Gerald G. Briggs

The physical discomforts of pregnancy induced by the surge of progesterone and the expanding uterus can result in sleep deprivation in pregnancy. An increased need to urinate, nausea and vomiting, heartburn, difficulty in finding a comfortable sleeping position, and, as the pregnancy progresses, the kicking and movement of the fetus, all conspire against a good night's sleep.

Prescribing sleeping medications in pregnancy may not be the best solution because long-term use can lead to habituation in the woman and her fetus. But patients often seek drug therapy to help them sleep, so it is essential to know what is relatively safe and what is not. Hypnotics fall into five subclasses:

▸ Oral barbiturates. Included in this group are aprobarbital (pregnancy risk factor C) (Alurate); pentobarbital (D) (Nembutal); and secobarbital (D) (Seconal). Developmental toxicity has not been proven, but more studies are needed regarding the potential for behavioral toxicity after long-term in utero exposure.

Their long elimination half-lives (24, 22–50, and 28 hours, respectively) can cause prolonged sedation, or hangover. They are controlled substances with potential for abuse, which makes them more difficult to prescribe.

Although they are excreted into milk in low amounts, they can be classified as compatible with breast-feeding.

▸ Benzodiazepines. Estazolam (ProSom), flurazepam (Dalmane), quazepam (Doral), and temazepam (Restoril) are in this category. Data on using these agents in pregnancy are limited. Although there has been no proven association between any of these agents and birth defects, they probably have effects on the embryo or fetus similar to diazepam (Valium), including neonatal motor depression (floppy infant syndrome) and/or withdrawal if used in the third trimester.

Moreover, all four agents are categorized as contraindicated (risk factor X) by their manufacturers, so they should not be prescribed. Small amounts of quazepam and temazepam are excreted into milk, and the other two agents are most likely in milk as well. Occasional dosing during breast-feeding is probably safe, but the long-term effects on a nursing infant are unknown.

▸ Nonbenzodiazepines. There are five drugs in this category: chloral hydrate (for example, Somnote), ramelteon (Rozerem), zaleplon (Sonata), and low-dose (25–75 mg) trazodone (Desyrel), all risk factor C, and zolpidem (Ambien), risk factor B.

The use for sleep of the antidepressant trazodone is off label, but the drug is sometimes combined with other antidepressants for this purpose.

As with the benzodiazepines, the human pregnancy data are limited or nonexistent. There are no animal data for chloral hydrate, an old product that is now rarely used, but animal data on the other nonbenzodiazepines suggest low risk in pregnancy. But, as with most drugs, the best course is to avoid them in the first trimester.

Occasional use in the second and third trimesters probably is low risk, but long-term use (more than 4 weeks) should be avoided. Small amounts of these drugs are excreted into milk, but occasional, short-term use probably is compatible with breast-feeding.

▸ OTC antihistamines. There are two in this category, diphenhydramine (such as Benadryl), and doxylamine (Unisom Nighttime Sleep Aid). Diphenhydra-mine (risk factor B) is safe throughout gestation, as is doxylamine (risk factor A). A major advantage of these antihistamines is that both have antiemetic properties that can reduce pregnancy-induced nausea and vomiting. If pyridoxine (vitamin B6) is taken with doxylamine, the combination is the antiemetic most frequently studied in pregnancy.

There is little or no experience with these agents during lactation. Although some manufacturers consider them contraindicated during breast-feeding, the lack of toxicity reports suggests these antihistamines probably are low risk for full-term nursing infants.

▸ Natural products. About 50 natural products are or have been advocated for sleep, but few have enough data to recommend their use in pregnancy or lactation. Moreover, the content and purity of natural products are often unregulated.

Natural agents that seem to be low risk are ginseng (not Siberian), honey, nutmeg, oats, and St. John's wort. But note that ginseng can cause hypertension and hypoglycemia.

Agents to be avoided include American hellebore, butterbur or other petasites, kava, marijuana, melatonin (available only as an orphan drug in the United States), mugwort, passion flower, quassia, rauwolfia, Siberian ginseng, taumelloolch, tulip tree, and valerian.

A nonpharmacologic approach is the best and safest course for pregnant patients with insomnia. If medications are required, occasional, short-term use is recommended; one of the OTC antihistamines is probably best.

A nonbenzodiazepine agent, such as zolpidem, would be my second choice. For more information, visit www.babycenter.com

The physical discomforts of pregnancy induced by the surge of progesterone and the expanding uterus can result in sleep deprivation in pregnancy. An increased need to urinate, nausea and vomiting, heartburn, difficulty in finding a comfortable sleeping position, and, as the pregnancy progresses, the kicking and movement of the fetus, all conspire against a good night's sleep.

Prescribing sleeping medications in pregnancy may not be the best solution because long-term use can lead to habituation in the woman and her fetus. But patients often seek drug therapy to help them sleep, so it is essential to know what is relatively safe and what is not. Hypnotics fall into five subclasses:

▸ Oral barbiturates. Included in this group are aprobarbital (pregnancy risk factor C) (Alurate); pentobarbital (D) (Nembutal); and secobarbital (D) (Seconal). Developmental toxicity has not been proven, but more studies are needed regarding the potential for behavioral toxicity after long-term in utero exposure.

Their long elimination half-lives (24, 22–50, and 28 hours, respectively) can cause prolonged sedation, or hangover. They are controlled substances with potential for abuse, which makes them more difficult to prescribe.

Although they are excreted into milk in low amounts, they can be classified as compatible with breast-feeding.

▸ Benzodiazepines. Estazolam (ProSom), flurazepam (Dalmane), quazepam (Doral), and temazepam (Restoril) are in this category. Data on using these agents in pregnancy are limited. Although there has been no proven association between any of these agents and birth defects, they probably have effects on the embryo or fetus similar to diazepam (Valium), including neonatal motor depression (floppy infant syndrome) and/or withdrawal if used in the third trimester.

Moreover, all four agents are categorized as contraindicated (risk factor X) by their manufacturers, so they should not be prescribed. Small amounts of quazepam and temazepam are excreted into milk, and the other two agents are most likely in milk as well. Occasional dosing during breast-feeding is probably safe, but the long-term effects on a nursing infant are unknown.

▸ Nonbenzodiazepines. There are five drugs in this category: chloral hydrate (for example, Somnote), ramelteon (Rozerem), zaleplon (Sonata), and low-dose (25–75 mg) trazodone (Desyrel), all risk factor C, and zolpidem (Ambien), risk factor B.

The use for sleep of the antidepressant trazodone is off label, but the drug is sometimes combined with other antidepressants for this purpose.

As with the benzodiazepines, the human pregnancy data are limited or nonexistent. There are no animal data for chloral hydrate, an old product that is now rarely used, but animal data on the other nonbenzodiazepines suggest low risk in pregnancy. But, as with most drugs, the best course is to avoid them in the first trimester.

Occasional use in the second and third trimesters probably is low risk, but long-term use (more than 4 weeks) should be avoided. Small amounts of these drugs are excreted into milk, but occasional, short-term use probably is compatible with breast-feeding.

▸ OTC antihistamines. There are two in this category, diphenhydramine (such as Benadryl), and doxylamine (Unisom Nighttime Sleep Aid). Diphenhydra-mine (risk factor B) is safe throughout gestation, as is doxylamine (risk factor A). A major advantage of these antihistamines is that both have antiemetic properties that can reduce pregnancy-induced nausea and vomiting. If pyridoxine (vitamin B6) is taken with doxylamine, the combination is the antiemetic most frequently studied in pregnancy.

There is little or no experience with these agents during lactation. Although some manufacturers consider them contraindicated during breast-feeding, the lack of toxicity reports suggests these antihistamines probably are low risk for full-term nursing infants.

▸ Natural products. About 50 natural products are or have been advocated for sleep, but few have enough data to recommend their use in pregnancy or lactation. Moreover, the content and purity of natural products are often unregulated.

Natural agents that seem to be low risk are ginseng (not Siberian), honey, nutmeg, oats, and St. John's wort. But note that ginseng can cause hypertension and hypoglycemia.

Agents to be avoided include American hellebore, butterbur or other petasites, kava, marijuana, melatonin (available only as an orphan drug in the United States), mugwort, passion flower, quassia, rauwolfia, Siberian ginseng, taumelloolch, tulip tree, and valerian.

A nonpharmacologic approach is the best and safest course for pregnant patients with insomnia. If medications are required, occasional, short-term use is recommended; one of the OTC antihistamines is probably best.

A nonbenzodiazepine agent, such as zolpidem, would be my second choice. For more information, visit www.babycenter.com

The physical discomforts of pregnancy induced by the surge of progesterone and the expanding uterus can result in sleep deprivation in pregnancy. An increased need to urinate, nausea and vomiting, heartburn, difficulty in finding a comfortable sleeping position, and, as the pregnancy progresses, the kicking and movement of the fetus, all conspire against a good night's sleep.

Prescribing sleeping medications in pregnancy may not be the best solution because long-term use can lead to habituation in the woman and her fetus. But patients often seek drug therapy to help them sleep, so it is essential to know what is relatively safe and what is not. Hypnotics fall into five subclasses:

▸ Oral barbiturates. Included in this group are aprobarbital (pregnancy risk factor C) (Alurate); pentobarbital (D) (Nembutal); and secobarbital (D) (Seconal). Developmental toxicity has not been proven, but more studies are needed regarding the potential for behavioral toxicity after long-term in utero exposure.

Their long elimination half-lives (24, 22–50, and 28 hours, respectively) can cause prolonged sedation, or hangover. They are controlled substances with potential for abuse, which makes them more difficult to prescribe.

Although they are excreted into milk in low amounts, they can be classified as compatible with breast-feeding.

▸ Benzodiazepines. Estazolam (ProSom), flurazepam (Dalmane), quazepam (Doral), and temazepam (Restoril) are in this category. Data on using these agents in pregnancy are limited. Although there has been no proven association between any of these agents and birth defects, they probably have effects on the embryo or fetus similar to diazepam (Valium), including neonatal motor depression (floppy infant syndrome) and/or withdrawal if used in the third trimester.

Moreover, all four agents are categorized as contraindicated (risk factor X) by their manufacturers, so they should not be prescribed. Small amounts of quazepam and temazepam are excreted into milk, and the other two agents are most likely in milk as well. Occasional dosing during breast-feeding is probably safe, but the long-term effects on a nursing infant are unknown.

▸ Nonbenzodiazepines. There are five drugs in this category: chloral hydrate (for example, Somnote), ramelteon (Rozerem), zaleplon (Sonata), and low-dose (25–75 mg) trazodone (Desyrel), all risk factor C, and zolpidem (Ambien), risk factor B.

The use for sleep of the antidepressant trazodone is off label, but the drug is sometimes combined with other antidepressants for this purpose.

As with the benzodiazepines, the human pregnancy data are limited or nonexistent. There are no animal data for chloral hydrate, an old product that is now rarely used, but animal data on the other nonbenzodiazepines suggest low risk in pregnancy. But, as with most drugs, the best course is to avoid them in the first trimester.

Occasional use in the second and third trimesters probably is low risk, but long-term use (more than 4 weeks) should be avoided. Small amounts of these drugs are excreted into milk, but occasional, short-term use probably is compatible with breast-feeding.

▸ OTC antihistamines. There are two in this category, diphenhydramine (such as Benadryl), and doxylamine (Unisom Nighttime Sleep Aid). Diphenhydra-mine (risk factor B) is safe throughout gestation, as is doxylamine (risk factor A). A major advantage of these antihistamines is that both have antiemetic properties that can reduce pregnancy-induced nausea and vomiting. If pyridoxine (vitamin B6) is taken with doxylamine, the combination is the antiemetic most frequently studied in pregnancy.

There is little or no experience with these agents during lactation. Although some manufacturers consider them contraindicated during breast-feeding, the lack of toxicity reports suggests these antihistamines probably are low risk for full-term nursing infants.

▸ Natural products. About 50 natural products are or have been advocated for sleep, but few have enough data to recommend their use in pregnancy or lactation. Moreover, the content and purity of natural products are often unregulated.

Natural agents that seem to be low risk are ginseng (not Siberian), honey, nutmeg, oats, and St. John's wort. But note that ginseng can cause hypertension and hypoglycemia.

Agents to be avoided include American hellebore, butterbur or other petasites, kava, marijuana, melatonin (available only as an orphan drug in the United States), mugwort, passion flower, quassia, rauwolfia, Siberian ginseng, taumelloolch, tulip tree, and valerian.

A nonpharmacologic approach is the best and safest course for pregnant patients with insomnia. If medications are required, occasional, short-term use is recommended; one of the OTC antihistamines is probably best.

A nonbenzodiazepine agent, such as zolpidem, would be my second choice. For more information, visit www.babycenter.com

The physical discomforts of pregnancy induced by the surge of progesterone and the expanding uterus can result in sleep deprivation in pregnancy. An increased need to urinate, nausea and vomiting, heartburn, difficulty in finding a comfortable sleeping position, and, as the pregnancy progresses, the kicking and movement of the fetus, all conspire against a good night's sleep.

Prescribing sleeping medications in pregnancy may not be the best solution because long-term use can lead to habituation in the woman and her fetus. But patients often seek drug therapy to help them sleep, so it is essential to know what is relatively safe and what is not. Hypnotics fall into five subclasses:

▸ Oral barbiturates. Included in this group are aprobarbital (pregnancy risk factor C) (Alurate); pentobarbital (D) (Nembutal); and secobarbital (D) (Seconal). Developmental toxicity has not been proven, but more studies are needed regarding the potential for behavioral toxicity after long-term in utero exposure. Their long elimination half-lives (24, 22–50, and 28 hours, respectively) can cause prolonged sedation, or hangover. They are controlled substances with potential for abuse, which makes them more difficult to prescribe. Although they are excreted into milk in low amounts, they can be classified as compatible with breast-feeding.

