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Drugs approved in 2013
In 2013, the Food and Drug Administration approved 27 new molecular entities (i.e., drugs) for human use. Because of their indications, it is unlikely that four will be used in pregnancy or lactation, so they are not discussed here. The four agents are ospemifene (Osphena), an estrogen agonist/antagonist used for severe dyspareunia; [223Ra]radium dichloride (Xofigo), for late-stage metastatic prostate cancer; conjugated estrogens/bazedoxifene (Duavee) for hot flashes associated with menopause and to prevent osteoporosis; and flutemetamol F-18 injection (Vizamyl), a radioactive diagnostic agent to aid in the evaluation of Alzheimer’s disease and dementia.
There are two other drugs that are unlikely to be used in pregnancy: macitentan (Opsumit) and riociguat (Adempas). These drugs are oral vasodilators indicated for the treatment of pulmonary hypertension. Both are teratogenic in rats and rabbits, but there are no reports of their use in human pregnancy. For female patients of reproductive potential, they are only available through restricted programs. Pregnancy must be excluded before starting therapy, monthly during treatment, and for 1 month after treatment is stopped.
The remaining 21 agents can be classified into the following categories: anticonvulsant (1), antidepressant (1), antidiabetics (2), antineoplastics (7), antihyperlipidemic (1), anti-infectives (4), diagnostics (2), immunologic (1), and respiratory (2). It is important to note that, except for two drugs (fluticasone in a combination product and dimethyl fumarate), there is no reported human pregnancy experience for these agents. Moreover, all probably cross the placenta to the embryo and/or the fetus, at least in some part of pregnancy.
Eslicarbazepine (Aptiom) is indicated as adjunctive treatment of partial-onset seizures. Developmental toxicity was observed in three animals: teratogenicity (mice), embryolethality (rats), and fetal growth restriction (rabbits). The no-effect dose was not found in two species, and was less than the human dose based on body surface area in the third. If a pregnant woman is taking this drug, she should be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 888-233-2334.
Vortioxetine (Brintellix) is indicated for the treatment of major depressive disorder. The drug was not teratogenic in animals but did cause developmental delays in one species. Although the antidepressant mechanism is not fully understood, it appears to be related to the inhibition of the reuptake of serotonin (5-hydroxytryptamine). If so, vortioxetine would be closely related to the drugs in the selective serotonin reuptake inhibitor (SSRI) class: citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), and vilazodone (Viibryd). The relationship could be important because the use of SSRIs or serotonin norepinephrine reuptake inhibitors (SNRIs) close to birth is related to significant toxicity in the newborn.
There are two new antidiabetic agents for the treatment of type 2 diabetes. Alogliptin (Nesina), a dipeptidyl peptidase–4 inhibitor, is in the same pharmacologic class as linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). Canagliflozin (Invokana) is a sodium-glucose cotransporter 2 inhibitor, the first drug in this class to be approved. The animal data for alogliptin suggest low risk, whereas canagliflozin caused renal toxicity in rats at exposures corresponding to the late second and third trimester in humans. Insulin remains the treatment of choice for pregnant diabetics because tight control of glucose levels is beneficial for the mother, embryo-fetus, and newborn.
The seven new antineoplastic agents are ado-trastuzumab emtansine (Kadcyla) for HER2-positive breast cancer; afatinib (Gilotrif) for non–small cell lung cancer; dabrafenib (Tafinlar) for unresectable or metastatic melanoma; ibrutinib (Imbruvica) for mantle cell lymphoma or chronic lymphocytic leukemia; obinutuzumab (Gazyva) for chronic lymphocytic leukemia; pomalidomide (Pomalyst) for multiple myeloma; and trametinib (Mekinist) for unresectable or metastatic melanoma. Only pomalidomide is contraindicated in pregnancy. Although obinutuzumab did not cause teratogenicity in monkeys, its use in the latter portion of pregnancy resulted in newborn depletion of B cells that took up to 6 months after birth to restore. Moreover, it is used in combination with chlorambucil, a known teratogen. The animal data suggest risk in the other five agents. Nevertheless, the maternal condition should determine whether any of these antineoplastics are used in a pregnant woman.
Mipomersen sodium (Kynamro) is given subcutaneously once a week as an adjunct to lipid-lowering medications. The drug caused embryo toxicity in one of three animal species.
Among the four anti-infectives are two oral agents for the treatment of chronic hepatitis C virus infection: simeprevir (Olysio) and sofosbuvir (Sovaldi). Because both agents are recommended to be combined with peginterferon alfa and ribavirin, they are classified as contraindicated in pregnancy. However, when used alone, the animal data suggest that sofosbuvir was low risk, whereas simeprevir might have higher risk.
Luliconazole (Luzu), an azole antifungal, is a cream used for the treatment of tinea pedis, tinea cruris, and tinea corporis. Systemic absorption is minimal. The animal data suggest low risk, but there are no human pregnancy reports. Nevertheless, topical use is probably compatible in pregnancy, as are the other topical azole antifungals in this pharmacologic class: clotrimazole (Lotrimin), econazole (Spectazole), ketoconazole (Kuric), miconazole (Micatin), oxiconazole (Oxistat), sertaconazole (Ertaczo), and sulconazole (Exelderm).
Dolutegravir (Tivicay) is an HIV-1 integrase strand transfer inhibitor given in combination with other antiretroviral drugs. The animal data suggest low risk. If indicated, the drug should not be withheld because of pregnancy.
Gadoterate meglumine (Dotarem), a gadolinium-based contrast agent, is indicated to detect and visualize areas with disruption of the blood brain barrier and/or abnormal vascularity. No developmental toxicity was observed in pregnant animals. Closely related diagnostic agents are gadobenate dimeglumine (MultiHance), gadodiamide (Omniscan), gadofosveset (Ablavar), gadopentetate dimeglumine (Magnevist), gadoteridol (Prohance), and gadoversetamide (OptiMARK). Although the animal data for these agents show risk, no harm has been reported in human pregnancies. However, the available human data are very limited, and the risk magnitude for embryo-fetal harm remains unknown.
Technetium (99mTc) tilmanocept (Lymphoseek) is a radioactive diagnostic agent used in patients with breast cancer or melanoma. The active ingredient is technetium (99mTc). Animal reproduction studies have not been conducted. 99mTc is probably compatible in pregnancy (see Drugs in Pregnancy and Lactation, 10th ed.; Philadelphia: Lippincott, Williams and Wilkins, 2014:1317-8; to be released in August), but the risk of the tilmanocept moiety is unknown.
The immunologic agent dimethyl fumarate (Tecfidera) is indicated for the treatment of patients with relapsing forms of multiple sclerosis. The drug caused developmental toxicity (embryolethality, impaired growth, and birth defects) in animals during all portions of pregnancy. In clinical trials, there were 38 exposed pregnancies with the following outcomes: 22 live births, 3 spontaneous abortions, 9 elective abortions, 3 ongoing pregnancies, and 1 lost to follow-up (CNS Drugs 2014;28:89-94). A pregnancy registry has been established, and patients should be encouraged to enroll by calling 800-456-2255.
