irreversible inhibition of platelet function and other clotting disorders, its use near term may enhance maternal blood loss at delivery and increase the incidence of intracranial hemorrhage in premature or low-birth-weight infants. Ergot alkaloid preparations are contraindicated in pregnancy because of their dose-related developmental toxicity and oxytocic properties.

Seven triptans indicated for the short-term treatment of migraine with or without aura are available: sumatriptan (Imitrex), almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), and zolmitriptan (Zomig).

In animal studies at doses or systemic exposures 10 times the human dose, triptans caused developmental toxicity. Human data, primarily from pregnancy registries, are only available for naratriptan, sumatriptan, and rizatriptan. As of early 2004, about 500 women had been prospectively enrolled, about 90% with first-trimester exposure. Except for a small cluster of five ventricular septal defects, a common heart condition, there was no consistent pattern of defects.

Other than ergot drugs (contraindicated) and amitriptyline (concern for long-term neurotoxicity), all antimigraine agents appear to be compatible with breast-feeding. However, there are few or no data available for gabapentin and topiramate. High doses of ergot alkaloids have been associated with toxicity in nursing infants. The effect of triptans on a nursing infant is unknown, but the small amount of drug found in milk does not appear to represent a risk and it is probable that they are all compatible with breast-feeding.

Migraine symptoms improve in up to 70% of women during pregnancy, usually during the second and third trimesters. But in 4%-8% of women, migraines worsen, and as many as 16% of all migraine cases during pregnancy may be new onset.

A 2002 review identified drugs or drug classes used for preventing migraine attacks (N. Engl. J. Med. 2002;346:257–70), including four drugs available in the United States that were considered well-accepted treatments or had proved to be effective: metoprolol, propranolol, amitriptyline, and valproate. Verapamil (Calan, Isoptin) and selective serotonin-reuptake inhibitors (SSRIs) were also widely used, but the reviewers concluded that there was poor evidence of benefit. Gabapentin (Neurontin) and topiramate (Topamax) were considered promising for migraine prophylaxis.

Of all these agents, only amitriptyline, verapamil, and low-dose propranolol (30–40 mg/day) have sufficient data to be classified as low risk throughout pregnancy. However, higher doses of propranolol may cause intrauterine growth retardation (IUGR) and other fetal/neonatal toxicity. Based on the drug class (antihistamine and calcium channel blocker), flunarizine is probably compatible with pregnancy. Gabapentin and topiramate should be avoided in the first trimester because of inadequate human data to assess their risk. Valproate is known to cause neural tube defects and other structural anomalies if used in the first trimester, and use of metoprolol during the second and third trimesters is associated with an increased risk of IUGR. Use of the SSRIs in the third trimester may cause newborn toxicity, and methysergide and other ergot alkaloids are contraindicated in pregnancy.

Numerous other drugs have been used in treating migraines, including acetaminophen (alone, or in combination with caffeine and butalbital, aspirin and caffeine, or isometheptene and dichloralphenazone); NSAIDs, including aspirin; chlorpromazine (Thorazine); dimenhydrinate (Dramamine); diphenhydramine (Benadryl); morphine; and meperidine. Others are dihydroergotamine (Migranal, D.H.E. 45), ergotamine (Ergomar) (alone or in combination with caffeine, or caffeine-belladonna-pentobarbital), intranasal lidocaine, and selective serotonin receptor agonists, also called triptans.

Combination products with butalbital are not recommended because in studies, the butalbital component did not increase efficacy. Acetaminophen, caffeine, dimenhydrinate, diphenhydramine, narcotic analgesics, and lidocaine are compatible in pregnancy. However, frequent, prolonged use of narcotic analgesics may result in maternal and fetal addiction.

Depending upon the gestational stage of exposure, several therapeutic agents can cause developmental toxicity in humans. NSAIDs, including aspirin, have been associated with miscarriage when used around the time of conception, and exposure in the third trimester is associated with premature closure of the ductus arteriosus with the risk of persistent pulmonary hypertension of the newborn.

Since aspirin causes irreversible inhibition of platelet function and other clotting disorders, its use near term may enhance maternal blood loss at delivery and increase the incidence of intracranial hemorrhage in premature or low-birth-weight infants. Ergot alkaloid preparations are contraindicated in pregnancy because of their dose-related developmental toxicity and oxytocic properties.

Seven triptans indicated for the short-term treatment of migraine with or without aura are available: sumatriptan (Imitrex), almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), and zolmitriptan (Zomig).