▸ Benzodiazepines. Estazolam (ProSom), flurazepam (Dalmane), quazepam (Doral), and temazepam (Restoril) are in this category. Data on using these agents in pregnancy are limited. Although there has been no proven association between any of these agents and birth defects, they probably have effects on the embryo or fetus similar to diazepam (Valium), including neonatal motor depression (floppy infant syndrome) and/or withdrawal if used in the third trimester. Moreover, all four agents are categorized as contraindicated (risk factor X) by their manufacturers, so they should not be prescribed. Small amounts of quazepam and temazepam are excreted into milk, and the other two agents are most likely in milk as well. Occasional dosing during breast-feeding is probably safe, but the long-term effects on a nursing infant are unknown.

▸ Nonbenzodiazepines. There are five drugs in this category: chloral hydrate (for example, Somnote), ramelteon (Rozerem), zaleplon (Sonata), and low-dose (25–75 mg) trazodone (Desyrel), all risk factor C, and zolpidem (Ambien), risk factor B. The use for sleep of the antidepressant trazodone is off label, but the drug is sometimes combined with other antidepressants for this purpose. As with the benzodiazepines, the human pregnancy data are limited or nonexistent. There are no animal data for chloral hydrate, an old product that is now rarely used, but animal data on the other nonbenzodiazepines suggest low risk in pregnancy. But, as with most drugs, the best course is to avoid them in the first trimester. Occasional use in the second and third trimesters probably is low risk, but long-term use (more than 4 weeks) should be avoided. Small amounts of these drugs are excreted into milk, but occasional, short-term use probably is compatible with breast-feeding.

▸ OTC antihistamines. There are two in this category, diphenhydramine (such as Benadryl), and doxylamine (Unisom Nighttime Sleep Aid). Di- phenhydramine (risk factor B) is safe throughout gestation, as is doxylamine (risk factor A). A major advantage of these antihistamines is that both have antiemetic properties that can reduce pregnancy-induced nausea and vomiting. If pyridoxine (vitamin B6) is taken with doxylamine, the combination is the antiemetic most frequently studied in pregnancy. There is little or no experience with these agents during lactation. Although some manufacturers consider them contraindicated during breast-feeding, the lack of toxicity reports suggests these antihistamines probably are low risk for full-term nursing infants.

▸ Natural products. About 50 natural products are or have been advocated for sleep, but few have enough data to recommend their use in pregnancy or lactation. Moreover, the content and purity of natural products are often unregulated.

Natural agents that seem to be low risk are ginseng (not Siberian), honey, nutmeg, oats, and St. John's wort. But note that ginseng can cause hypertension and hypoglycemia. Agents to be avoided include American hellebore, butterbur or other petasites, kava, marijuana, melatonin (available only as an orphan drug in the United States), mugwort, passion flower, quassia, rauwolfia, Siberian ginseng, taumelloolch, tulip tree, and valerian.

A nonpharmacologic approach is the best and safest course for pregnant patients with insomnia. If medications are required, occasional, short-term use is recommended; one of the OTC antihistamines is probably best. A nonbenzodiazepine agent, such as zolpidem would be my second choice. For more information, visit www.babycenter.com

The physical discomforts of pregnancy induced by the surge of progesterone and the expanding uterus can result in sleep deprivation in pregnancy. An increased need to urinate, nausea and vomiting, heartburn, difficulty in finding a comfortable sleeping position, and, as the pregnancy progresses, the kicking and movement of the fetus, all conspire against a good night's sleep.

Prescribing sleeping medications in pregnancy may not be the best solution because long-term use can lead to habituation in the woman and her fetus. But patients often seek drug therapy to help them sleep, so it is essential to know what is relatively safe and what is not. Hypnotics fall into five subclasses:

▸ Oral barbiturates. Included in this group are aprobarbital (pregnancy risk factor C) (Alurate); pentobarbital (D) (Nembutal); and secobarbital (D) (Seconal). Developmental toxicity has not been proven, but more studies are needed regarding the potential for behavioral toxicity after long-term in utero exposure. Their long elimination half-lives (24, 22–50, and 28 hours, respectively) can cause prolonged sedation, or hangover. They are controlled substances with potential for abuse, which makes them more difficult to prescribe. Although they are excreted into milk in low amounts, they can be classified as compatible with breast-feeding.

▸ Benzodiazepines. Estazolam (ProSom), flurazepam (Dalmane), quazepam (Doral), and temazepam (Restoril) are in this category. Data on using these agents in pregnancy are limited. Although there has been no proven association between any of these agents and birth defects, they probably have effects on the embryo or fetus similar to diazepam (Valium), including neonatal motor depression (floppy infant syndrome) and/or withdrawal if used in the third trimester. Moreover, all four agents are categorized as contraindicated (risk factor X) by their manufacturers, so they should not be prescribed. Small amounts of quazepam and temazepam are excreted into milk, and the other two agents are most likely in milk as well. Occasional dosing during breast-feeding is probably safe, but the long-term effects on a nursing infant are unknown.

▸ Nonbenzodiazepines. There are five drugs in this category: chloral hydrate (for example, Somnote), ramelteon (Rozerem), zaleplon (Sonata), and low-dose (25–75 mg) trazodone (Desyrel), all risk factor C, and zolpidem (Ambien), risk factor B. The use for sleep of the antidepressant trazodone is off label, but the drug is sometimes combined with other antidepressants for this purpose. As with the benzodiazepines, the human pregnancy data are limited or nonexistent. There are no animal data for chloral hydrate, an old product that is now rarely used, but animal data on the other nonbenzodiazepines suggest low risk in pregnancy. But, as with most drugs, the best course is to avoid them in the first trimester. Occasional use in the second and third trimesters probably is low risk, but long-term use (more than 4 weeks) should be avoided. Small amounts of these drugs are excreted into milk, but occasional, short-term use probably is compatible with breast-feeding.

▸ OTC antihistamines. There are two in this category, diphenhydramine (such as Benadryl), and doxylamine (Unisom Nighttime Sleep Aid). Di- phenhydramine (risk factor B) is safe throughout gestation, as is doxylamine (risk factor A). A major advantage of these antihistamines is that both have antiemetic properties that can reduce pregnancy-induced nausea and vomiting. If pyridoxine (vitamin B6) is taken with doxylamine, the combination is the antiemetic most frequently studied in pregnancy. There is little or no experience with these agents during lactation. Although some manufacturers consider them contraindicated during breast-feeding, the lack of toxicity reports suggests these antihistamines probably are low risk for full-term nursing infants.

▸ Natural products. About 50 natural products are or have been advocated for sleep, but few have enough data to recommend their use in pregnancy or lactation. Moreover, the content and purity of natural products are often unregulated.

Natural agents that seem to be low risk are ginseng (not Siberian), honey, nutmeg, oats, and St. John's wort. But note that ginseng can cause hypertension and hypoglycemia. Agents to be avoided include American hellebore, butterbur or other petasites, kava, marijuana, melatonin (available only as an orphan drug in the United States), mugwort, passion flower, quassia, rauwolfia, Siberian ginseng, taumelloolch, tulip tree, and valerian.

A nonpharmacologic approach is the best and safest course for pregnant patients with insomnia. If medications are required, occasional, short-term use is recommended; one of the OTC antihistamines is probably best. A nonbenzodiazepine agent, such as zolpidem would be my second choice. For more information, visit www.babycenter.com

The physical discomforts of pregnancy induced by the surge of progesterone and the expanding uterus can result in sleep deprivation in pregnancy. An increased need to urinate, nausea and vomiting, heartburn, difficulty in finding a comfortable sleeping position, and, as the pregnancy progresses, the kicking and movement of the fetus, all conspire against a good night's sleep.

Prescribing sleeping medications in pregnancy may not be the best solution because long-term use can lead to habituation in the woman and her fetus. But patients often seek drug therapy to help them sleep, so it is essential to know what is relatively safe and what is not. Hypnotics fall into five subclasses:

▸ Oral barbiturates. Included in this group are aprobarbital (pregnancy risk factor C) (Alurate); pentobarbital (D) (Nembutal); and secobarbital (D) (Seconal). Developmental toxicity has not been proven, but more studies are needed regarding the potential for behavioral toxicity after long-term in utero exposure. Their long elimination half-lives (24, 22–50, and 28 hours, respectively) can cause prolonged sedation, or hangover. They are controlled substances with potential for abuse, which makes them more difficult to prescribe. Although they are excreted into milk in low amounts, they can be classified as compatible with breast-feeding.

▸ Benzodiazepines. Estazolam (ProSom), flurazepam (Dalmane), quazepam (Doral), and temazepam (Restoril) are in this category. Data on using these agents in pregnancy are limited. Although there has been no proven association between any of these agents and birth defects, they probably have effects on the embryo or fetus similar to diazepam (Valium), including neonatal motor depression (floppy infant syndrome) and/or withdrawal if used in the third trimester. Moreover, all four agents are categorized as contraindicated (risk factor X) by their manufacturers, so they should not be prescribed. Small amounts of quazepam and temazepam are excreted into milk, and the other two agents are most likely in milk as well. Occasional dosing during breast-feeding is probably safe, but the long-term effects on a nursing infant are unknown.

▸ Nonbenzodiazepines. There are five drugs in this category: chloral hydrate (for example, Somnote), ramelteon (Rozerem), zaleplon (Sonata), and low-dose (25–75 mg) trazodone (Desyrel), all risk factor C, and zolpidem (Ambien), risk factor B. The use for sleep of the antidepressant trazodone is off label, but the drug is sometimes combined with other antidepressants for this purpose. As with the benzodiazepines, the human pregnancy data are limited or nonexistent. There are no animal data for chloral hydrate, an old product that is now rarely used, but animal data on the other nonbenzodiazepines suggest low risk in pregnancy. But, as with most drugs, the best course is to avoid them in the first trimester. Occasional use in the second and third trimesters probably is low risk, but long-term use (more than 4 weeks) should be avoided. Small amounts of these drugs are excreted into milk, but occasional, short-term use probably is compatible with breast-feeding.

▸ OTC antihistamines. There are two in this category, diphenhydramine (such as Benadryl), and doxylamine (Unisom Nighttime Sleep Aid). Di- phenhydramine (risk factor B) is safe throughout gestation, as is doxylamine (risk factor A). A major advantage of these antihistamines is that both have antiemetic properties that can reduce pregnancy-induced nausea and vomiting. If pyridoxine (vitamin B6) is taken with doxylamine, the combination is the antiemetic most frequently studied in pregnancy. There is little or no experience with these agents during lactation. Although some manufacturers consider them contraindicated during breast-feeding, the lack of toxicity reports suggests these antihistamines probably are low risk for full-term nursing infants.

▸ Natural products. About 50 natural products are or have been advocated for sleep, but few have enough data to recommend their use in pregnancy or lactation. Moreover, the content and purity of natural products are often unregulated.

Natural agents that seem to be low risk are ginseng (not Siberian), honey, nutmeg, oats, and St. John's wort. But note that ginseng can cause hypertension and hypoglycemia. Agents to be avoided include American hellebore, butterbur or other petasites, kava, marijuana, melatonin (available only as an orphan drug in the United States), mugwort, passion flower, quassia, rauwolfia, Siberian ginseng, taumelloolch, tulip tree, and valerian.

A nonpharmacologic approach is the best and safest course for pregnant patients with insomnia. If medications are required, occasional, short-term use is recommended; one of the OTC antihistamines is probably best. A nonbenzodiazepine agent, such as zolpidem would be my second choice. For more information, visit www.babycenter.com

Vaccines have arguably saved more lives and prevented more diseases than any other class of drug. The American College of Obstetricians and Gynecologists states that vaccination before conception is preferred to vaccination during pregnancy, but the benefits of immunization to the pregnant woman usually outweigh the theoretical risks (Committee Opinion, No. 282, January 2003). Only vaccines recommended for adults of reproductive age are included in the following discussion.

Vaccines are classified as bacterial or viral; whole (killed, inactivated, or live attenuated); or partial microorganisms that can induce antibody formation. Although these vaccines can cause infections of the embryo or fetus, and pregnant women should be informed of the presence of live organisms if they are given a live attenuated virus vaccine, there is no convincing evidence that any vaccine, bacterial or viral, has caused fetal or embryonic harm. Theoretically, however, live attenuated bacterial or viral vaccines could cause disseminated infection in pregnant patients with impaired immunity, such as those with HIV or AIDS.

Indications for two bacterial vaccines (both capsular polysaccharide—quadrivalent meningococcal and polyvalent pneumococcal) are not altered by pregnancy. Vaccinating a pregnant woman with the live attenuated BCG vaccine is generally not recommended, but may be indicated if the woman works in a setting where many patients are infected with resistant strains of TB.

There are two typhoid vaccines available. The oral live attenuated virus vaccine is not recommended during pregnancy, except in cases of the prospective mother's continued, close exposure or travel to typhoid-endemic areas. However, the capsular polysaccharide intramuscular vaccine should be safer in pregnancy because it does not contain live bacteria.

Live attenuated virus vaccines are normally contraindicated in pregnant women because of the known or potential risks from the wild viruses. These include influenza intranasal, measles, mumps, rubella, smallpox, varicella, and yellow fever. Vaccinating in the postpartum period or avoiding conception for at least 30 days after inoculation are two strategies to avoid exposure during pregnancy.

A live attenuated virus vaccine may be indicated in pregnancy under special circumstances. For example, because the risk of fetal vaccinia is low, smallpox vaccine is recommended for pregnant women exposed to smallpox or monkeypox. Yellow fever vaccine also should be given in pregnancy if exposure is unavoidable.

Rubella infection occurring early in gestation is known to cause congenital rubella syndrome. Over a 10-year period, nearly 700 pregnant women were given rubella vaccine. There was no evidence of embryonic/fetal adverse effects, but subclinical infection was found in 2% of the infants from susceptible mothers. A woman given the vaccine 3 weeks after conception had documented embryonic/fetal infection throughout gestation but still delivered a healthy infant.