Two new respiratory combination products were approved in 2013, both for chronic obstructive pulmonary disease: fluticasone/vilanterol (Breo Ellipta) and umeclidinium/vilanterol (Anoro Ellipta). Inhaled fluticasone, a corticosteroid, is compatible in pregnancy (see Drugs in Pregnancy and Lactation, 9th ed.; Philadelphia: Lippincott, Williams and Wilkins; 2011:599-601). Vilanterol is a long-acting beta2-adrenergic agonist that is probably compatible in pregnancy. The absolute bioavailability of inhaled fluticasone and vilanterol in nonpregnant adults was about 15% and 27%, respectively. The animal data for the combination or when given individually suggest low risk in pregnancy. Umeclidinium is a long-acting anticholinergic. It also is absorbed from the lung, but the amount was not specified by the manufacturer. The animal data for umeclidinium suggest low risk.
There are no reports of the above drugs being used during breastfeeding, but excretion into breast milk should be expected. The effect of these exposures on a nursing infant is unknown. However, if a mother is taking one of these drugs and breastfeeding, her infant should be monitored for adverse effects, especially those that are the most common (typically listed on the first page of the package insert) in patients taking the drug. Close monitoring is particularly important during the first 2 postpartum months. A 2003 study found that most adverse reactions in nursing infants occurred within that time period (Clin. Pediatr. 2003;42:325-40).
Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no other relevant financial disclosures. Contact him at [email protected].
In 2013, the Food and Drug Administration approved 27 new molecular entities (i.e., drugs) for human use. Because of their indications, it is unlikely that four will be used in pregnancy or lactation, so they are not discussed here. The four agents are ospemifene (Osphena), an estrogen agonist/antagonist used for severe dyspareunia; [223Ra]radium dichloride (Xofigo), for late-stage metastatic prostate cancer; conjugated estrogens/bazedoxifene (Duavee) for hot flashes associated with menopause and to prevent osteoporosis; and flutemetamol F-18 injection (Vizamyl), a radioactive diagnostic agent to aid in the evaluation of Alzheimer’s disease and dementia.
There are two other drugs that are unlikely to be used in pregnancy: macitentan (Opsumit) and riociguat (Adempas). These drugs are oral vasodilators indicated for the treatment of pulmonary hypertension. Both are teratogenic in rats and rabbits, but there are no reports of their use in human pregnancy. For female patients of reproductive potential, they are only available through restricted programs. Pregnancy must be excluded before starting therapy, monthly during treatment, and for 1 month after treatment is stopped.
The remaining 21 agents can be classified into the following categories: anticonvulsant (1), antidepressant (1), antidiabetics (2), antineoplastics (7), antihyperlipidemic (1), anti-infectives (4), diagnostics (2), immunologic (1), and respiratory (2). It is important to note that, except for two drugs (fluticasone in a combination product and dimethyl fumarate), there is no reported human pregnancy experience for these agents. Moreover, all probably cross the placenta to the embryo and/or the fetus, at least in some part of pregnancy.
Eslicarbazepine (Aptiom) is indicated as adjunctive treatment of partial-onset seizures. Developmental toxicity was observed in three animals: teratogenicity (mice), embryolethality (rats), and fetal growth restriction (rabbits). The no-effect dose was not found in two species, and was less than the human dose based on body surface area in the third. If a pregnant woman is taking this drug, she should be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 888-233-2334.
Vortioxetine (Brintellix) is indicated for the treatment of major depressive disorder. The drug was not teratogenic in animals but did cause developmental delays in one species. Although the antidepressant mechanism is not fully understood, it appears to be related to the inhibition of the reuptake of serotonin (5-hydroxytryptamine). If so, vortioxetine would be closely related to the drugs in the selective serotonin reuptake inhibitor (SSRI) class: citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), and vilazodone (Viibryd). The relationship could be important because the use of SSRIs or serotonin norepinephrine reuptake inhibitors (SNRIs) close to birth is related to significant toxicity in the newborn.
There are two new antidiabetic agents for the treatment of type 2 diabetes. Alogliptin (Nesina), a dipeptidyl peptidase–4 inhibitor, is in the same pharmacologic class as linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). Canagliflozin (Invokana) is a sodium-glucose cotransporter 2 inhibitor, the first drug in this class to be approved. The animal data for alogliptin suggest low risk, whereas canagliflozin caused renal toxicity in rats at exposures corresponding to the late second and third trimester in humans. Insulin remains the treatment of choice for pregnant diabetics because tight control of glucose levels is beneficial for the mother, embryo-fetus, and newborn.
The seven new antineoplastic agents are ado-trastuzumab emtansine (Kadcyla) for HER2-positive breast cancer; afatinib (Gilotrif) for non–small cell lung cancer; dabrafenib (Tafinlar) for unresectable or metastatic melanoma; ibrutinib (Imbruvica) for mantle cell lymphoma or chronic lymphocytic leukemia; obinutuzumab (Gazyva) for chronic lymphocytic leukemia; pomalidomide (Pomalyst) for multiple myeloma; and trametinib (Mekinist) for unresectable or metastatic melanoma. Only pomalidomide is contraindicated in pregnancy. Although obinutuzumab did not cause teratogenicity in monkeys, its use in the latter portion of pregnancy resulted in newborn depletion of B cells that took up to 6 months after birth to restore. Moreover, it is used in combination with chlorambucil, a known teratogen. The animal data suggest risk in the other five agents. Nevertheless, the maternal condition should determine whether any of these antineoplastics are used in a pregnant woman.
Mipomersen sodium (Kynamro) is given subcutaneously once a week as an adjunct to lipid-lowering medications. The drug caused embryo toxicity in one of three animal species.
Among the four anti-infectives are two oral agents for the treatment of chronic hepatitis C virus infection: simeprevir (Olysio) and sofosbuvir (Sovaldi). Because both agents are recommended to be combined with peginterferon alfa and ribavirin, they are classified as contraindicated in pregnancy. However, when used alone, the animal data suggest that sofosbuvir was low risk, whereas simeprevir might have higher risk.
Luliconazole (Luzu), an azole antifungal, is a cream used for the treatment of tinea pedis, tinea cruris, and tinea corporis. Systemic absorption is minimal. The animal data suggest low risk, but there are no human pregnancy reports. Nevertheless, topical use is probably compatible in pregnancy, as are the other topical azole antifungals in this pharmacologic class: clotrimazole (Lotrimin), econazole (Spectazole), ketoconazole (Kuric), miconazole (Micatin), oxiconazole (Oxistat), sertaconazole (Ertaczo), and sulconazole (Exelderm).
Dolutegravir (Tivicay) is an HIV-1 integrase strand transfer inhibitor given in combination with other antiretroviral drugs. The animal data suggest low risk. If indicated, the drug should not be withheld because of pregnancy.