In animal studies at doses or systemic exposures 10 times the human dose, triptans caused developmental toxicity. Human data, primarily from pregnancy registries, are only available for naratriptan, sumatriptan, and rizatriptan. As of early 2004, about 500 women had been prospectively enrolled, about 90% with first-trimester exposure. Except for a small cluster of five ventricular septal defects, a common heart condition, there was no consistent pattern of defects.

Other than ergot drugs (contraindicated) and amitriptyline (concern for long-term neurotoxicity), all antimigraine agents appear to be compatible with breast-feeding. However, there are few or no data available for gabapentin and topiramate. High doses of ergot alkaloids have been associated with toxicity in nursing infants. The effect of triptans on a nursing infant is unknown, but the small amount of drug found in milk does not appear to represent a risk and it is probable that they are all compatible with breast-feeding.

Migraine symptoms improve in up to 70% of women during pregnancy, usually during the second and third trimesters. But in 4%-8% of women, migraines worsen, and as many as 16% of all migraine cases during pregnancy may be new onset.

A 2002 review identified drugs or drug classes used for preventing migraine attacks (N. Engl. J. Med. 2002;346:257–70), including four drugs available in the United States that were considered well-accepted treatments or had proved to be effective: metoprolol, propranolol, amitriptyline, and valproate. Verapamil (Calan, Isoptin) and selective serotonin-reuptake inhibitors (SSRIs) were also widely used, but the reviewers concluded that there was poor evidence of benefit. Gabapentin (Neurontin) and topiramate (Topamax) were considered promising for migraine prophylaxis.

Of all these agents, only amitriptyline, verapamil, and low-dose propranolol (30–40 mg/day) have sufficient data to be classified as low risk throughout pregnancy. However, higher doses of propranolol may cause intrauterine growth retardation (IUGR) and other fetal/neonatal toxicity. Based on the drug class (antihistamine and calcium channel blocker), flunarizine is probably compatible with pregnancy. Gabapentin and topiramate should be avoided in the first trimester because of inadequate human data to assess their risk. Valproate is known to cause neural tube defects and other structural anomalies if used in the first trimester, and use of metoprolol during the second and third trimesters is associated with an increased risk of IUGR. Use of the SSRIs in the third trimester may cause newborn toxicity, and methysergide and other ergot alkaloids are contraindicated in pregnancy.

Numerous other drugs have been used in treating migraines, including acetaminophen (alone, or in combination with caffeine and butalbital, aspirin and caffeine, or isometheptene and dichloralphenazone); NSAIDs, including aspirin; chlorpromazine (Thorazine); dimenhydrinate (Dramamine); diphenhydramine (Benadryl); morphine; and meperidine. Others are dihydroergotamine (Migranal, D.H.E. 45), ergotamine (Ergomar) (alone or in combination with caffeine, or caffeine-belladonna-pentobarbital), intranasal lidocaine, and selective serotonin receptor agonists, also called triptans.

Combination products with butalbital are not recommended because in studies, the butalbital component did not increase efficacy. Acetaminophen, caffeine, dimenhydrinate, diphenhydramine, narcotic analgesics, and lidocaine are compatible in pregnancy. However, frequent, prolonged use of narcotic analgesics may result in maternal and fetal addiction.

Depending upon the gestational stage of exposure, several therapeutic agents can cause developmental toxicity in humans. NSAIDs, including aspirin, have been associated with miscarriage when used around the time of conception, and exposure in the third trimester is associated with premature closure of the ductus arteriosus with the risk of persistent pulmonary hypertension of the newborn.

Since aspirin causes irreversible inhibition of platelet function and other clotting disorders, its use near term may enhance maternal blood loss at delivery and increase the incidence of intracranial hemorrhage in premature or low-birth-weight infants. Ergot alkaloid preparations are contraindicated in pregnancy because of their dose-related developmental toxicity and oxytocic properties.

Seven triptans indicated for the short-term treatment of migraine with or without aura are available: sumatriptan (Imitrex), almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), and zolmitriptan (Zomig).

In animal studies at doses or systemic exposures 10 times the human dose, triptans caused developmental toxicity. Human data, primarily from pregnancy registries, are only available for naratriptan, sumatriptan, and rizatriptan. As of early 2004, about 500 women had been prospectively enrolled, about 90% with first-trimester exposure. Except for a small cluster of five ventricular septal defects, a common heart condition, there was no consistent pattern of defects.

Other than ergot drugs (contraindicated) and amitriptyline (concern for long-term neurotoxicity), all antimigraine agents appear to be compatible with breast-feeding. However, there are few or no data available for gabapentin and topiramate. High doses of ergot alkaloids have been associated with toxicity in nursing infants. The effect of triptans on a nursing infant is unknown, but the small amount of drug found in milk does not appear to represent a risk and it is probable that they are all compatible with breast-feeding.