Although contraindicated, varicella vaccine is thought to present much less risk to the embryo and fetus than from infection with the wild virus. In a pregnancy registry involving more than 800 women who had been vaccinated within 3 months of or anytime during pregnancy, there was no evidence of congenital varicella syndrome (CVS) or malformations consistent with CVS.

Inactivated poliovirus vaccine is not routinely recommended for adults living in the United States; however, it is recommended for unimmunized adults in close contact with a child receiving oral polio vaccine (OPV, which is not available in United States) or who have an increased risk of exposure to OPV or wild poliovirus. Hepatitis A (inactivated) and hepatitis B (recombinant surface antigen) vaccines can be used in pregnancy for pre- and postexposure in women at risk of infection.

The indications for rabies vaccine (killed virus) are not altered by pregnancy. In a prospective study, the vaccine was given to 202 pregnant women who had been exposed to rabies. No increase in maternal or fetal complications was observed, compared with nonexposed controls. There also does not appear to be an increased risk to the embryo or fetus from vaccination within 30 days of conception with quadrivalent human papillomavirus (HPV) recombinant vaccine

However, if pregnancy is detected, ACOG recommends delaying completion of the three-dose vaccination schedule until pregnancy is completed (Committee Opinion, No. 344, September 2006).

Vaccination with inactivated influenza vaccine is considered by ACOG to be an essential element of prenatal care (Committee Opinion, No. 305, November 2004). The vaccine can be given at any time during pregnancy. However, the intranasal influenza vaccine, a live attenuated virus preparation, should not be used in pregnancy.

Excretion of live viruses from vaccines into breast milk may occur. There is a report of tertiary contact vaccinia transmission for smallpox vaccine from a mother to her nursing infant. The effects of the other live virus vaccines on a nursing infant are unknown, but the risk of adverse effects appears to be very low. Vaccines that do not contain live viruses probably carry no risk to the infant.

Pregnancy registries exist for four vaccines. Health care professionals are encouraged to report exposures of pregnant women to the appropriate registry: hepatitis B vaccine (800-670-6126); HPV vaccine (800-986-8999); meningococcal vaccine (800-822-2463); and varicella vaccine (800-986-8999)

Vaccines have arguably saved more lives and prevented more diseases than any other class of drug. The American College of Obstetricians and Gynecologists states that vaccination before conception is preferred to vaccination during pregnancy, but the benefits of immunization to the pregnant woman usually outweigh the theoretical risks (Committee Opinion, No. 282, January 2003). Only vaccines recommended for adults of reproductive age are included in the following discussion.

Vaccines are classified as bacterial or viral; whole (killed, inactivated, or live attenuated); or partial microorganisms that can induce antibody formation. Although these vaccines can cause infections of the embryo or fetus, and pregnant women should be informed of the presence of live organisms if they are given a live attenuated virus vaccine, there is no convincing evidence that any vaccine, bacterial or viral, has caused fetal or embryonic harm. Theoretically, however, live attenuated bacterial or viral vaccines could cause disseminated infection in pregnant patients with impaired immunity, such as those with HIV or AIDS.

Indications for two bacterial vaccines (both capsular polysaccharide—quadrivalent meningococcal and polyvalent pneumococcal) are not altered by pregnancy. Vaccinating a pregnant woman with the live attenuated BCG vaccine is generally not recommended, but may be indicated if the woman works in a setting where many patients are infected with resistant strains of TB.

There are two typhoid vaccines available. The oral live attenuated virus vaccine is not recommended during pregnancy, except in cases of the prospective mother's continued, close exposure or travel to typhoid-endemic areas. However, the capsular polysaccharide intramuscular vaccine should be safer in pregnancy because it does not contain live bacteria.

Live attenuated virus vaccines are normally contraindicated in pregnant women because of the known or potential risks from the wild viruses. These include influenza intranasal, measles, mumps, rubella, smallpox, varicella, and yellow fever. Vaccinating in the postpartum period or avoiding conception for at least 30 days after inoculation are two strategies to avoid exposure during pregnancy.

A live attenuated virus vaccine may be indicated in pregnancy under special circumstances. For example, because the risk of fetal vaccinia is low, smallpox vaccine is recommended for pregnant women exposed to smallpox or monkeypox. Yellow fever vaccine also should be given in pregnancy if exposure is unavoidable.

Rubella infection occurring early in gestation is known to cause congenital rubella syndrome. Over a 10-year period, nearly 700 pregnant women were given rubella vaccine. There was no evidence of embryonic/fetal adverse effects, but subclinical infection was found in 2% of the infants from susceptible mothers. A woman given the vaccine 3 weeks after conception had documented embryonic/fetal infection throughout gestation but still delivered a healthy infant.

Although contraindicated, varicella vaccine is thought to present much less risk to the embryo and fetus than from infection with the wild virus. In a pregnancy registry involving more than 800 women who had been vaccinated within 3 months of or anytime during pregnancy, there was no evidence of congenital varicella syndrome (CVS) or malformations consistent with CVS.

Inactivated poliovirus vaccine is not routinely recommended for adults living in the United States; however, it is recommended for unimmunized adults in close contact with a child receiving oral polio vaccine (OPV, which is not available in United States) or who have an increased risk of exposure to OPV or wild poliovirus. Hepatitis A (inactivated) and hepatitis B (recombinant surface antigen) vaccines can be used in pregnancy for pre- and postexposure in women at risk of infection.

The indications for rabies vaccine (killed virus) are not altered by pregnancy. In a prospective study, the vaccine was given to 202 pregnant women who had been exposed to rabies. No increase in maternal or fetal complications was observed, compared with nonexposed controls. There also does not appear to be an increased risk to the embryo or fetus from vaccination within 30 days of conception with quadrivalent human papillomavirus (HPV) recombinant vaccine

However, if pregnancy is detected, ACOG recommends delaying completion of the three-dose vaccination schedule until pregnancy is completed (Committee Opinion, No. 344, September 2006).

Vaccination with inactivated influenza vaccine is considered by ACOG to be an essential element of prenatal care (Committee Opinion, No. 305, November 2004). The vaccine can be given at any time during pregnancy. However, the intranasal influenza vaccine, a live attenuated virus preparation, should not be used in pregnancy.

Excretion of live viruses from vaccines into breast milk may occur. There is a report of tertiary contact vaccinia transmission for smallpox vaccine from a mother to her nursing infant. The effects of the other live virus vaccines on a nursing infant are unknown, but the risk of adverse effects appears to be very low. Vaccines that do not contain live viruses probably carry no risk to the infant.

Pregnancy registries exist for four vaccines. Health care professionals are encouraged to report exposures of pregnant women to the appropriate registry: hepatitis B vaccine (800-670-6126); HPV vaccine (800-986-8999); meningococcal vaccine (800-822-2463); and varicella vaccine (800-986-8999)

Vaccines have arguably saved more lives and prevented more diseases than any other class of drug. The American College of Obstetricians and Gynecologists states that vaccination before conception is preferred to vaccination during pregnancy, but the benefits of immunization to the pregnant woman usually outweigh the theoretical risks (Committee Opinion, No. 282, January 2003). Only vaccines recommended for adults of reproductive age are included in the following discussion.

Vaccines are classified as bacterial or viral; whole (killed, inactivated, or live attenuated); or partial microorganisms that can induce antibody formation. Although these vaccines can cause infections of the embryo or fetus, and pregnant women should be informed of the presence of live organisms if they are given a live attenuated virus vaccine, there is no convincing evidence that any vaccine, bacterial or viral, has caused fetal or embryonic harm. Theoretically, however, live attenuated bacterial or viral vaccines could cause disseminated infection in pregnant patients with impaired immunity, such as those with HIV or AIDS.

Indications for two bacterial vaccines (both capsular polysaccharide—quadrivalent meningococcal and polyvalent pneumococcal) are not altered by pregnancy. Vaccinating a pregnant woman with the live attenuated BCG vaccine is generally not recommended, but may be indicated if the woman works in a setting where many patients are infected with resistant strains of TB.

There are two typhoid vaccines available. The oral live attenuated virus vaccine is not recommended during pregnancy, except in cases of the prospective mother's continued, close exposure or travel to typhoid-endemic areas. However, the capsular polysaccharide intramuscular vaccine should be safer in pregnancy because it does not contain live bacteria.

Live attenuated virus vaccines are normally contraindicated in pregnant women because of the known or potential risks from the wild viruses. These include influenza intranasal, measles, mumps, rubella, smallpox, varicella, and yellow fever. Vaccinating in the postpartum period or avoiding conception for at least 30 days after inoculation are two strategies to avoid exposure during pregnancy.

A live attenuated virus vaccine may be indicated in pregnancy under special circumstances. For example, because the risk of fetal vaccinia is low, smallpox vaccine is recommended for pregnant women exposed to smallpox or monkeypox. Yellow fever vaccine also should be given in pregnancy if exposure is unavoidable.

Rubella infection occurring early in gestation is known to cause congenital rubella syndrome. Over a 10-year period, nearly 700 pregnant women were given rubella vaccine. There was no evidence of embryonic/fetal adverse effects, but subclinical infection was found in 2% of the infants from susceptible mothers. A woman given the vaccine 3 weeks after conception had documented embryonic/fetal infection throughout gestation but still delivered a healthy infant.

Although contraindicated, varicella vaccine is thought to present much less risk to the embryo and fetus than from infection with the wild virus. In a pregnancy registry involving more than 800 women who had been vaccinated within 3 months of or anytime during pregnancy, there was no evidence of congenital varicella syndrome (CVS) or malformations consistent with CVS.

Inactivated poliovirus vaccine is not routinely recommended for adults living in the United States; however, it is recommended for unimmunized adults in close contact with a child receiving oral polio vaccine (OPV, which is not available in United States) or who have an increased risk of exposure to OPV or wild poliovirus. Hepatitis A (inactivated) and hepatitis B (recombinant surface antigen) vaccines can be used in pregnancy for pre- and postexposure in women at risk of infection.

The indications for rabies vaccine (killed virus) are not altered by pregnancy. In a prospective study, the vaccine was given to 202 pregnant women who had been exposed to rabies. No increase in maternal or fetal complications was observed, compared with nonexposed controls. There also does not appear to be an increased risk to the embryo or fetus from vaccination within 30 days of conception with quadrivalent human papillomavirus (HPV) recombinant vaccine

However, if pregnancy is detected, ACOG recommends delaying completion of the three-dose vaccination schedule until pregnancy is completed (Committee Opinion, No. 344, September 2006).

Vaccination with inactivated influenza vaccine is considered by ACOG to be an essential element of prenatal care (Committee Opinion, No. 305, November 2004). The vaccine can be given at any time during pregnancy. However, the intranasal influenza vaccine, a live attenuated virus preparation, should not be used in pregnancy.

Excretion of live viruses from vaccines into breast milk may occur. There is a report of tertiary contact vaccinia transmission for smallpox vaccine from a mother to her nursing infant. The effects of the other live virus vaccines on a nursing infant are unknown, but the risk of adverse effects appears to be very low. Vaccines that do not contain live viruses probably carry no risk to the infant.

Pregnancy registries exist for four vaccines. Health care professionals are encouraged to report exposures of pregnant women to the appropriate registry: hepatitis B vaccine (800-670-6126); HPV vaccine (800-986-8999); meningococcal vaccine (800-822-2463); and varicella vaccine (800-986-8999)

Vaccines have arguably saved more lives and prevented more diseases than any other class of drug. The American College of Obstetricians and Gynecologists states that vaccination before conception is preferred to vaccination during pregnancy, but the benefits of immunization to the pregnant woman usually outweigh the theoretical risks (Committee Opinion, No. 282, January 2003). Only vaccines recommended for adults of reproductive age are discussed here.

Vaccines are classified as bacterial or viral; whole (killed, inactivated, or live attenuated); or partial microorganisms that can induce antibody formation. Although vaccines can cause infections of the embryo or fetus, and pregnant women should be informed of the presence of live organisms if they are given a live attenuated virus vaccine, there is no convincing evidence that any vaccine, bacterial or viral, has caused fetal or embryonic harm. Theoretically, however, live attenuated bacterial or viral vaccines could cause disseminated infection in pregnant patients with impaired immunity, such as those with HIV or AIDS.

Indications for two bacterial vaccines (both capsular polysaccharide-quadrivalent meningococcal and polyvalent pneumococcal) are not altered by pregnancy. Vaccinating a pregnant woman with the live attenuated BCG vaccine is not recommended, but may be indicated if the woman works in a setting where many patients are infected with resistant strains of TB.

There are two typhoid vaccines available. The oral live attenuated virus vaccine is not advised during pregnancy, except when the mother's in continued, close exposure or travels to typhoid-endemic areas. The capsular polysaccharide intramuscular vaccine should be safer in pregnancy because it does not contain live bacteria.

Live attenuated virus vaccines are normally contraindicated in pregnant women because of the known or potential risks from the wild viruses. These include influenza intranasal, measles, mumps, rubella, smallpox, varicella, and yellow fever. Vaccinating in the postpartum period or avoiding conception for at least 30 days after inoculation are two strategies to avoid exposure during pregnancy.

A live attenuated virus vaccine may be indicated in pregnancy under special circumstances. For example, because the risk of fetal vaccinia is low, smallpox vaccine is recommended for pregnant women exposed to smallpox or monkeypox. Yellow fever vaccine also should be given in pregnancy if exposure is unavoidable.

Rubella infection early in gestation causes congenital rubella syndrome. Over a 10-year period, nearly 700 pregnant women were given rubella vaccine. There was no evidence of embryonic/fetal adverse effects, but subclinical infection was found in 2% of the infants from susceptible mothers. A woman given the vaccine 3 weeks after conception had documented embryonic/fetal infection throughout gestation but still delivered a healthy infant.

Though contraindicated, varicella vaccine may present less risk to the embryo and fetus than from infection with the wild virus. In a pregnancy registry of more than 800 women who had been vaccinated within 3 months of or anytime during pregnancy, there was no evidence of congenital varicella syndrome (CVS) or mal- formations consistent with it.