Gadoterate meglumine (Dotarem), a gadolinium-based contrast agent, is indicated to detect and visualize areas with disruption of the blood brain barrier and/or abnormal vascularity. No developmental toxicity was observed in pregnant animals. Closely related diagnostic agents are gadobenate dimeglumine (MultiHance), gadodiamide (Omniscan), gadofosveset (Ablavar), gadopentetate dimeglumine (Magnevist), gadoteridol (Prohance), and gadoversetamide (OptiMARK). Although the animal data for these agents show risk, no harm has been reported in human pregnancies. However, the available human data are very limited, and the risk magnitude for embryo-fetal harm remains unknown.
Technetium (99mTc) tilmanocept (Lymphoseek) is a radioactive diagnostic agent used in patients with breast cancer or melanoma. The active ingredient is technetium (99mTc). Animal reproduction studies have not been conducted. 99mTc is probably compatible in pregnancy (see Drugs in Pregnancy and Lactation, 10th ed.; Philadelphia: Lippincott, Williams and Wilkins, 2014:1317-8; to be released in August), but the risk of the tilmanocept moiety is unknown.
The immunologic agent dimethyl fumarate (Tecfidera) is indicated for the treatment of patients with relapsing forms of multiple sclerosis. The drug caused developmental toxicity (embryolethality, impaired growth, and birth defects) in animals during all portions of pregnancy. In clinical trials, there were 38 exposed pregnancies with the following outcomes: 22 live births, 3 spontaneous abortions, 9 elective abortions, 3 ongoing pregnancies, and 1 lost to follow-up (CNS Drugs 2014;28:89-94). A pregnancy registry has been established, and patients should be encouraged to enroll by calling 800-456-2255.
Two new respiratory combination products were approved in 2013, both for chronic obstructive pulmonary disease: fluticasone/vilanterol (Breo Ellipta) and umeclidinium/vilanterol (Anoro Ellipta). Inhaled fluticasone, a corticosteroid, is compatible in pregnancy (see Drugs in Pregnancy and Lactation, 9th ed.; Philadelphia: Lippincott, Williams and Wilkins; 2011:599-601). Vilanterol is a long-acting beta2-adrenergic agonist that is probably compatible in pregnancy. The absolute bioavailability of inhaled fluticasone and vilanterol in nonpregnant adults was about 15% and 27%, respectively. The animal data for the combination or when given individually suggest low risk in pregnancy. Umeclidinium is a long-acting anticholinergic. It also is absorbed from the lung, but the amount was not specified by the manufacturer. The animal data for umeclidinium suggest low risk.
There are no reports of the above drugs being used during breastfeeding, but excretion into breast milk should be expected. The effect of these exposures on a nursing infant is unknown. However, if a mother is taking one of these drugs and breastfeeding, her infant should be monitored for adverse effects, especially those that are the most common (typically listed on the first page of the package insert) in patients taking the drug. Close monitoring is particularly important during the first 2 postpartum months. A 2003 study found that most adverse reactions in nursing infants occurred within that time period (Clin. Pediatr. 2003;42:325-40).
Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no other relevant financial disclosures. Contact him at [email protected].
In 2013, the Food and Drug Administration approved 27 new molecular entities (i.e., drugs) for human use. Because of their indications, it is unlikely that four will be used in pregnancy or lactation, so they are not discussed here. The four agents are ospemifene (Osphena), an estrogen agonist/antagonist used for severe dyspareunia; [223Ra]radium dichloride (Xofigo), for late-stage metastatic prostate cancer; conjugated estrogens/bazedoxifene (Duavee) for hot flashes associated with menopause and to prevent osteoporosis; and flutemetamol F-18 injection (Vizamyl), a radioactive diagnostic agent to aid in the evaluation of Alzheimer’s disease and dementia.
There are two other drugs that are unlikely to be used in pregnancy: macitentan (Opsumit) and riociguat (Adempas). These drugs are oral vasodilators indicated for the treatment of pulmonary hypertension. Both are teratogenic in rats and rabbits, but there are no reports of their use in human pregnancy. For female patients of reproductive potential, they are only available through restricted programs. Pregnancy must be excluded before starting therapy, monthly during treatment, and for 1 month after treatment is stopped.
The remaining 21 agents can be classified into the following categories: anticonvulsant (1), antidepressant (1), antidiabetics (2), antineoplastics (7), antihyperlipidemic (1), anti-infectives (4), diagnostics (2), immunologic (1), and respiratory (2). It is important to note that, except for two drugs (fluticasone in a combination product and dimethyl fumarate), there is no reported human pregnancy experience for these agents. Moreover, all probably cross the placenta to the embryo and/or the fetus, at least in some part of pregnancy.
Eslicarbazepine (Aptiom) is indicated as adjunctive treatment of partial-onset seizures. Developmental toxicity was observed in three animals: teratogenicity (mice), embryolethality (rats), and fetal growth restriction (rabbits). The no-effect dose was not found in two species, and was less than the human dose based on body surface area in the third. If a pregnant woman is taking this drug, she should be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 888-233-2334.
Vortioxetine (Brintellix) is indicated for the treatment of major depressive disorder. The drug was not teratogenic in animals but did cause developmental delays in one species. Although the antidepressant mechanism is not fully understood, it appears to be related to the inhibition of the reuptake of serotonin (5-hydroxytryptamine). If so, vortioxetine would be closely related to the drugs in the selective serotonin reuptake inhibitor (SSRI) class: citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), and vilazodone (Viibryd). The relationship could be important because the use of SSRIs or serotonin norepinephrine reuptake inhibitors (SNRIs) close to birth is related to significant toxicity in the newborn.
There are two new antidiabetic agents for the treatment of type 2 diabetes. Alogliptin (Nesina), a dipeptidyl peptidase–4 inhibitor, is in the same pharmacologic class as linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). Canagliflozin (Invokana) is a sodium-glucose cotransporter 2 inhibitor, the first drug in this class to be approved. The animal data for alogliptin suggest low risk, whereas canagliflozin caused renal toxicity in rats at exposures corresponding to the late second and third trimester in humans. Insulin remains the treatment of choice for pregnant diabetics because tight control of glucose levels is beneficial for the mother, embryo-fetus, and newborn.
The seven new antineoplastic agents are ado-trastuzumab emtansine (Kadcyla) for HER2-positive breast cancer; afatinib (Gilotrif) for non–small cell lung cancer; dabrafenib (Tafinlar) for unresectable or metastatic melanoma; ibrutinib (Imbruvica) for mantle cell lymphoma or chronic lymphocytic leukemia; obinutuzumab (Gazyva) for chronic lymphocytic leukemia; pomalidomide (Pomalyst) for multiple myeloma; and trametinib (Mekinist) for unresectable or metastatic melanoma. Only pomalidomide is contraindicated in pregnancy. Although obinutuzumab did not cause teratogenicity in monkeys, its use in the latter portion of pregnancy resulted in newborn depletion of B cells that took up to 6 months after birth to restore. Moreover, it is used in combination with chlorambucil, a known teratogen. The animal data suggest risk in the other five agents. Nevertheless, the maternal condition should determine whether any of these antineoplastics are used in a pregnant woman.