Inactivated poliovirus vaccine is not routinely recommended for adults living in the United States; however, it is recommended for unimmunized adults in close contact with a child receiving oral polio vaccine (OPV, which is not available in United States) or who have an increased risk of exposure to OPV or wild poliovirus. Hepatitis A (inactivated) and hepatitis B (recombinant surface antigen) vaccines can be used in pregnancy for pre- and postexposure in women at risk of infection.

The indications for rabies vaccine (killed virus) are not altered by pregnancy. There also seems to be no increased risk to the embryo or fetus from vaccination within 30 days of conception with quadrivalent human papillomavirus (HPV) recombinant vaccine. But if pregnancy is detected, ACOG suggests delaying completion of the three-dose vaccination schedule until after the pregnancy (Committee Opinion, No. 344, September 2006).

The ACOGconsiders vaccination with inactivated influenza vaccine to be an essential element of prenatal care (Committee Opinion, No. 305, November 2004). The vaccine can be given at any time during pregnancy, but the intranasal influenza vaccine, a live attenuated virus preparation, should not be used in pregnancy.

Excretion of live viruses from vaccines into breast milk may occur. There is a report of tertiary contact vaccinia transmission for smallpox vaccine from a mother to her nursing infant. The effects of the other live virus vaccines on a nursing infant are unknown, but the risk of adverse effects seems to be low. Vaccines that do not contain live viruses probably carry no risk to the infant.

There are pregnancy registries for four vaccines. Health care professionals should report exposures of pregnant women to the appropriate registry: hepatitis B vaccine (800-670-6126); HPV vaccine (800-986-8999); meningococcal vaccine (800-822-2463); and varicella vaccine (800-986-8999).

Vaccines have arguably saved more lives and prevented more diseases than any other class of drug. The American College of Obstetricians and Gynecologists states that vaccination before conception is preferred to vaccination during pregnancy, but the benefits of immunization to the pregnant woman usually outweigh the theoretical risks (Committee Opinion, No. 282, January 2003). Only vaccines recommended for adults of reproductive age are discussed here.

Vaccines are classified as bacterial or viral; whole (killed, inactivated, or live attenuated); or partial microorganisms that can induce antibody formation. Although vaccines can cause infections of the embryo or fetus, and pregnant women should be informed of the presence of live organisms if they are given a live attenuated virus vaccine, there is no convincing evidence that any vaccine, bacterial or viral, has caused fetal or embryonic harm. Theoretically, however, live attenuated bacterial or viral vaccines could cause disseminated infection in pregnant patients with impaired immunity, such as those with HIV or AIDS.

Indications for two bacterial vaccines (both capsular polysaccharide-quadrivalent meningococcal and polyvalent pneumococcal) are not altered by pregnancy. Vaccinating a pregnant woman with the live attenuated BCG vaccine is not recommended, but may be indicated if the woman works in a setting where many patients are infected with resistant strains of TB.

There are two typhoid vaccines available. The oral live attenuated virus vaccine is not advised during pregnancy, except when the mother's in continued, close exposure or travels to typhoid-endemic areas. The capsular polysaccharide intramuscular vaccine should be safer in pregnancy because it does not contain live bacteria.

Live attenuated virus vaccines are normally contraindicated in pregnant women because of the known or potential risks from the wild viruses. These include influenza intranasal, measles, mumps, rubella, smallpox, varicella, and yellow fever. Vaccinating in the postpartum period or avoiding conception for at least 30 days after inoculation are two strategies to avoid exposure during pregnancy.

A live attenuated virus vaccine may be indicated in pregnancy under special circumstances. For example, because the risk of fetal vaccinia is low, smallpox vaccine is recommended for pregnant women exposed to smallpox or monkeypox. Yellow fever vaccine also should be given in pregnancy if exposure is unavoidable.

Rubella infection early in gestation causes congenital rubella syndrome. Over a 10-year period, nearly 700 pregnant women were given rubella vaccine. There was no evidence of embryonic/fetal adverse effects, but subclinical infection was found in 2% of the infants from susceptible mothers. A woman given the vaccine 3 weeks after conception had documented embryonic/fetal infection throughout gestation but still delivered a healthy infant.

Though contraindicated, varicella vaccine may present less risk to the embryo and fetus than from infection with the wild virus. In a pregnancy registry of more than 800 women who had been vaccinated within 3 months of or anytime during pregnancy, there was no evidence of congenital varicella syndrome (CVS) or mal- formations consistent with it.

Inactivated poliovirus vaccine is not routinely recommended for adults living in the United States; however, it is recommended for unimmunized adults in close contact with a child receiving oral polio vaccine (OPV, which is not available in United States) or who have an increased risk of exposure to OPV or wild poliovirus. Hepatitis A (inactivated) and hepatitis B (recombinant surface antigen) vaccines can be used in pregnancy for pre- and postexposure in women at risk of infection.

The indications for rabies vaccine (killed virus) are not altered by pregnancy. There also seems to be no increased risk to the embryo or fetus from vaccination within 30 days of conception with quadrivalent human papillomavirus (HPV) recombinant vaccine. But if pregnancy is detected, ACOG suggests delaying completion of the three-dose vaccination schedule until after the pregnancy (Committee Opinion, No. 344, September 2006).

The ACOGconsiders vaccination with inactivated influenza vaccine to be an essential element of prenatal care (Committee Opinion, No. 305, November 2004). The vaccine can be given at any time during pregnancy, but the intranasal influenza vaccine, a live attenuated virus preparation, should not be used in pregnancy.

Excretion of live viruses from vaccines into breast milk may occur. There is a report of tertiary contact vaccinia transmission for smallpox vaccine from a mother to her nursing infant. The effects of the other live virus vaccines on a nursing infant are unknown, but the risk of adverse effects seems to be low. Vaccines that do not contain live viruses probably carry no risk to the infant.

There are pregnancy registries for four vaccines. Health care professionals should report exposures of pregnant women to the appropriate registry: hepatitis B vaccine (800-670-6126); HPV vaccine (800-986-8999); meningococcal vaccine (800-822-2463); and varicella vaccine (800-986-8999).

Vaccines have arguably saved more lives and prevented more diseases than any other class of drug. The American College of Obstetricians and Gynecologists states that vaccination before conception is preferred to vaccination during pregnancy, but the benefits of immunization to the pregnant woman usually outweigh the theoretical risks (Committee Opinion, No. 282, January 2003). Only vaccines recommended for adults of reproductive age are discussed here.

Vaccines are classified as bacterial or viral; whole (killed, inactivated, or live attenuated); or partial microorganisms that can induce antibody formation. Although vaccines can cause infections of the embryo or fetus, and pregnant women should be informed of the presence of live organisms if they are given a live attenuated virus vaccine, there is no convincing evidence that any vaccine, bacterial or viral, has caused fetal or embryonic harm. Theoretically, however, live attenuated bacterial or viral vaccines could cause disseminated infection in pregnant patients with impaired immunity, such as those with HIV or AIDS.

Indications for two bacterial vaccines (both capsular polysaccharide-quadrivalent meningococcal and polyvalent pneumococcal) are not altered by pregnancy. Vaccinating a pregnant woman with the live attenuated BCG vaccine is not recommended, but may be indicated if the woman works in a setting where many patients are infected with resistant strains of TB.

There are two typhoid vaccines available. The oral live attenuated virus vaccine is not advised during pregnancy, except when the mother's in continued, close exposure or travels to typhoid-endemic areas. The capsular polysaccharide intramuscular vaccine should be safer in pregnancy because it does not contain live bacteria.

Live attenuated virus vaccines are normally contraindicated in pregnant women because of the known or potential risks from the wild viruses. These include influenza intranasal, measles, mumps, rubella, smallpox, varicella, and yellow fever. Vaccinating in the postpartum period or avoiding conception for at least 30 days after inoculation are two strategies to avoid exposure during pregnancy.

A live attenuated virus vaccine may be indicated in pregnancy under special circumstances. For example, because the risk of fetal vaccinia is low, smallpox vaccine is recommended for pregnant women exposed to smallpox or monkeypox. Yellow fever vaccine also should be given in pregnancy if exposure is unavoidable.

Rubella infection early in gestation causes congenital rubella syndrome. Over a 10-year period, nearly 700 pregnant women were given rubella vaccine. There was no evidence of embryonic/fetal adverse effects, but subclinical infection was found in 2% of the infants from susceptible mothers. A woman given the vaccine 3 weeks after conception had documented embryonic/fetal infection throughout gestation but still delivered a healthy infant.

Though contraindicated, varicella vaccine may present less risk to the embryo and fetus than from infection with the wild virus. In a pregnancy registry of more than 800 women who had been vaccinated within 3 months of or anytime during pregnancy, there was no evidence of congenital varicella syndrome (CVS) or mal- formations consistent with it.

Inactivated poliovirus vaccine is not routinely recommended for adults living in the United States; however, it is recommended for unimmunized adults in close contact with a child receiving oral polio vaccine (OPV, which is not available in United States) or who have an increased risk of exposure to OPV or wild poliovirus. Hepatitis A (inactivated) and hepatitis B (recombinant surface antigen) vaccines can be used in pregnancy for pre- and postexposure in women at risk of infection.

The indications for rabies vaccine (killed virus) are not altered by pregnancy. There also seems to be no increased risk to the embryo or fetus from vaccination within 30 days of conception with quadrivalent human papillomavirus (HPV) recombinant vaccine. But if pregnancy is detected, ACOG suggests delaying completion of the three-dose vaccination schedule until after the pregnancy (Committee Opinion, No. 344, September 2006).

The ACOGconsiders vaccination with inactivated influenza vaccine to be an essential element of prenatal care (Committee Opinion, No. 305, November 2004). The vaccine can be given at any time during pregnancy, but the intranasal influenza vaccine, a live attenuated virus preparation, should not be used in pregnancy.

Excretion of live viruses from vaccines into breast milk may occur. There is a report of tertiary contact vaccinia transmission for smallpox vaccine from a mother to her nursing infant. The effects of the other live virus vaccines on a nursing infant are unknown, but the risk of adverse effects seems to be low. Vaccines that do not contain live viruses probably carry no risk to the infant.

There are pregnancy registries for four vaccines. Health care professionals should report exposures of pregnant women to the appropriate registry: hepatitis B vaccine (800-670-6126); HPV vaccine (800-986-8999); meningococcal vaccine (800-822-2463); and varicella vaccine (800-986-8999).

Both prescription and over-the-counter nonsteroidal anti-inflammatory drugs are frequently used in pregnancy, including during the first trimester. When used around the time of conception, there is evidence that NSAIDs impair fertility by interfering with blastocyst implantation, resulting in spontaneous abortions.

Exposure to these agents in the latter part of the second trimester and throughout the third is known to cause functional toxicity in the fetus and newborn consisting of renal impairment, oligohydramnios, premature closure of the ductus arteriosus, and primary pulmonary hypertension of the newborn. Increased risks for other toxicities—such as intraventricular hemorrhage, necrotizing enterocolitis, patent ductus arteriosus requiring ligation, platelet dysfunction, and gastrointestinal bleeding—have been reported in association with prenatal exposure to NSAIDs, but a causative role has not yet been proved.

When used in the first 3 months of gestation, there have been conflicting reports associating the use of NSAIDs with structural anomalies. However, a Canadian study published in September has strengthened the argument that NSAIDs can cause birth defects, particularly cardiac septal defects. In the following discussion, the evidence for and against this association is examined:

▸ A large observational cohort study conducted in Denmark compared the outcomes of 1,106 pregnancies exposed to NSAIDs in the first trimester with 17,529 controls and found no significant association between NSAID use during pregnancy and congenital defects (BMJ 2001;322:266–70). A weakness of this study was that it included only women who had received an NSAID prescribed at doses equivalent to 400 mg or 600 mg of ibuprofen. The study did not identify women who might have taken NSAIDs that were available as OTC products at doses equivalent to 200 mg of ibuprofen.

▸ A Food and Drug Administration analysis of Michigan Medicaid data on a large number of women exposed in the first trimester to three NSAIDs between 1985 and 1992 found no evidence of an increased risk of cardiac or orofacial defects for any of the drugs. There were 19 birth defects among the 258 women (7.4%) exposed to diflunisal, 143 birth defects among the 3,178 women (4.5%) exposed to ibuprofen, and 70 birth defects among the 1,448 women (4.8%) exposed to naproxen. These rates were higher than the expected number of birth defects (10, 129, and 62, respectively), but these types of studies only raise hypotheses and cannot show causation (Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 5th ed. Baltimore: Williams & Wilkins, 1998: ix).

▸ A 2001 prospective observational cohort study that examined the relationship between first-trimester exposure to NSAIDs in 2,557 women and congenital defects found no association with birth defects in general. However, significant associations with cardiac defects and orofacial clefts were noted: There were 36 cardiac defects, representing an odds ratio of 1.86, and 8 orofacial defects, an odds ratio of 2.81. Both were statistically significant increases over the expected rates (Reprod. Toxicol. 2001;15:371–5).

▸ A 2003 study using data from Swedish health registers of 1,142 infants with orofacial clefts (isolated or nonisolated) found a greater risk associated with naproxen exposure. Compared to the expected number (2.9), 8 of the infants had been exposed to naproxen, a relative risk of 2.72 (Cleft Palate Craniofac. J. 2003;40:624–8).

Another study identified 5,015 infants in the same registry with cardiovascular defects, and compared them with 577,730 controls, finding no significant association when all NSAIDs were grouped together or with individual agents, with the exception of naproxen. Among babies born to 1,679 naproxen-exposed women, 24 had cardiovascular defects, a statistically significant odds ratio of 1.7 (Reprod. Toxicol. 2003;17:255–61).