Mipomersen sodium (Kynamro) is given subcutaneously once a week as an adjunct to lipid-lowering medications. The drug caused embryo toxicity in one of three animal species.
Among the four anti-infectives are two oral agents for the treatment of chronic hepatitis C virus infection: simeprevir (Olysio) and sofosbuvir (Sovaldi). Because both agents are recommended to be combined with peginterferon alfa and ribavirin, they are classified as contraindicated in pregnancy. However, when used alone, the animal data suggest that sofosbuvir was low risk, whereas simeprevir might have higher risk.
Luliconazole (Luzu), an azole antifungal, is a cream used for the treatment of tinea pedis, tinea cruris, and tinea corporis. Systemic absorption is minimal. The animal data suggest low risk, but there are no human pregnancy reports. Nevertheless, topical use is probably compatible in pregnancy, as are the other topical azole antifungals in this pharmacologic class: clotrimazole (Lotrimin), econazole (Spectazole), ketoconazole (Kuric), miconazole (Micatin), oxiconazole (Oxistat), sertaconazole (Ertaczo), and sulconazole (Exelderm).
Dolutegravir (Tivicay) is an HIV-1 integrase strand transfer inhibitor given in combination with other antiretroviral drugs. The animal data suggest low risk. If indicated, the drug should not be withheld because of pregnancy.
Gadoterate meglumine (Dotarem), a gadolinium-based contrast agent, is indicated to detect and visualize areas with disruption of the blood brain barrier and/or abnormal vascularity. No developmental toxicity was observed in pregnant animals. Closely related diagnostic agents are gadobenate dimeglumine (MultiHance), gadodiamide (Omniscan), gadofosveset (Ablavar), gadopentetate dimeglumine (Magnevist), gadoteridol (Prohance), and gadoversetamide (OptiMARK). Although the animal data for these agents show risk, no harm has been reported in human pregnancies. However, the available human data are very limited, and the risk magnitude for embryo-fetal harm remains unknown.
Technetium (99mTc) tilmanocept (Lymphoseek) is a radioactive diagnostic agent used in patients with breast cancer or melanoma. The active ingredient is technetium (99mTc). Animal reproduction studies have not been conducted. 99mTc is probably compatible in pregnancy (see Drugs in Pregnancy and Lactation, 10th ed.; Philadelphia: Lippincott, Williams and Wilkins, 2014:1317-8; to be released in August), but the risk of the tilmanocept moiety is unknown.
The immunologic agent dimethyl fumarate (Tecfidera) is indicated for the treatment of patients with relapsing forms of multiple sclerosis. The drug caused developmental toxicity (embryolethality, impaired growth, and birth defects) in animals during all portions of pregnancy. In clinical trials, there were 38 exposed pregnancies with the following outcomes: 22 live births, 3 spontaneous abortions, 9 elective abortions, 3 ongoing pregnancies, and 1 lost to follow-up (CNS Drugs 2014;28:89-94). A pregnancy registry has been established, and patients should be encouraged to enroll by calling 800-456-2255.
Two new respiratory combination products were approved in 2013, both for chronic obstructive pulmonary disease: fluticasone/vilanterol (Breo Ellipta) and umeclidinium/vilanterol (Anoro Ellipta). Inhaled fluticasone, a corticosteroid, is compatible in pregnancy (see Drugs in Pregnancy and Lactation, 9th ed.; Philadelphia: Lippincott, Williams and Wilkins; 2011:599-601). Vilanterol is a long-acting beta2-adrenergic agonist that is probably compatible in pregnancy. The absolute bioavailability of inhaled fluticasone and vilanterol in nonpregnant adults was about 15% and 27%, respectively. The animal data for the combination or when given individually suggest low risk in pregnancy. Umeclidinium is a long-acting anticholinergic. It also is absorbed from the lung, but the amount was not specified by the manufacturer. The animal data for umeclidinium suggest low risk.
There are no reports of the above drugs being used during breastfeeding, but excretion into breast milk should be expected. The effect of these exposures on a nursing infant is unknown. However, if a mother is taking one of these drugs and breastfeeding, her infant should be monitored for adverse effects, especially those that are the most common (typically listed on the first page of the package insert) in patients taking the drug. Close monitoring is particularly important during the first 2 postpartum months. A 2003 study found that most adverse reactions in nursing infants occurred within that time period (Clin. Pediatr. 2003;42:325-40).
Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no other relevant financial disclosures. Contact him at [email protected].
Antidotes, detoxification agents, and pregnancy
By their very nature, antidotes and detoxification agents are needed in situations where the health and well-being of the mother are in jeopardy. In nearly all such cases, the mother’s condition will take priority over the safety of the embryo-fetus. Only two of the drugs (ethanol and penicillamine) are known to cause embryo or fetal harm but, for most of these drugs, the reported human pregnancy experience is very limited or absent. Nevertheless, pregnant women should be treated the same way as nonpregnant women.
Activated charcoal prevents absorption of substances from the gut and is no risk to the mother or her pregnancy. Similarly, ipecac syrup, which is used to induce vomiting, is safe in pregnancy.
Several agents are available for the reversal of opioid (natural or synthetic) overdose that is causing respiratory depression and/or marked sedation: naloxone, naltrexone, and nalmefene, a long-acting derivative of naltrexone (plasma half-life about 10 hours). Of the three agents, naloxone is the one for which there is the most human pregnancy experience. It has no intrinsic respiratory depressive activity or other narcotic effects of its own. All of these agents can be used in pregnancy for acute narcotic overdose.
Acetylcysteine is used to prevent or lessen hepatic injury following the ingestion of potentially hepatic toxic doses of acetaminophen. The antidote is not teratogenic or embryo toxic, and limited human pregnancy data have not shown fetal toxicity. After IV administration, acetylcysteine crosses the placenta in sufficient amounts to achieve protective serum levels in the fetus.
Potentially life-threatening digoxin overdose can be treated with IV digoxin immune Fab (ovine). The use of the agent has been reported in 44 pregnancies, but none of the cases involved digitalis overdose (all women had severe preeclampsia). No fetal harm secondary to the drug was observed.
Flumazenil is indicated for the reversal of benzodiazepine overdose. The drug is not teratogenic or embryo-fetal toxic in animals at systemic exposures near those obtained in humans. Based on very limited data, it appears to cross the human placenta and to reverse the depressive effects of benzodiazepines on the fetus.