▸ A case-control study conducted in Quebec found a significant association between congenital anomalies, specifically cardiac septal defects, and the use of NSAIDs in the first trimester. Case infants were those with any congenital anomaly diagnosed in the first year of life, who were matched with up to 10 controls (infants without a congenital anomaly) for maternal age, urban or rural residence, gestational age, and diabetes status.

There were 93 infants (8.8%) with congenital anomalies born to 1,056 mothers who had filled prescriptions for NSAIDs in the first trimester. Among controls, there were 2,478 infants (7%) with anomalies born to 35,331 mothers. Among women who had filled a prescription for an NSAID during the first trimester, the adjusted odds ratio for any congenital anomaly was 2.21, and the adjusted odds ratio for cardiac septal closure was 3.34. Both odds ratios were statistically significant. There were no significant associations for oral clefts or defects involving other major organ systems.

The five NSAIDs most commonly used by these women were naproxen (35%), ibuprofen (26%), rofecoxib (15%), diclofenac (9%), and celecoxib (9%). The only statistically significant association was between ibuprofen prescriptions in the first trimester and congenital defects (Birth Defects Res. B. Dev. Reprod. Toxicol. 2006;77:268–79).

Taken in sum, the data from these studies provide increasingly convincing evidence that NSAIDs are human teratogens, especially for cardiac septal defects and, possibly, for orofacial clefts. Additional research is needed, but women who may become pregnant or are pregnant should be counseled regarding this possible risk. Importantly, they should be made aware that NSAIDs are available without a prescription and that although the OTC strength is lower than the strength of the prescription product, a safe dose has not been determined.

Both prescription and over-the-counter nonsteroidal anti-inflammatory drugs are frequently used in pregnancy, including during the first trimester. When used around the time of conception, there is evidence that NSAIDs impair fertility by interfering with blastocyst implantation, resulting in spontaneous abortions.

Exposure to these agents in the latter part of the second trimester and throughout the third is known to cause functional toxicity in the fetus and newborn consisting of renal impairment, oligohydramnios, premature closure of the ductus arteriosus, and primary pulmonary hypertension of the newborn. Increased risks for other toxicities—such as intraventricular hemorrhage, necrotizing enterocolitis, patent ductus arteriosus requiring ligation, platelet dysfunction, and gastrointestinal bleeding—have been reported in association with prenatal exposure to NSAIDs, but a causative role has not yet been proved.

When used in the first 3 months of gestation, there have been conflicting reports associating the use of NSAIDs with structural anomalies. However, a Canadian study published in September has strengthened the argument that NSAIDs can cause birth defects, particularly cardiac septal defects. In the following discussion, the evidence for and against this association is examined:

▸ A large observational cohort study conducted in Denmark compared the outcomes of 1,106 pregnancies exposed to NSAIDs in the first trimester with 17,529 controls and found no significant association between NSAID use during pregnancy and congenital defects (BMJ 2001;322:266–70). A weakness of this study was that it included only women who had received an NSAID prescribed at doses equivalent to 400 mg or 600 mg of ibuprofen. The study did not identify women who might have taken NSAIDs that were available as OTC products at doses equivalent to 200 mg of ibuprofen.

▸ A Food and Drug Administration analysis of Michigan Medicaid data on a large number of women exposed in the first trimester to three NSAIDs between 1985 and 1992 found no evidence of an increased risk of cardiac or orofacial defects for any of the drugs. There were 19 birth defects among the 258 women (7.4%) exposed to diflunisal, 143 birth defects among the 3,178 women (4.5%) exposed to ibuprofen, and 70 birth defects among the 1,448 women (4.8%) exposed to naproxen. These rates were higher than the expected number of birth defects (10, 129, and 62, respectively), but these types of studies only raise hypotheses and cannot show causation (Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 5th ed. Baltimore: Williams & Wilkins, 1998: ix).

▸ A 2001 prospective observational cohort study that examined the relationship between first-trimester exposure to NSAIDs in 2,557 women and congenital defects found no association with birth defects in general. However, significant associations with cardiac defects and orofacial clefts were noted: There were 36 cardiac defects, representing an odds ratio of 1.86, and 8 orofacial defects, an odds ratio of 2.81. Both were statistically significant increases over the expected rates (Reprod. Toxicol. 2001;15:371–5).

▸ A 2003 study using data from Swedish health registers of 1,142 infants with orofacial clefts (isolated or nonisolated) found a greater risk associated with naproxen exposure. Compared to the expected number (2.9), 8 of the infants had been exposed to naproxen, a relative risk of 2.72 (Cleft Palate Craniofac. J. 2003;40:624–8).

Another study identified 5,015 infants in the same registry with cardiovascular defects, and compared them with 577,730 controls, finding no significant association when all NSAIDs were grouped together or with individual agents, with the exception of naproxen. Among babies born to 1,679 naproxen-exposed women, 24 had cardiovascular defects, a statistically significant odds ratio of 1.7 (Reprod. Toxicol. 2003;17:255–61).

▸ A case-control study conducted in Quebec found a significant association between congenital anomalies, specifically cardiac septal defects, and the use of NSAIDs in the first trimester. Case infants were those with any congenital anomaly diagnosed in the first year of life, who were matched with up to 10 controls (infants without a congenital anomaly) for maternal age, urban or rural residence, gestational age, and diabetes status.

There were 93 infants (8.8%) with congenital anomalies born to 1,056 mothers who had filled prescriptions for NSAIDs in the first trimester. Among controls, there were 2,478 infants (7%) with anomalies born to 35,331 mothers. Among women who had filled a prescription for an NSAID during the first trimester, the adjusted odds ratio for any congenital anomaly was 2.21, and the adjusted odds ratio for cardiac septal closure was 3.34. Both odds ratios were statistically significant. There were no significant associations for oral clefts or defects involving other major organ systems.

The five NSAIDs most commonly used by these women were naproxen (35%), ibuprofen (26%), rofecoxib (15%), diclofenac (9%), and celecoxib (9%). The only statistically significant association was between ibuprofen prescriptions in the first trimester and congenital defects (Birth Defects Res. B. Dev. Reprod. Toxicol. 2006;77:268–79).

Taken in sum, the data from these studies provide increasingly convincing evidence that NSAIDs are human teratogens, especially for cardiac septal defects and, possibly, for orofacial clefts. Additional research is needed, but women who may become pregnant or are pregnant should be counseled regarding this possible risk. Importantly, they should be made aware that NSAIDs are available without a prescription and that although the OTC strength is lower than the strength of the prescription product, a safe dose has not been determined.

Both prescription and over-the-counter nonsteroidal anti-inflammatory drugs are frequently used in pregnancy, including during the first trimester. When used around the time of conception, there is evidence that NSAIDs impair fertility by interfering with blastocyst implantation, resulting in spontaneous abortions.

Exposure to these agents in the latter part of the second trimester and throughout the third is known to cause functional toxicity in the fetus and newborn consisting of renal impairment, oligohydramnios, premature closure of the ductus arteriosus, and primary pulmonary hypertension of the newborn. Increased risks for other toxicities—such as intraventricular hemorrhage, necrotizing enterocolitis, patent ductus arteriosus requiring ligation, platelet dysfunction, and gastrointestinal bleeding—have been reported in association with prenatal exposure to NSAIDs, but a causative role has not yet been proved.

When used in the first 3 months of gestation, there have been conflicting reports associating the use of NSAIDs with structural anomalies. However, a Canadian study published in September has strengthened the argument that NSAIDs can cause birth defects, particularly cardiac septal defects. In the following discussion, the evidence for and against this association is examined:

▸ A large observational cohort study conducted in Denmark compared the outcomes of 1,106 pregnancies exposed to NSAIDs in the first trimester with 17,529 controls and found no significant association between NSAID use during pregnancy and congenital defects (BMJ 2001;322:266–70). A weakness of this study was that it included only women who had received an NSAID prescribed at doses equivalent to 400 mg or 600 mg of ibuprofen. The study did not identify women who might have taken NSAIDs that were available as OTC products at doses equivalent to 200 mg of ibuprofen.

▸ A Food and Drug Administration analysis of Michigan Medicaid data on a large number of women exposed in the first trimester to three NSAIDs between 1985 and 1992 found no evidence of an increased risk of cardiac or orofacial defects for any of the drugs. There were 19 birth defects among the 258 women (7.4%) exposed to diflunisal, 143 birth defects among the 3,178 women (4.5%) exposed to ibuprofen, and 70 birth defects among the 1,448 women (4.8%) exposed to naproxen. These rates were higher than the expected number of birth defects (10, 129, and 62, respectively), but these types of studies only raise hypotheses and cannot show causation (Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 5th ed. Baltimore: Williams & Wilkins, 1998: ix).

▸ A 2001 prospective observational cohort study that examined the relationship between first-trimester exposure to NSAIDs in 2,557 women and congenital defects found no association with birth defects in general. However, significant associations with cardiac defects and orofacial clefts were noted: There were 36 cardiac defects, representing an odds ratio of 1.86, and 8 orofacial defects, an odds ratio of 2.81. Both were statistically significant increases over the expected rates (Reprod. Toxicol. 2001;15:371–5).

▸ A 2003 study using data from Swedish health registers of 1,142 infants with orofacial clefts (isolated or nonisolated) found a greater risk associated with naproxen exposure. Compared to the expected number (2.9), 8 of the infants had been exposed to naproxen, a relative risk of 2.72 (Cleft Palate Craniofac. J. 2003;40:624–8).

Another study identified 5,015 infants in the same registry with cardiovascular defects, and compared them with 577,730 controls, finding no significant association when all NSAIDs were grouped together or with individual agents, with the exception of naproxen. Among babies born to 1,679 naproxen-exposed women, 24 had cardiovascular defects, a statistically significant odds ratio of 1.7 (Reprod. Toxicol. 2003;17:255–61).

▸ A case-control study conducted in Quebec found a significant association between congenital anomalies, specifically cardiac septal defects, and the use of NSAIDs in the first trimester. Case infants were those with any congenital anomaly diagnosed in the first year of life, who were matched with up to 10 controls (infants without a congenital anomaly) for maternal age, urban or rural residence, gestational age, and diabetes status.

There were 93 infants (8.8%) with congenital anomalies born to 1,056 mothers who had filled prescriptions for NSAIDs in the first trimester. Among controls, there were 2,478 infants (7%) with anomalies born to 35,331 mothers. Among women who had filled a prescription for an NSAID during the first trimester, the adjusted odds ratio for any congenital anomaly was 2.21, and the adjusted odds ratio for cardiac septal closure was 3.34. Both odds ratios were statistically significant. There were no significant associations for oral clefts or defects involving other major organ systems.

The five NSAIDs most commonly used by these women were naproxen (35%), ibuprofen (26%), rofecoxib (15%), diclofenac (9%), and celecoxib (9%). The only statistically significant association was between ibuprofen prescriptions in the first trimester and congenital defects (Birth Defects Res. B. Dev. Reprod. Toxicol. 2006;77:268–79).

Taken in sum, the data from these studies provide increasingly convincing evidence that NSAIDs are human teratogens, especially for cardiac septal defects and, possibly, for orofacial clefts. Additional research is needed, but women who may become pregnant or are pregnant should be counseled regarding this possible risk. Importantly, they should be made aware that NSAIDs are available without a prescription and that although the OTC strength is lower than the strength of the prescription product, a safe dose has not been determined.

Prescription and over-the-counter nonsteroidal anti-inflammatory drugs are frequently used in pregnancy, including during the first trimester. When used around the time of conception, there is evidence that NSAIDs impair fertility by interfering with blastocyst implantation, resulting in spontaneous abortions.

Exposure to these agents toward the end of the second trimester and throughout the third is known to cause functional toxicity in the fetus and newborn, consisting of renal impairment, oligohydramnios, premature closure of the ductus arteriosus, and primary pulmonary hypertension of the newborn. Increased risks for other toxicities—such as intraventricular hemorrhage, necrotizing enterocolitis, patent ductus arteriosus requiring ligation, platelet dysfunction, and gastrointestinal bleeding—have been reported in association with prenatal exposure to NSAIDs, but a causative role has not yet been proved.

When used in the first 3 months of gestation, there have been conflicting reports associating the use of NSAIDs with structural anomalies. However, a Canadian study published in September has strengthened the argument that NSAIDs can cause birth defects, particularly cardiac septal defects. In the following discussion, the evidence for and against this association is examined:

A large observational cohort study conducted in Denmark compared the outcomes of 1,106 pregnancies exposed to NSAIDs in the first trimester with 17,529 controls and found no significant association between NSAID use during pregnancy and congenital defects (BMJ 2001;322:266–70). A weakness of this study was that it included only women who had received an NSAID prescribed at doses equivalent to 400 mg or 600 mg of ibuprofen. The study did not identify women who might have taken NSAIDs that were available as OTC products at doses equivalent to 200 mg of ibuprofen.

A Food and Drug Administration analysis of Michigan Medicaid data on a large number of women exposed in the first trimester to three NSAIDs between 1985 and 1992 found no evidence of an increased risk of cardiac or orofacial defects for any of the drugs. There were 19 birth defects among the 258 women (7.4%) exposed to diflunisal, 143 birth defects among the 3,178 women (4.5%) exposed to ibuprofen, and 70 birth defects among the 1,448 women (4.8%) exposed to naproxen. These rates were higher than the expected number of birth defects (10, 129, and 62, respectively), but these types of studies only raise hypotheses and cannot show causation (Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 5th ed. Baltimore: Williams & Wilkins, 1998: ix).

A 2001 prospective observational cohort study that examined the relationship between first-trimester exposure to NSAIDs in 2,557 women and congenital defects found no association with birth defects in general. However, significant associations with cardiac defects and orofacial clefts were noted: There were 36 cardiac defects, representing an odds ratio of 1.86, and 8 orofacial defects, an odds ratio of 2.81. Both were statistically significant increases over the expected rates (Reprod. Toxicol. 2001;15:371–5).