Fomepizole is used for the treatment of ethylene glycol or methanol ingestion. It inhibits alcohol dehydrogenase, an enzyme that catalyzes the oxidation of the two chemicals to their toxic metabolites. The drug was not teratogenic in mice, but only one case of human pregnancy exposure has been reported, and the pregnancy outcome was unknown. Ethanol also has been used for poisonings with these two chemicals. Although the fetal effects of this short-term (24-48 hours) use have not been studied, neurotoxicity is a potential complication.
Glucarpidase is indicated for the treatment of toxic plasma methotrexate levels. It converts methotrexate to inactive metabolites. There are no reports of its use in human or animal pregnancies. Human reports are unlikely because methotrexate is contraindicated in pregnancy.
There are six agents available to treat heavy metal (arsenic, gold, iron, lead, and mercury) intoxication: deferasirox (iron), deferoxamine (iron), dimercaprol (arsenic, gold, lead, and mercury), edetate calcium disodium (lead), penicillamine (copper and mercury), and succimer (lead).
Deferasirox is indicated for chronic iron overload due to blood transfusions. Three reports have described its use in the first half of pregnancy without embryo or fetal harm. Deferoxamine is used for the treatment of both acute and chronic iron overload. Although the drug causes toxicity in two animal species, the human pregnancy experience is substantial, and no embryo or fetal adverse effects attributable to the agent have been reported. Dimercaprol (British anti-Lewisite; BAL) is used for the treatment of arsenic, gold, and acute mercury poisoning (not effective for chronic mercury poisoning). It is also combined with edetate calcium disodium for lead poisoning. High doses are embryotoxic and teratogenic in mice. The published human pregnancy experience is limited and all involved exposures after the first trimester. High levels of arsenic or lead were found in the newborns in two cases.
Edetate calcium disodium forms stable chelates with a number of metals, but it is primarily used for lead overdose, either alone or in combination with dimercaprol. There are only a few reports of its use in human pregnancy, all occurring late in gestation. A potential complication of therapy is maternal hypotension that could jeopardize placental perfusion. The agent also chelates zinc, resulting in zinc deficiency. This mechanism was thought to be involved in the teratogenic effects seen in animals.
Penicillamine has been used in mercury poisoning (one report), in addition to its indication as a chelating agent for copper in the treatment of Wilson’s disease. Exposure in the first trimester is related to a risk of connective tissue anomalies, primarily cutis laxa. Succimer (dimercaptosuccinic acid; DMSA) has been used for lead, arsenic, mercury, and cadmium poisoning. It also chelates zinc quite effectively. The agent is toxic and/or teratogenic in mice and rats, but some of the effects may have been secondary to zinc deficiency. Because of the complete absence of human pregnancy experience, antidotes other than succimer probably are preferable.
Lanthanum carbonate and sevelamer are indicated to reduce serum phosphate levels in patients with end-stage renal disease. The drugs bind dietary phosphate from food during digestion in the gut. There are no reports of their use in human pregnancy. The systemic bioavailability is minimal, and the drugs should have no effect on the embryo or fetus. However, they may prevent intestinal vitamin absorption, especially of fat-soluble vitamins.
The cholinergic agent physostigmine is capable of reversing the central nervous system effects of anticholinergics, such as scopolamine and tricyclic antidepressants. The reported human pregnancy experience is limited to the third trimester.
Methylene blue has been used for cyanide poisoning. In humans, it is teratogenic and fetal toxic when given by intra-amniotic injection, but its oral use as an antidote in pregnancy has not been reported. The cyanide antidote package contains amyl nitrite, sodium nitrite, and sodium thiosulfate. The effects of these agents on human pregnancy also are unknown, as are the effects of high-dose hydroxocobalamin, an analogue of vitamin B12 also used in cyanide poisoning.
Pralidoxime (2-PAM) reactivates cholinesterase that has been inactivated by organophosphate pesticides and chemicals with anticholinesterase activity, thereby relieving the paralysis of the muscles of respiration. The drug is available in an autoinjector that can be used rapidly in cases of exposure to nerve agents possessing anticholinesterase activity (organophosphate poisoning). Animal reproduction tests have not been conducted with pralidoxime, and the human pregnancy experience is limited to a few cases of insecticide poisoning (second and third trimesters). Healthy infants were later delivered in these cases.
Four antivenins are commercially available for acute envenomation: black widow spider antivenin, Centruroides (scorpion) immune F(ab\')2 (equine), crotalidae polyvalent immune Fab (ovine) (North American rattlesnake), and North American coral snake antivenin (equine). In addition, botulism antitoxin heptavalent (equine) is used for food poisoning caused by the neurotoxic bacterium Clostridium botulinum. Animal reproduction studies have not been conducted with these products, and human reports are limited or absent.
Sapropterin, a cofactor for the enzyme phenylalanine hydroxylase, reduces blood phenylalanine levels in patients with phenylketonuria. The drug is given daily if diet alone does not control maternal phenylalanine levels. Use of the drug in human pregnancy has not been reported.
A number of other agents can be classified as antidotes, in addition to their primary indications, because they can reverse the toxic effects of other agents. These antidotes include atropine (severe bradycardia, poisonings with organophosphates and carbamates), calcium chloride or gluconate (severe hypocalcemia, calcium-channel-blocker overdose, exposure to hydrofluoric acid), glucagon (hypoglycemia), folinic acid (methotrexate overdose), protamine (heparin overdose), pyridoxine (isoniazid-induced seizures; adjunct in ethylene glycol poisoning), and vitamin K (phytonadione) (warfarin overdose). The pregnancy data are extensive for many of these agents and are not suggestive of significant embryo or fetal risk.
Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no relevant financial disclosures. Contact him at [email protected].
By their very nature, antidotes and detoxification agents are needed in situations where the health and well-being of the mother are in jeopardy. In nearly all such cases, the mother’s condition will take priority over the safety of the embryo-fetus. Only two of the drugs (ethanol and penicillamine) are known to cause embryo or fetal harm but, for most of these drugs, the reported human pregnancy experience is very limited or absent. Nevertheless, pregnant women should be treated the same way as nonpregnant women.
Activated charcoal prevents absorption of substances from the gut and is no risk to the mother or her pregnancy. Similarly, ipecac syrup, which is used to induce vomiting, is safe in pregnancy.
Several agents are available for the reversal of opioid (natural or synthetic) overdose that is causing respiratory depression and/or marked sedation: naloxone, naltrexone, and nalmefene, a long-acting derivative of naltrexone (plasma half-life about 10 hours). Of the three agents, naloxone is the one for which there is the most human pregnancy experience. It has no intrinsic respiratory depressive activity or other narcotic effects of its own. All of these agents can be used in pregnancy for acute narcotic overdose.
Acetylcysteine is used to prevent or lessen hepatic injury following the ingestion of potentially hepatic toxic doses of acetaminophen. The antidote is not teratogenic or embryo toxic, and limited human pregnancy data have not shown fetal toxicity. After IV administration, acetylcysteine crosses the placenta in sufficient amounts to achieve protective serum levels in the fetus.
Potentially life-threatening digoxin overdose can be treated with IV digoxin immune Fab (ovine). The use of the agent has been reported in 44 pregnancies, but none of the cases involved digitalis overdose (all women had severe preeclampsia). No fetal harm secondary to the drug was observed.
Flumazenil is indicated for the reversal of benzodiazepine overdose. The drug is not teratogenic or embryo-fetal toxic in animals at systemic exposures near those obtained in humans. Based on very limited data, it appears to cross the human placenta and to reverse the depressive effects of benzodiazepines on the fetus.
Fomepizole is used for the treatment of ethylene glycol or methanol ingestion. It inhibits alcohol dehydrogenase, an enzyme that catalyzes the oxidation of the two chemicals to their toxic metabolites. The drug was not teratogenic in mice, but only one case of human pregnancy exposure has been reported, and the pregnancy outcome was unknown. Ethanol also has been used for poisonings with these two chemicals. Although the fetal effects of this short-term (24-48 hours) use have not been studied, neurotoxicity is a potential complication.
Glucarpidase is indicated for the treatment of toxic plasma methotrexate levels. It converts methotrexate to inactive metabolites. There are no reports of its use in human or animal pregnancies. Human reports are unlikely because methotrexate is contraindicated in pregnancy.
There are six agents available to treat heavy metal (arsenic, gold, iron, lead, and mercury) intoxication: deferasirox (iron), deferoxamine (iron), dimercaprol (arsenic, gold, lead, and mercury), edetate calcium disodium (lead), penicillamine (copper and mercury), and succimer (lead).
Deferasirox is indicated for chronic iron overload due to blood transfusions. Three reports have described its use in the first half of pregnancy without embryo or fetal harm. Deferoxamine is used for the treatment of both acute and chronic iron overload. Although the drug causes toxicity in two animal species, the human pregnancy experience is substantial, and no embryo or fetal adverse effects attributable to the agent have been reported. Dimercaprol (British anti-Lewisite; BAL) is used for the treatment of arsenic, gold, and acute mercury poisoning (not effective for chronic mercury poisoning). It is also combined with edetate calcium disodium for lead poisoning. High doses are embryotoxic and teratogenic in mice. The published human pregnancy experience is limited and all involved exposures after the first trimester. High levels of arsenic or lead were found in the newborns in two cases.
Edetate calcium disodium forms stable chelates with a number of metals, but it is primarily used for lead overdose, either alone or in combination with dimercaprol. There are only a few reports of its use in human pregnancy, all occurring late in gestation. A potential complication of therapy is maternal hypotension that could jeopardize placental perfusion. The agent also chelates zinc, resulting in zinc deficiency. This mechanism was thought to be involved in the teratogenic effects seen in animals.
Penicillamine has been used in mercury poisoning (one report), in addition to its indication as a chelating agent for copper in the treatment of Wilson’s disease. Exposure in the first trimester is related to a risk of connective tissue anomalies, primarily cutis laxa. Succimer (dimercaptosuccinic acid; DMSA) has been used for lead, arsenic, mercury, and cadmium poisoning. It also chelates zinc quite effectively. The agent is toxic and/or teratogenic in mice and rats, but some of the effects may have been secondary to zinc deficiency. Because of the complete absence of human pregnancy experience, antidotes other than succimer probably are preferable.
Lanthanum carbonate and sevelamer are indicated to reduce serum phosphate levels in patients with end-stage renal disease. The drugs bind dietary phosphate from food during digestion in the gut. There are no reports of their use in human pregnancy. The systemic bioavailability is minimal, and the drugs should have no effect on the embryo or fetus. However, they may prevent intestinal vitamin absorption, especially of fat-soluble vitamins.
The cholinergic agent physostigmine is capable of reversing the central nervous system effects of anticholinergics, such as scopolamine and tricyclic antidepressants. The reported human pregnancy experience is limited to the third trimester.
Methylene blue has been used for cyanide poisoning. In humans, it is teratogenic and fetal toxic when given by intra-amniotic injection, but its oral use as an antidote in pregnancy has not been reported. The cyanide antidote package contains amyl nitrite, sodium nitrite, and sodium thiosulfate. The effects of these agents on human pregnancy also are unknown, as are the effects of high-dose hydroxocobalamin, an analogue of vitamin B12 also used in cyanide poisoning.
Pralidoxime (2-PAM) reactivates cholinesterase that has been inactivated by organophosphate pesticides and chemicals with anticholinesterase activity, thereby relieving the paralysis of the muscles of respiration. The drug is available in an autoinjector that can be used rapidly in cases of exposure to nerve agents possessing anticholinesterase activity (organophosphate poisoning). Animal reproduction tests have not been conducted with pralidoxime, and the human pregnancy experience is limited to a few cases of insecticide poisoning (second and third trimesters). Healthy infants were later delivered in these cases.
Four antivenins are commercially available for acute envenomation: black widow spider antivenin, Centruroides (scorpion) immune F(ab\')2 (equine), crotalidae polyvalent immune Fab (ovine) (North American rattlesnake), and North American coral snake antivenin (equine). In addition, botulism antitoxin heptavalent (equine) is used for food poisoning caused by the neurotoxic bacterium Clostridium botulinum. Animal reproduction studies have not been conducted with these products, and human reports are limited or absent.
Sapropterin, a cofactor for the enzyme phenylalanine hydroxylase, reduces blood phenylalanine levels in patients with phenylketonuria. The drug is given daily if diet alone does not control maternal phenylalanine levels. Use of the drug in human pregnancy has not been reported.
A number of other agents can be classified as antidotes, in addition to their primary indications, because they can reverse the toxic effects of other agents. These antidotes include atropine (severe bradycardia, poisonings with organophosphates and carbamates), calcium chloride or gluconate (severe hypocalcemia, calcium-channel-blocker overdose, exposure to hydrofluoric acid), glucagon (hypoglycemia), folinic acid (methotrexate overdose), protamine (heparin overdose), pyridoxine (isoniazid-induced seizures; adjunct in ethylene glycol poisoning), and vitamin K (phytonadione) (warfarin overdose). The pregnancy data are extensive for many of these agents and are not suggestive of significant embryo or fetal risk.
Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no relevant financial disclosures. Contact him at [email protected].
By their very nature, antidotes and detoxification agents are needed in situations where the health and well-being of the mother are in jeopardy. In nearly all such cases, the mother’s condition will take priority over the safety of the embryo-fetus. Only two of the drugs (ethanol and penicillamine) are known to cause embryo or fetal harm but, for most of these drugs, the reported human pregnancy experience is very limited or absent. Nevertheless, pregnant women should be treated the same way as nonpregnant women.
Activated charcoal prevents absorption of substances from the gut and is no risk to the mother or her pregnancy. Similarly, ipecac syrup, which is used to induce vomiting, is safe in pregnancy.