A 2003 study using data from Swedish health registers of 1,142 infants with orofacial clefts (isolated or nonisolated) found a greater risk associated with naproxen exposure. Compared to the expected number (2.9), 8 of the infants had been exposed to naproxen, a relative risk of 2.72 (Cleft Palate Craniofac. J. 2003;40:624–8).

Another study identified 5,015 infants in the same registry with cardiovascular defects, and compared them with 577,730 controls, finding no significant association when all NSAIDs were grouped together or with individual agents, with the exception of naproxen. Among babies born to 1,679 women exposed to naproxen, 24 had cardiovascular defects, a statistically significant odds ratio of 1.7 (Reprod. Toxicol. 2003;17:255–61).

The latest study, a case-control study conducted in Quebec, found a significant association between congenital anomalies, specifically cardiac septal defects, and the use of NSAIDs in the first trimester. Case infants were those with any congenital anomaly diagnosed in the first year of life, who were matched with up to 10 controls (infants without a congenital anomaly) for maternal age, urban or rural residence, gestational age, and diabetes status. The data were adjusted for common comorbidities.

There were 93 infants (8.8%) with congenital anomalies born to 1,056 mothers who had filled prescriptions for NSAIDs in the first trimester. Among controls, there were 2,478 infants (7%) with anomalies born to 35,331 mothers who had not filled such a prescription. Among women who had filled a prescription for an NSAID during the first trimester, the adjusted odds ratio for any congenital anomaly was 2.21, and the adjusted odds ratio for cardiac septal closure was 3.34. Both were significant. There were no significant associations for oral clefts or defects involving other major organ systems (Birth Defects Res. B. Dev. Reprod. Toxicol. 2006;77:268–79).

Taken in sum, the data from these studies provide increasingly convincing evidence that NSAIDs are human teratogens, especially for cardiac septal defects and, possibly, for orofacial clefts. Additional research is needed, but women who may become pregnant or are pregnant should be counseled regarding this possible risk.

Prescription and over-the-counter nonsteroidal anti-inflammatory drugs are frequently used in pregnancy, including during the first trimester. When used around the time of conception, there is evidence that NSAIDs impair fertility by interfering with blastocyst implantation, resulting in spontaneous abortions.

Exposure to these agents toward the end of the second trimester and throughout the third is known to cause functional toxicity in the fetus and newborn, consisting of renal impairment, oligohydramnios, premature closure of the ductus arteriosus, and primary pulmonary hypertension of the newborn. Increased risks for other toxicities—such as intraventricular hemorrhage, necrotizing enterocolitis, patent ductus arteriosus requiring ligation, platelet dysfunction, and gastrointestinal bleeding—have been reported in association with prenatal exposure to NSAIDs, but a causative role has not yet been proved.

When used in the first 3 months of gestation, there have been conflicting reports associating the use of NSAIDs with structural anomalies. However, a Canadian study published in September has strengthened the argument that NSAIDs can cause birth defects, particularly cardiac septal defects. In the following discussion, the evidence for and against this association is examined:

A large observational cohort study conducted in Denmark compared the outcomes of 1,106 pregnancies exposed to NSAIDs in the first trimester with 17,529 controls and found no significant association between NSAID use during pregnancy and congenital defects (BMJ 2001;322:266–70). A weakness of this study was that it included only women who had received an NSAID prescribed at doses equivalent to 400 mg or 600 mg of ibuprofen. The study did not identify women who might have taken NSAIDs that were available as OTC products at doses equivalent to 200 mg of ibuprofen.

A Food and Drug Administration analysis of Michigan Medicaid data on a large number of women exposed in the first trimester to three NSAIDs between 1985 and 1992 found no evidence of an increased risk of cardiac or orofacial defects for any of the drugs. There were 19 birth defects among the 258 women (7.4%) exposed to diflunisal, 143 birth defects among the 3,178 women (4.5%) exposed to ibuprofen, and 70 birth defects among the 1,448 women (4.8%) exposed to naproxen. These rates were higher than the expected number of birth defects (10, 129, and 62, respectively), but these types of studies only raise hypotheses and cannot show causation (Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 5th ed. Baltimore: Williams & Wilkins, 1998: ix).

A 2001 prospective observational cohort study that examined the relationship between first-trimester exposure to NSAIDs in 2,557 women and congenital defects found no association with birth defects in general. However, significant associations with cardiac defects and orofacial clefts were noted: There were 36 cardiac defects, representing an odds ratio of 1.86, and 8 orofacial defects, an odds ratio of 2.81. Both were statistically significant increases over the expected rates (Reprod. Toxicol. 2001;15:371–5).

A 2003 study using data from Swedish health registers of 1,142 infants with orofacial clefts (isolated or nonisolated) found a greater risk associated with naproxen exposure. Compared to the expected number (2.9), 8 of the infants had been exposed to naproxen, a relative risk of 2.72 (Cleft Palate Craniofac. J. 2003;40:624–8).

Another study identified 5,015 infants in the same registry with cardiovascular defects, and compared them with 577,730 controls, finding no significant association when all NSAIDs were grouped together or with individual agents, with the exception of naproxen. Among babies born to 1,679 women exposed to naproxen, 24 had cardiovascular defects, a statistically significant odds ratio of 1.7 (Reprod. Toxicol. 2003;17:255–61).

The latest study, a case-control study conducted in Quebec, found a significant association between congenital anomalies, specifically cardiac septal defects, and the use of NSAIDs in the first trimester. Case infants were those with any congenital anomaly diagnosed in the first year of life, who were matched with up to 10 controls (infants without a congenital anomaly) for maternal age, urban or rural residence, gestational age, and diabetes status. The data were adjusted for common comorbidities.

There were 93 infants (8.8%) with congenital anomalies born to 1,056 mothers who had filled prescriptions for NSAIDs in the first trimester. Among controls, there were 2,478 infants (7%) with anomalies born to 35,331 mothers who had not filled such a prescription. Among women who had filled a prescription for an NSAID during the first trimester, the adjusted odds ratio for any congenital anomaly was 2.21, and the adjusted odds ratio for cardiac septal closure was 3.34. Both were significant. There were no significant associations for oral clefts or defects involving other major organ systems (Birth Defects Res. B. Dev. Reprod. Toxicol. 2006;77:268–79).

Taken in sum, the data from these studies provide increasingly convincing evidence that NSAIDs are human teratogens, especially for cardiac septal defects and, possibly, for orofacial clefts. Additional research is needed, but women who may become pregnant or are pregnant should be counseled regarding this possible risk.

Prescription and over-the-counter nonsteroidal anti-inflammatory drugs are frequently used in pregnancy, including during the first trimester. When used around the time of conception, there is evidence that NSAIDs impair fertility by interfering with blastocyst implantation, resulting in spontaneous abortions.

Exposure to these agents toward the end of the second trimester and throughout the third is known to cause functional toxicity in the fetus and newborn, consisting of renal impairment, oligohydramnios, premature closure of the ductus arteriosus, and primary pulmonary hypertension of the newborn. Increased risks for other toxicities—such as intraventricular hemorrhage, necrotizing enterocolitis, patent ductus arteriosus requiring ligation, platelet dysfunction, and gastrointestinal bleeding—have been reported in association with prenatal exposure to NSAIDs, but a causative role has not yet been proved.

When used in the first 3 months of gestation, there have been conflicting reports associating the use of NSAIDs with structural anomalies. However, a Canadian study published in September has strengthened the argument that NSAIDs can cause birth defects, particularly cardiac septal defects. In the following discussion, the evidence for and against this association is examined:

A large observational cohort study conducted in Denmark compared the outcomes of 1,106 pregnancies exposed to NSAIDs in the first trimester with 17,529 controls and found no significant association between NSAID use during pregnancy and congenital defects (BMJ 2001;322:266–70). A weakness of this study was that it included only women who had received an NSAID prescribed at doses equivalent to 400 mg or 600 mg of ibuprofen. The study did not identify women who might have taken NSAIDs that were available as OTC products at doses equivalent to 200 mg of ibuprofen.

A Food and Drug Administration analysis of Michigan Medicaid data on a large number of women exposed in the first trimester to three NSAIDs between 1985 and 1992 found no evidence of an increased risk of cardiac or orofacial defects for any of the drugs. There were 19 birth defects among the 258 women (7.4%) exposed to diflunisal, 143 birth defects among the 3,178 women (4.5%) exposed to ibuprofen, and 70 birth defects among the 1,448 women (4.8%) exposed to naproxen. These rates were higher than the expected number of birth defects (10, 129, and 62, respectively), but these types of studies only raise hypotheses and cannot show causation (Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 5th ed. Baltimore: Williams & Wilkins, 1998: ix).

A 2001 prospective observational cohort study that examined the relationship between first-trimester exposure to NSAIDs in 2,557 women and congenital defects found no association with birth defects in general. However, significant associations with cardiac defects and orofacial clefts were noted: There were 36 cardiac defects, representing an odds ratio of 1.86, and 8 orofacial defects, an odds ratio of 2.81. Both were statistically significant increases over the expected rates (Reprod. Toxicol. 2001;15:371–5).

A 2003 study using data from Swedish health registers of 1,142 infants with orofacial clefts (isolated or nonisolated) found a greater risk associated with naproxen exposure. Compared to the expected number (2.9), 8 of the infants had been exposed to naproxen, a relative risk of 2.72 (Cleft Palate Craniofac. J. 2003;40:624–8).

Another study identified 5,015 infants in the same registry with cardiovascular defects, and compared them with 577,730 controls, finding no significant association when all NSAIDs were grouped together or with individual agents, with the exception of naproxen. Among babies born to 1,679 women exposed to naproxen, 24 had cardiovascular defects, a statistically significant odds ratio of 1.7 (Reprod. Toxicol. 2003;17:255–61).

The latest study, a case-control study conducted in Quebec, found a significant association between congenital anomalies, specifically cardiac septal defects, and the use of NSAIDs in the first trimester. Case infants were those with any congenital anomaly diagnosed in the first year of life, who were matched with up to 10 controls (infants without a congenital anomaly) for maternal age, urban or rural residence, gestational age, and diabetes status. The data were adjusted for common comorbidities.

There were 93 infants (8.8%) with congenital anomalies born to 1,056 mothers who had filled prescriptions for NSAIDs in the first trimester. Among controls, there were 2,478 infants (7%) with anomalies born to 35,331 mothers who had not filled such a prescription. Among women who had filled a prescription for an NSAID during the first trimester, the adjusted odds ratio for any congenital anomaly was 2.21, and the adjusted odds ratio for cardiac septal closure was 3.34. Both were significant. There were no significant associations for oral clefts or defects involving other major organ systems (Birth Defects Res. B. Dev. Reprod. Toxicol. 2006;77:268–79).

Taken in sum, the data from these studies provide increasingly convincing evidence that NSAIDs are human teratogens, especially for cardiac septal defects and, possibly, for orofacial clefts. Additional research is needed, but women who may become pregnant or are pregnant should be counseled regarding this possible risk.

It has been known for years that some first-generation antiepileptic drugs (AEDs) cause birth defects, intrauterine growth retardation (IUGR), and, possibly, developmental delay, but these toxicities were not thought to apply to the second-generation AEDs. New information has challenged that belief.

The first-generation AEDs known to cause birth defects and other developmental toxicities include the hydantoins (ethotoin [Peganone], fosphenytoin [Cerebyx], mephenytoin [Mesantoin], and phenytoin [Dilantin]), phenobarbital, primidone (Mysoline), carbamazepine (Tegretol), and valproic acid derivatives (Depakene, Depakote). In a 2001 study, the incidence of embryopathy (major and minor anomalies, microcephaly, and IUGR) after first-trimester monotherapy was 21% (phenytoin), 27% (phenobarbital), 14% (carbamazepine), 21% any monotherapy, and 28% (polytherapy) (N. Engl. J. Med. 2001;344:1132–8).

Phenytoin causes a pattern of defects called fetal hydantoin syndrome (FHS) as well as other defects, such as those involving the heart and growth. Carbamazepine can cause a syndrome of minor craniofacial defects, fingernail hypoplasia, and developmental delay as well as neural-tube defects (NTDs).

The defects observed with primidone are similar to those in FHS. Phenobarbital has been associated with an increase in congenital defects when used for epilepsy, but not when used for other indications. Use of valproic acid derivatives between the 17th and 30th day after fertilization is associated with a 1%–2% risk of NTDs. Other defects are those of the head and face, digits, urogenital tract, and mental and physical growth.

Carbamazepine, phenytoin, primidone, and phenobarbital affect folate metabolism or absorption, and this may increase the risk of birth defects, including NTDs. Women taking these agents should take folic acid 4–5 mg/day, preferably starting before conception. Anticonvulsants, particularly the hydantoins and barbiturates, are related to hemorrhagic disease of the newborn, so adequate doses of vitamin K should be administered to newborns exposed to AEDs in utero.

In contrast, first-generation AEDs that do not appear to be associated with a significant risk of birth defects include the benzodiazepines (clonazepam [Klonopin], clorazepate [Tranxene], diazepam [Valium], and lorazepam [Ativan]) and succinimides (ethosuximide [Zarontin] and methsuximide [Celontin]). However, some of these drugs have very little human data, and the benzodiazepines are known to cause toxicity in the newborn, most notably, floppy infant syndrome and withdrawal syndrome.

Until recently, second-generation AEDs had not been linked to congenital defects. But new data from the North American AED Pregnancy Registry and five other pregnancy registries have shown a very significant risk of isolated, nonsyndromic oral clefts after first-trimester exposure to lamotrigine (Lamictal) monotherapy (Birth Defects Res. A Clin. Mol. Teratol. 2006;76:313–428).

The human pregnancy experience is too limited to assess the embryo/fetal risk for the other second-generation agents: felbamate (Felbatol), gabapentin (Neurontin), pregabalin (Lyrica), levetiracetam (Keppra), tiagabine (Gabitril), and topiramate (Topamax). Although the data also are limited for zonisamide (Zonegran), the drug is teratogenic in three animal species and embryo lethal in a fourth and therefore is best avoided in the first trimester. Oxcarbazepine (Trileptal), a drug closely related to carbamazepine, has been associated with minor facial defects, but the data are too limited to assess the risk in humans.

In summary, women with epilepsy should not be denied treatment with the most effective agents for their condition because of pregnancy or nursing. They should be treated with the lowest dose and the fewest drugs possible to control their seizures. They should take folic acid (4–5 mg/day), and vitamin K should be given to the newborns.

AEDs that appear to have the lowest risk for major birth defects are the benzodiazepines, the succinimides, and the second-generation agents. However, the human pregnancy data are very limited for many of these agents.

Carbamazepine and phenytoin are considered compatible with breast-feeding, and gabapentin, levetiracetam, oxcarbazepine, and tiagabine are probably compatible. Two AEDs (primidone and phenobarbital) are known to cause toxicity in the nursing infant and should not be given during breast-feeding. There are no data for the remaining AEDs, but they have the potential to cause toxicity and, if used during breast-feeding, the infants should be closely monitored.

It has been known for years that some first-generation antiepileptic drugs (AEDs) cause birth defects, intrauterine growth retardation (IUGR), and, possibly, developmental delay, but these toxicities were not thought to apply to the second-generation AEDs. New information has challenged that belief.

The first-generation AEDs known to cause birth defects and other developmental toxicities include the hydantoins (ethotoin [Peganone], fosphenytoin [Cerebyx], mephenytoin [Mesantoin], and phenytoin [Dilantin]), phenobarbital, primidone (Mysoline), carbamazepine (Tegretol), and valproic acid derivatives (Depakene, Depakote). In a 2001 study, the incidence of embryopathy (major and minor anomalies, microcephaly, and IUGR) after first-trimester monotherapy was 21% (phenytoin), 27% (phenobarbital), 14% (carbamazepine), 21% any monotherapy, and 28% (polytherapy) (N. Engl. J. Med. 2001;344:1132–8).

Phenytoin causes a pattern of defects called fetal hydantoin syndrome (FHS) as well as other defects, such as those involving the heart and growth. Carbamazepine can cause a syndrome of minor craniofacial defects, fingernail hypoplasia, and developmental delay as well as neural-tube defects (NTDs).

The defects observed with primidone are similar to those in FHS. Phenobarbital has been associated with an increase in congenital defects when used for epilepsy, but not when used for other indications. Use of valproic acid derivatives between the 17th and 30th day after fertilization is associated with a 1%–2% risk of NTDs. Other defects are those of the head and face, digits, urogenital tract, and mental and physical growth.

Carbamazepine, phenytoin, primidone, and phenobarbital affect folate metabolism or absorption, and this may increase the risk of birth defects, including NTDs. Women taking these agents should take folic acid 4–5 mg/day, preferably starting before conception. Anticonvulsants, particularly the hydantoins and barbiturates, are related to hemorrhagic disease of the newborn, so adequate doses of vitamin K should be administered to newborns exposed to AEDs in utero.

In contrast, first-generation AEDs that do not appear to be associated with a significant risk of birth defects include the benzodiazepines (clonazepam [Klonopin], clorazepate [Tranxene], diazepam [Valium], and lorazepam [Ativan]) and succinimides (ethosuximide [Zarontin] and methsuximide [Celontin]). However, some of these drugs have very little human data, and the benzodiazepines are known to cause toxicity in the newborn, most notably, floppy infant syndrome and withdrawal syndrome.

Until recently, second-generation AEDs had not been linked to congenital defects. But new data from the North American AED Pregnancy Registry and five other pregnancy registries have shown a very significant risk of isolated, nonsyndromic oral clefts after first-trimester exposure to lamotrigine (Lamictal) monotherapy (Birth Defects Res. A Clin. Mol. Teratol. 2006;76:313–428).

The human pregnancy experience is too limited to assess the embryo/fetal risk for the other second-generation agents: felbamate (Felbatol), gabapentin (Neurontin), pregabalin (Lyrica), levetiracetam (Keppra), tiagabine (Gabitril), and topiramate (Topamax). Although the data also are limited for zonisamide (Zonegran), the drug is teratogenic in three animal species and embryo lethal in a fourth and therefore is best avoided in the first trimester. Oxcarbazepine (Trileptal), a drug closely related to carbamazepine, has been associated with minor facial defects, but the data are too limited to assess the risk in humans.

In summary, women with epilepsy should not be denied treatment with the most effective agents for their condition because of pregnancy or nursing. They should be treated with the lowest dose and the fewest drugs possible to control their seizures. They should take folic acid (4–5 mg/day), and vitamin K should be given to the newborns.

AEDs that appear to have the lowest risk for major birth defects are the benzodiazepines, the succinimides, and the second-generation agents. However, the human pregnancy data are very limited for many of these agents.

Carbamazepine and phenytoin are considered compatible with breast-feeding, and gabapentin, levetiracetam, oxcarbazepine, and tiagabine are probably compatible. Two AEDs (primidone and phenobarbital) are known to cause toxicity in the nursing infant and should not be given during breast-feeding. There are no data for the remaining AEDs, but they have the potential to cause toxicity and, if used during breast-feeding, the infants should be closely monitored.

It has been known for years that some first-generation antiepileptic drugs (AEDs) cause birth defects, intrauterine growth retardation (IUGR), and, possibly, developmental delay, but these toxicities were not thought to apply to the second-generation AEDs. New information has challenged that belief.

The first-generation AEDs known to cause birth defects and other developmental toxicities include the hydantoins (ethotoin [Peganone], fosphenytoin [Cerebyx], mephenytoin [Mesantoin], and phenytoin [Dilantin]), phenobarbital, primidone (Mysoline), carbamazepine (Tegretol), and valproic acid derivatives (Depakene, Depakote). In a 2001 study, the incidence of embryopathy (major and minor anomalies, microcephaly, and IUGR) after first-trimester monotherapy was 21% (phenytoin), 27% (phenobarbital), 14% (carbamazepine), 21% any monotherapy, and 28% (polytherapy) (N. Engl. J. Med. 2001;344:1132–8).

Phenytoin causes a pattern of defects called fetal hydantoin syndrome (FHS) as well as other defects, such as those involving the heart and growth. Carbamazepine can cause a syndrome of minor craniofacial defects, fingernail hypoplasia, and developmental delay as well as neural-tube defects (NTDs).

The defects observed with primidone are similar to those in FHS. Phenobarbital has been associated with an increase in congenital defects when used for epilepsy, but not when used for other indications. Use of valproic acid derivatives between the 17th and 30th day after fertilization is associated with a 1%–2% risk of NTDs. Other defects are those of the head and face, digits, urogenital tract, and mental and physical growth.

Carbamazepine, phenytoin, primidone, and phenobarbital affect folate metabolism or absorption, and this may increase the risk of birth defects, including NTDs. Women taking these agents should take folic acid 4–5 mg/day, preferably starting before conception. Anticonvulsants, particularly the hydantoins and barbiturates, are related to hemorrhagic disease of the newborn, so adequate doses of vitamin K should be administered to newborns exposed to AEDs in utero.

In contrast, first-generation AEDs that do not appear to be associated with a significant risk of birth defects include the benzodiazepines (clonazepam [Klonopin], clorazepate [Tranxene], diazepam [Valium], and lorazepam [Ativan]) and succinimides (ethosuximide [Zarontin] and methsuximide [Celontin]). However, some of these drugs have very little human data, and the benzodiazepines are known to cause toxicity in the newborn, most notably, floppy infant syndrome and withdrawal syndrome.

Until recently, second-generation AEDs had not been linked to congenital defects. But new data from the North American AED Pregnancy Registry and five other pregnancy registries have shown a very significant risk of isolated, nonsyndromic oral clefts after first-trimester exposure to lamotrigine (Lamictal) monotherapy (Birth Defects Res. A Clin. Mol. Teratol. 2006;76:313–428).

The human pregnancy experience is too limited to assess the embryo/fetal risk for the other second-generation agents: felbamate (Felbatol), gabapentin (Neurontin), pregabalin (Lyrica), levetiracetam (Keppra), tiagabine (Gabitril), and topiramate (Topamax). Although the data also are limited for zonisamide (Zonegran), the drug is teratogenic in three animal species and embryo lethal in a fourth and therefore is best avoided in the first trimester. Oxcarbazepine (Trileptal), a drug closely related to carbamazepine, has been associated with minor facial defects, but the data are too limited to assess the risk in humans.

In summary, women with epilepsy should not be denied treatment with the most effective agents for their condition because of pregnancy or nursing. They should be treated with the lowest dose and the fewest drugs possible to control their seizures. They should take folic acid (4–5 mg/day), and vitamin K should be given to the newborns.

AEDs that appear to have the lowest risk for major birth defects are the benzodiazepines, the succinimides, and the second-generation agents. However, the human pregnancy data are very limited for many of these agents.

Carbamazepine and phenytoin are considered compatible with breast-feeding, and gabapentin, levetiracetam, oxcarbazepine, and tiagabine are probably compatible. Two AEDs (primidone and phenobarbital) are known to cause toxicity in the nursing infant and should not be given during breast-feeding. There are no data for the remaining AEDs, but they have the potential to cause toxicity and, if used during breast-feeding, the infants should be closely monitored.

Although it has been known for years that some first-generation antiepileptic drugs (AEDs) cause birth defects, intrauterine growth retardation (IUGR), and, possibly, developmental delay, these toxicities were not thought to apply to the second-generation AEDs. New information has challenged that belief.

The first-generation AEDs known to cause birth defects and other developmental toxicities include the hydantoins (ethotoin [Peganone], fosphenytoin [Cerebyx], mephenytoin [Mesantoin], and phenytoin [Dilantin]), phenobarbital, primidone (Mysoline), carbamazepine (Tegretol), and valproic acid derivatives (Depakene, Depakote). In a 2001 study, the incidence of embryopathy (major and minor anomalies, microcephaly, and IUGR) after first-trimester monotherapy was 21% (phenytoin), 27% (phenobarbital), 14% (carbamazepine), 21% any monotherapy, and 28% (polytherapy) (N. Engl. J. Med. 2001;344:1132–8).

Phenytoin also causes a pattern of defects collectively called the fetal hydantoin syndrome (FHS), characterized by variable degrees of hypoplasia and ossification of the distal phalanges and craniofacial abnormalities. Other defects, such as those involving the heart and growth, are commonly observed. A syndrome with carbamazepine consisting of minor craniofacial defects, fingernail hypoplasia, and developmental delay has been observed; this drug may also cause neural-tube defects (NTDs).

The defects observed with primidone are similar to those in FHS. Phenobarbital has been associated with an increase in congenital defects when used for epilepsy, but not when used for other indications. The use of valproic acid derivatives between the 17th and 30th day after fertilization is associated with a 1%–2% risk of NTDs. Other defects are those of the head and face, digits, urogenital tract, and mental and physical growth. Carbamazepine, phenytoin, primidone, and phenobarbital affect folate metabolism or absorption, and this may increase the risk of birth defects, including NTDs. Women taking these agents should take folic acid 4–5 mg/day, preferably starting before conception. Moreover, anticonvulsants, particularly the hydantoins and barbiturates, are related to hemorrhagic disease of the newborn, so adequate doses of vitamin K should be administered to newborns exposed to AEDs in utero.

In contrast, first-generation AEDs that do not appear to be associated with a significant risk of birth defects include the benzodiazepines (clonazepam [Klonopin], clorazepate [Tranxene], diazepam [Valium], and lorazepam [Ativan]) and succinimides (ethosuximide [Zarontin] and methsuximide [Celontin]). However, some of these drugs have very little human data, and the benzodiazepines are known to cause toxicity in the newborn, most notably, floppy infant syndrome and withdrawal syndrome. In addition, the risk for birth defects from seizures alone is at least two to three times greater than the background risk of 2%–3%.

Until recently, the second-generation AEDs had not been associated with congenital defects. However, new data from the North American AED Pregnancy Registry and five other pregnancy registries have shown a very significant risk of isolated, nonsyndromic oral clefts after first-trimester exposure to lamotrigine (Lamictal) monotherapy (Birth Defects Res. A Clin. Mol. Teratol. 2006;76:313–428). The prevalence of oral clefts in the North American registry was 8.9/1,000, even though all of the mothers had been supplemented with folic acid before conception. This was significantly higher than the prevalence of 0.37/1,000 in a comparison group.

The human pregnancy experience is too limited to assess the embryo/fetal risk for the other second-generation agents: felbamate (Felbatol), gabapentin (Neurontin), pregabalin (Lyrica), levetiracetam (Keppra), tiagabine (Gabitril), and topiramate (Topamax). Although the data also are limited for zonisamide (Zonegran), the drug is teratogenic in three animal species and embryo lethal in a fourth and therefore is best avoided in the first trimester. Oxcarbazepine (Trileptal), a drug closely related to carbamazepine, has been associated with minor facial defects, but the data are too limited to assess the risk in humans.

To summarize, women with epilepsy should not be denied treatment with the most effective agents for their condition because of pregnancy or nursing. They should be treated with the lowest dose and the fewest drugs possible to control their seizures. Periodic serum levels are needed throughout pregnancy to ensure that therapeutic levels are maintained. They should take folic acid (4–5 mg/day), and vitamin K should be given to the newborns.

It is also important to counsel that seizures are a risk to both the mother and the embryo/fetus, as is the drug therapy. AEDs that appear to have the lowest risk for major birth defects are the benzodiazepines, the succinimides, and the second-generation agents. However, the human pregnancy data are very limited for many of these agents.

Carbamazepine and phenytoin are considered compatible with breast-feeding, and gabapentin, levetiracetam, oxcarbazepine, and tiagabine are probably compatible. Two AEDs (primidone and phenobarbital) are known to cause toxicity in the nursing infant and should not be given during breast-feeding. There are no data for the remaining AEDs, but they have the potential to cause toxicity and, if used during breast-feeding, the infants should be closely monitored.

Although it has been known for years that some first-generation antiepileptic drugs (AEDs) cause birth defects, intrauterine growth retardation (IUGR), and, possibly, developmental delay, these toxicities were not thought to apply to the second-generation AEDs. New information has challenged that belief.

The first-generation AEDs known to cause birth defects and other developmental toxicities include the hydantoins (ethotoin [Peganone], fosphenytoin [Cerebyx], mephenytoin [Mesantoin], and phenytoin [Dilantin]), phenobarbital, primidone (Mysoline), carbamazepine (Tegretol), and valproic acid derivatives (Depakene, Depakote). In a 2001 study, the incidence of embryopathy (major and minor anomalies, microcephaly, and IUGR) after first-trimester monotherapy was 21% (phenytoin), 27% (phenobarbital), 14% (carbamazepine), 21% any monotherapy, and 28% (polytherapy) (N. Engl. J. Med. 2001;344:1132–8).

Phenytoin also causes a pattern of defects collectively called the fetal hydantoin syndrome (FHS), characterized by variable degrees of hypoplasia and ossification of the distal phalanges and craniofacial abnormalities. Other defects, such as those involving the heart and growth, are commonly observed. A syndrome with carbamazepine consisting of minor craniofacial defects, fingernail hypoplasia, and developmental delay has been observed; this drug may also cause neural-tube defects (NTDs).

The defects observed with primidone are similar to those in FHS. Phenobarbital has been associated with an increase in congenital defects when used for epilepsy, but not when used for other indications. The use of valproic acid derivatives between the 17th and 30th day after fertilization is associated with a 1%–2% risk of NTDs. Other defects are those of the head and face, digits, urogenital tract, and mental and physical growth. Carbamazepine, phenytoin, primidone, and phenobarbital affect folate metabolism or absorption, and this may increase the risk of birth defects, including NTDs. Women taking these agents should take folic acid 4–5 mg/day, preferably starting before conception. Moreover, anticonvulsants, particularly the hydantoins and barbiturates, are related to hemorrhagic disease of the newborn, so adequate doses of vitamin K should be administered to newborns exposed to AEDs in utero.

In contrast, first-generation AEDs that do not appear to be associated with a significant risk of birth defects include the benzodiazepines (clonazepam [Klonopin], clorazepate [Tranxene], diazepam [Valium], and lorazepam [Ativan]) and succinimides (ethosuximide [Zarontin] and methsuximide [Celontin]). However, some of these drugs have very little human data, and the benzodiazepines are known to cause toxicity in the newborn, most notably, floppy infant syndrome and withdrawal syndrome. In addition, the risk for birth defects from seizures alone is at least two to three times greater than the background risk of 2%–3%.

Until recently, the second-generation AEDs had not been associated with congenital defects. However, new data from the North American AED Pregnancy Registry and five other pregnancy registries have shown a very significant risk of isolated, nonsyndromic oral clefts after first-trimester exposure to lamotrigine (Lamictal) monotherapy (Birth Defects Res. A Clin. Mol. Teratol. 2006;76:313–428). The prevalence of oral clefts in the North American registry was 8.9/1,000, even though all of the mothers had been supplemented with folic acid before conception. This was significantly higher than the prevalence of 0.37/1,000 in a comparison group.

The human pregnancy experience is too limited to assess the embryo/fetal risk for the other second-generation agents: felbamate (Felbatol), gabapentin (Neurontin), pregabalin (Lyrica), levetiracetam (Keppra), tiagabine (Gabitril), and topiramate (Topamax). Although the data also are limited for zonisamide (Zonegran), the drug is teratogenic in three animal species and embryo lethal in a fourth and therefore is best avoided in the first trimester. Oxcarbazepine (Trileptal), a drug closely related to carbamazepine, has been associated with minor facial defects, but the data are too limited to assess the risk in humans.

To summarize, women with epilepsy should not be denied treatment with the most effective agents for their condition because of pregnancy or nursing. They should be treated with the lowest dose and the fewest drugs possible to control their seizures. Periodic serum levels are needed throughout pregnancy to ensure that therapeutic levels are maintained. They should take folic acid (4–5 mg/day), and vitamin K should be given to the newborns.

It is also important to counsel that seizures are a risk to both the mother and the embryo/fetus, as is the drug therapy. AEDs that appear to have the lowest risk for major birth defects are the benzodiazepines, the succinimides, and the second-generation agents. However, the human pregnancy data are very limited for many of these agents.

Carbamazepine and phenytoin are considered compatible with breast-feeding, and gabapentin, levetiracetam, oxcarbazepine, and tiagabine are probably compatible. Two AEDs (primidone and phenobarbital) are known to cause toxicity in the nursing infant and should not be given during breast-feeding. There are no data for the remaining AEDs, but they have the potential to cause toxicity and, if used during breast-feeding, the infants should be closely monitored.

Although it has been known for years that some first-generation antiepileptic drugs (AEDs) cause birth defects, intrauterine growth retardation (IUGR), and, possibly, developmental delay, these toxicities were not thought to apply to the second-generation AEDs. New information has challenged that belief.

The first-generation AEDs known to cause birth defects and other developmental toxicities include the hydantoins (ethotoin [Peganone], fosphenytoin [Cerebyx], mephenytoin [Mesantoin], and phenytoin [Dilantin]), phenobarbital, primidone (Mysoline), carbamazepine (Tegretol), and valproic acid derivatives (Depakene, Depakote). In a 2001 study, the incidence of embryopathy (major and minor anomalies, microcephaly, and IUGR) after first-trimester monotherapy was 21% (phenytoin), 27% (phenobarbital), 14% (carbamazepine), 21% any monotherapy, and 28% (polytherapy) (N. Engl. J. Med. 2001;344:1132–8).

Phenytoin also causes a pattern of defects collectively called the fetal hydantoin syndrome (FHS), characterized by variable degrees of hypoplasia and ossification of the distal phalanges and craniofacial abnormalities. Other defects, such as those involving the heart and growth, are commonly observed. A syndrome with carbamazepine consisting of minor craniofacial defects, fingernail hypoplasia, and developmental delay has been observed; this drug may also cause neural-tube defects (NTDs).

The defects observed with primidone are similar to those in FHS. Phenobarbital has been associated with an increase in congenital defects when used for epilepsy, but not when used for other indications. The use of valproic acid derivatives between the 17th and 30th day after fertilization is associated with a 1%–2% risk of NTDs. Other defects are those of the head and face, digits, urogenital tract, and mental and physical growth. Carbamazepine, phenytoin, primidone, and phenobarbital affect folate metabolism or absorption, and this may increase the risk of birth defects, including NTDs. Women taking these agents should take folic acid 4–5 mg/day, preferably starting before conception. Moreover, anticonvulsants, particularly the hydantoins and barbiturates, are related to hemorrhagic disease of the newborn, so adequate doses of vitamin K should be administered to newborns exposed to AEDs in utero.

In contrast, first-generation AEDs that do not appear to be associated with a significant risk of birth defects include the benzodiazepines (clonazepam [Klonopin], clorazepate [Tranxene], diazepam [Valium], and lorazepam [Ativan]) and succinimides (ethosuximide [Zarontin] and methsuximide [Celontin]). However, some of these drugs have very little human data, and the benzodiazepines are known to cause toxicity in the newborn, most notably, floppy infant syndrome and withdrawal syndrome. In addition, the risk for birth defects from seizures alone is at least two to three times greater than the background risk of 2%–3%.

Until recently, the second-generation AEDs had not been associated with congenital defects. However, new data from the North American AED Pregnancy Registry and five other pregnancy registries have shown a very significant risk of isolated, nonsyndromic oral clefts after first-trimester exposure to lamotrigine (Lamictal) monotherapy (Birth Defects Res. A Clin. Mol. Teratol. 2006;76:313–428). The prevalence of oral clefts in the North American registry was 8.9/1,000, even though all of the mothers had been supplemented with folic acid before conception. This was significantly higher than the prevalence of 0.37/1,000 in a comparison group.

The human pregnancy experience is too limited to assess the embryo/fetal risk for the other second-generation agents: felbamate (Felbatol), gabapentin (Neurontin), pregabalin (Lyrica), levetiracetam (Keppra), tiagabine (Gabitril), and topiramate (Topamax). Although the data also are limited for zonisamide (Zonegran), the drug is teratogenic in three animal species and embryo lethal in a fourth and therefore is best avoided in the first trimester. Oxcarbazepine (Trileptal), a drug closely related to carbamazepine, has been associated with minor facial defects, but the data are too limited to assess the risk in humans.

To summarize, women with epilepsy should not be denied treatment with the most effective agents for their condition because of pregnancy or nursing. They should be treated with the lowest dose and the fewest drugs possible to control their seizures. Periodic serum levels are needed throughout pregnancy to ensure that therapeutic levels are maintained. They should take folic acid (4–5 mg/day), and vitamin K should be given to the newborns.

It is also important to counsel that seizures are a risk to both the mother and the embryo/fetus, as is the drug therapy. AEDs that appear to have the lowest risk for major birth defects are the benzodiazepines, the succinimides, and the second-generation agents. However, the human pregnancy data are very limited for many of these agents.

Carbamazepine and phenytoin are considered compatible with breast-feeding, and gabapentin, levetiracetam, oxcarbazepine, and tiagabine are probably compatible. Two AEDs (primidone and phenobarbital) are known to cause toxicity in the nursing infant and should not be given during breast-feeding. There are no data for the remaining AEDs, but they have the potential to cause toxicity and, if used during breast-feeding, the infants should be closely monitored.

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 many years for peptic ulcer and functional GI disorders such as diarrhea, hypermotility, neurogenic colon, irritable bowel syndrome, ulcerative colitis, biliary tract spasm, and similar conditions. The agents—available under many 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.

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 many years for peptic ulcer and functional GI disorders such as diarrhea, hypermotility, neurogenic colon, irritable bowel syndrome, ulcerative colitis, biliary tract spasm, and similar conditions. The agents—available under many 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.

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 many years for peptic ulcer and functional GI disorders such as diarrhea, hypermotility, neurogenic colon, irritable bowel syndrome, ulcerative colitis, biliary tract spasm, and similar conditions. The agents—available under many 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.

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: Several studies have linked this infection to severe nausea/vomiting of pregnancy. Eradication regimens involve dual, triple, or quadruple therapy, typically 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 best course is to delay therapy until after the first trimester. Of the four anti-infectives used (amoxicillin, clarithromycin, metronidazole, and tetracycline), only tetracycline clearly causes developmental toxicity, but the carcinogenic potential of metronidazole has not been tested adequately.

Two proton pump inhibitors, lansoprazole (Prevacid) and omeprazole (Prilosec, Zegerid), are the antisecretory agents of choice for H. pylori eradication as neither appears to pose 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 prevent 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.

▸ 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 on the second half of pregnancy, which indicate 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. Only fragments of pancreatin and pancrelipase are absorbed systemically. Human data are limited, but 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, but the embryo or fetus is exposed to very small quantities.

▸ 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, INTERNAL MEDICINE NEWS, Feb. 15, 2006, p. 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), which 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: Mesalamine (5-aminosalicylic acid, 5-ASA) (Asacol, Canasa, Pentasa, Rowasa) is compatible with pregnancy. Reports have described several hundred pregnant women who had taken 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 agents appear to be compatible with pregnancy.

A third drug, 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 human experience is limited, sulfasalazine appears to be compatible with pregnancy.

All of the inflammatory bowel disease 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: Several studies have linked this infection to severe nausea/vomiting of pregnancy. Eradication regimens involve dual, triple, or quadruple therapy, typically 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 best course is to delay therapy until after the first trimester. Of the four anti-infectives used (amoxicillin, clarithromycin, metronidazole, and tetracycline), only tetracycline clearly causes developmental toxicity, but the carcinogenic potential of metronidazole has not been tested adequately.

Two proton pump inhibitors, lansoprazole (Prevacid) and omeprazole (Prilosec, Zegerid), are the antisecretory agents of choice for H. pylori eradication as neither appears to pose 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 prevent 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.

▸ 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 on the second half of pregnancy, which indicate 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. Only fragments of pancreatin and pancrelipase are absorbed systemically. Human data are limited, but 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, but the embryo or fetus is exposed to very small quantities.

▸ 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, INTERNAL MEDICINE NEWS, Feb. 15, 2006, p. 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), which 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: Mesalamine (5-aminosalicylic acid, 5-ASA) (Asacol, Canasa, Pentasa, Rowasa) is compatible with pregnancy. Reports have described several hundred pregnant women who had taken 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 agents appear to be compatible with pregnancy.

A third drug, 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 human experience is limited, sulfasalazine appears to be compatible with pregnancy.

All of the inflammatory bowel disease 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: Several studies have linked this infection to severe nausea/vomiting of pregnancy. Eradication regimens involve dual, triple, or quadruple therapy, typically 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 best course is to delay therapy until after the first trimester. Of the four anti-infectives used (amoxicillin, clarithromycin, metronidazole, and tetracycline), only tetracycline clearly causes developmental toxicity, but the carcinogenic potential of metronidazole has not been tested adequately.

Two proton pump inhibitors, lansoprazole (Prevacid) and omeprazole (Prilosec, Zegerid), are the antisecretory agents of choice for H. pylori eradication as neither appears to pose 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 prevent 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.

▸ 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 on the second half of pregnancy, which indicate 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. Only fragments of pancreatin and pancrelipase are absorbed systemically. Human data are limited, but 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, but the embryo or fetus is exposed to very small quantities.

▸ 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, INTERNAL MEDICINE NEWS, Feb. 15, 2006, p. 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), which 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: Mesalamine (5-aminosalicylic acid, 5-ASA) (Asacol, Canasa, Pentasa, Rowasa) is compatible with pregnancy. Reports have described several hundred pregnant women who had taken 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 agents appear to be compatible with pregnancy.

A third drug, 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 human experience is limited, sulfasalazine appears to be compatible with pregnancy.

All of the inflammatory bowel disease 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.