Several agents are available for the reversal of opioid (natural or synthetic) overdose that is causing respiratory depression and/or marked sedation: naloxone, naltrexone, and nalmefene, a long-acting derivative of naltrexone (plasma half-life about 10 hours). Of the three agents, naloxone is the one for which there is the most human pregnancy experience. It has no intrinsic respiratory depressive activity or other narcotic effects of its own. All of these agents can be used in pregnancy for acute narcotic overdose.
Acetylcysteine is used to prevent or lessen hepatic injury following the ingestion of potentially hepatic toxic doses of acetaminophen. The antidote is not teratogenic or embryo toxic, and limited human pregnancy data have not shown fetal toxicity. After IV administration, acetylcysteine crosses the placenta in sufficient amounts to achieve protective serum levels in the fetus.
Potentially life-threatening digoxin overdose can be treated with IV digoxin immune Fab (ovine). The use of the agent has been reported in 44 pregnancies, but none of the cases involved digitalis overdose (all women had severe preeclampsia). No fetal harm secondary to the drug was observed.
Flumazenil is indicated for the reversal of benzodiazepine overdose. The drug is not teratogenic or embryo-fetal toxic in animals at systemic exposures near those obtained in humans. Based on very limited data, it appears to cross the human placenta and to reverse the depressive effects of benzodiazepines on the fetus.
Fomepizole is used for the treatment of ethylene glycol or methanol ingestion. It inhibits alcohol dehydrogenase, an enzyme that catalyzes the oxidation of the two chemicals to their toxic metabolites. The drug was not teratogenic in mice, but only one case of human pregnancy exposure has been reported, and the pregnancy outcome was unknown. Ethanol also has been used for poisonings with these two chemicals. Although the fetal effects of this short-term (24-48 hours) use have not been studied, neurotoxicity is a potential complication.
Glucarpidase is indicated for the treatment of toxic plasma methotrexate levels. It converts methotrexate to inactive metabolites. There are no reports of its use in human or animal pregnancies. Human reports are unlikely because methotrexate is contraindicated in pregnancy.
There are six agents available to treat heavy metal (arsenic, gold, iron, lead, and mercury) intoxication: deferasirox (iron), deferoxamine (iron), dimercaprol (arsenic, gold, lead, and mercury), edetate calcium disodium (lead), penicillamine (copper and mercury), and succimer (lead).
Deferasirox is indicated for chronic iron overload due to blood transfusions. Three reports have described its use in the first half of pregnancy without embryo or fetal harm. Deferoxamine is used for the treatment of both acute and chronic iron overload. Although the drug causes toxicity in two animal species, the human pregnancy experience is substantial, and no embryo or fetal adverse effects attributable to the agent have been reported. Dimercaprol (British anti-Lewisite; BAL) is used for the treatment of arsenic, gold, and acute mercury poisoning (not effective for chronic mercury poisoning). It is also combined with edetate calcium disodium for lead poisoning. High doses are embryotoxic and teratogenic in mice. The published human pregnancy experience is limited and all involved exposures after the first trimester. High levels of arsenic or lead were found in the newborns in two cases.
Edetate calcium disodium forms stable chelates with a number of metals, but it is primarily used for lead overdose, either alone or in combination with dimercaprol. There are only a few reports of its use in human pregnancy, all occurring late in gestation. A potential complication of therapy is maternal hypotension that could jeopardize placental perfusion. The agent also chelates zinc, resulting in zinc deficiency. This mechanism was thought to be involved in the teratogenic effects seen in animals.
Penicillamine has been used in mercury poisoning (one report), in addition to its indication as a chelating agent for copper in the treatment of Wilson’s disease. Exposure in the first trimester is related to a risk of connective tissue anomalies, primarily cutis laxa. Succimer (dimercaptosuccinic acid; DMSA) has been used for lead, arsenic, mercury, and cadmium poisoning. It also chelates zinc quite effectively. The agent is toxic and/or teratogenic in mice and rats, but some of the effects may have been secondary to zinc deficiency. Because of the complete absence of human pregnancy experience, antidotes other than succimer probably are preferable.
Lanthanum carbonate and sevelamer are indicated to reduce serum phosphate levels in patients with end-stage renal disease. The drugs bind dietary phosphate from food during digestion in the gut. There are no reports of their use in human pregnancy. The systemic bioavailability is minimal, and the drugs should have no effect on the embryo or fetus. However, they may prevent intestinal vitamin absorption, especially of fat-soluble vitamins.
The cholinergic agent physostigmine is capable of reversing the central nervous system effects of anticholinergics, such as scopolamine and tricyclic antidepressants. The reported human pregnancy experience is limited to the third trimester.
Methylene blue has been used for cyanide poisoning. In humans, it is teratogenic and fetal toxic when given by intra-amniotic injection, but its oral use as an antidote in pregnancy has not been reported. The cyanide antidote package contains amyl nitrite, sodium nitrite, and sodium thiosulfate. The effects of these agents on human pregnancy also are unknown, as are the effects of high-dose hydroxocobalamin, an analogue of vitamin B12 also used in cyanide poisoning.
Pralidoxime (2-PAM) reactivates cholinesterase that has been inactivated by organophosphate pesticides and chemicals with anticholinesterase activity, thereby relieving the paralysis of the muscles of respiration. The drug is available in an autoinjector that can be used rapidly in cases of exposure to nerve agents possessing anticholinesterase activity (organophosphate poisoning). Animal reproduction tests have not been conducted with pralidoxime, and the human pregnancy experience is limited to a few cases of insecticide poisoning (second and third trimesters). Healthy infants were later delivered in these cases.
Four antivenins are commercially available for acute envenomation: black widow spider antivenin, Centruroides (scorpion) immune F(ab\')2 (equine), crotalidae polyvalent immune Fab (ovine) (North American rattlesnake), and North American coral snake antivenin (equine). In addition, botulism antitoxin heptavalent (equine) is used for food poisoning caused by the neurotoxic bacterium Clostridium botulinum. Animal reproduction studies have not been conducted with these products, and human reports are limited or absent.
Sapropterin, a cofactor for the enzyme phenylalanine hydroxylase, reduces blood phenylalanine levels in patients with phenylketonuria. The drug is given daily if diet alone does not control maternal phenylalanine levels. Use of the drug in human pregnancy has not been reported.
A number of other agents can be classified as antidotes, in addition to their primary indications, because they can reverse the toxic effects of other agents. These antidotes include atropine (severe bradycardia, poisonings with organophosphates and carbamates), calcium chloride or gluconate (severe hypocalcemia, calcium-channel-blocker overdose, exposure to hydrofluoric acid), glucagon (hypoglycemia), folinic acid (methotrexate overdose), protamine (heparin overdose), pyridoxine (isoniazid-induced seizures; adjunct in ethylene glycol poisoning), and vitamin K (phytonadione) (warfarin overdose). The pregnancy data are extensive for many of these agents and are not suggestive of significant embryo or fetal risk.
Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no relevant financial disclosures. Contact him at [email protected].
New drugs approved in 2012
In 2012, the Food and Drug Administration approved 39 new molecular entities (i.e., drugs). This was the highest number of approvals in the 2003 to 2012 period. Of the 39, 2 have not yet come onto the market, 3 are highly unlikely to be used in women of reproductive age, and 1 is a four-drug combination for HIV-1 infection.
The remaining 33 agents are classified as anorexiant (1), anticoagulant (1), anticonvulsant (1), antidote (1), antilipemic (1), antineoplastic (11), antituberculosis (1), dermatologic (1), endocrine/metabolic (3), gastrointestinal (4), hematologic (1), immunologic (2), impotence (1), ophthalmic (2), respiratory (1), and urinary tract agent (1).
There is no reported human pregnancy experience for any of these agents. Consequently, the potential risk to the embryo and/or fetus must be estimated based on the indication, mechanism of action, other drugs with a similar mechanism, route of administration, molecular weight, elimination half-life, and animal reproduction data. Some of these drugs have been included in the quarterly updates to the 9th edition of my book "Drugs in Pregnancy and Lactation." The remainder will appear in the 10th edition, scheduled to be released in the spring of 2014.
Lorcaserin (Belviq) is an anorexiant. Because weight loss in pregnancy usually offers no benefit to a pregnant woman, the manufacturer classifies the drug as contraindicated in pregnancy.
A new anticoagulant, apixaban (Eliquis), is used to reduce the risk of stroke in patients with atrial fibrillation. The animal data suggest low risk and, when combined with the indication, the drug should not be withheld because of pregnancy.
The animal data for the anticonvulsant perampanel (Fycompa) suggest risk, but the absence of human pregnancy experience prevents a full assessment of the embryo-fetal risk. If the drug is used in pregnancy, physicians are encouraged to recommend that their patients enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 1-888-233-2334.
The antidote, glucarpidase (Voraxaze), is used to treat toxic levels of methotrexate. Because methotrexate is contraindicated in pregnancy, it appears that there will be few opportunities for use of this drug in a pregnant woman. The same can be said for the antilipemic agent, lomitapide (Juxtapid). Decreasing the levels of lipids and cholesterol offers no benefit in pregnancy. The manufacturer classifies the agent as contraindicated because of the toxicity observed in three animal species.
Among the new antineoplastic agents approved, six are kinase inhibitors. Of these, five are in the subclass of tyrosine kinase inhibitors (trade name; indication): Axitinib (Inlyta; renal cancer), bosutinib (Bosulif; leukemia), cabozantinib (Cometriq; thyroid cancer), ponatinib (Iclusig; leukemia), and ziv-aflibercept (Zaltrap; colorectal cancer). The sixth kinase inhibitor is a multikinase inhibitor: regorafenib (Stivarga; colorectal cancer).
Other new antineoplastics are the antiandrogen enzalutamide (Xtandi; prostate cancer but could be used for other cancers), the proteasome inhibitor carfilzomib (Kyprolis; multiple myeloma), and the protein synthesis inhibitor omacetaxine (Synribo; leukemia). Pertuzumab (Perjeta; breast cancer) is a monoclonal antibody that is given in combination with trastuzumab and docetaxel. Vismodegib (Erivedge; basal cell cancer) is a miscellaneous antineoplastic that has been associated with amenorrhea in clinical trials. Animal data suggest risk of embryo-fetal harm.
All of the above antineoplastics are contraindicated in pregnancy because their mechanisms suggest the potential for embryo-fetal harm. However, if a drug is the best choice for a woman with a severe or a potentially fatal disease, it should not be withheld because the maternal benefit should far outweigh the unknown embryo-fetal risk.
Bedaquiline (Sirturo) is a new antituberculosis agent that can be used in pregnancy because of the low risk in animal studies and its indication. The dermatologic agent, ingenol mebutate (Picato) is used topically for actinic keratosis and appears to be compatible in pregnancy, because blood levels of the drug and two of its metabolites were below the lower limit of quantification (0.1 ng/mL).
The three endocrine/metabolic agents are ivacaftor (Kalydeco; cystic fibrosis), taliglucerase alfa (Elelyso; Gaucher disease), and pasireotide (Signifor; Cushing’s disease). The animal data for ivacaftor suggest low risk. Taliglucerase alfa appears to be compatible in pregnancy because it might reduce the risk of spontaneous abortion and bleeding complications. However, based on animal data, if a pregnant woman takes pasireotide, she should be informed of the potential risk, including abortion, to her embryo and/or fetus.
There are four gastrointestinal agents: crofelemer (Fulyzaq; antidiarrheal), linaclotide (Linzess; laxative), teduglutide (Gattex; short bowel syndrome), and the combination of sodium picosulfate, magnesium oxide, and citric acid (Prepopik; osmotic laxative). All appear to be compatible in pregnancy because of limited, if any, absorption (crofelemer, linaclotide, and sodium picosulfate) or because it is an analogue of a naturally occurring peptide (teduglutide).
The animal data for the hematologic agent, peginesatide (Omontys; anemia in patients with chronic renal disease) suggest risk. The drug has a high molecular weightthat should limit its passage across the placenta, but it still might cross in the third trimester. Because it stimulates erythropoiesis in human red blood cell precursors, it could do the same in the fetus if it crosses.
The two immunologic drugs are teriflunomide (Aubagio; multiple sclerosis) and tofacitinib (Xeljanz; rheumatoid arthritis). Teriflunomide, the principal active metabolite of leflunomide and responsible for leflunomide’s activity, is contraindicated in pregnancy. If a woman conceives while taking this drug, an 11-day procedure for accelerated elimination is recommended because it takes an average of 8 months (and it may be as long as 2 years) to reach plasma concentrations that are considered minimal risk (see package insert for procedure). The animal data for tofacitinib suggest risk. It is contraindicated if combined with methotrexate.
At first glance, it does not appear that the vasodilator avanafil (Stendra; impotence agent) will be used in pregnancy. However, a similar agent, sildenafil, has been used for the treatment of pulmonary arterial hypertension, a high-risk condition in pregnancy. Based on its indication, mechanism of action, and low-risk animal data, avanafil can be used in pregnancy if indicated.
Aclidinium bromide (Tudorza Pressair; bronchodilator) is a respiratory agent used in chronic obstructive pulmonary disease, chronic bronchitis, and emphysema. The animal data suggest low risk. The low plasma concentrations suggest that the drug represents a low, if any, risk in pregnancy.
The two ophthalmic preparations are ocriplasmin (Jetrea; symptomatic vitreomacular adhesions) and tafluprost (Zioptan; glaucoma). Both are probably compatible in pregnancy because of the undetectable or very low systemic concentrations.
The animal data for mirabegron (Myrbetriq; antispasmodic for overactive bladder) suggest low risk. It is an adrenergic agonist that increases bladder capacity. Although there are no human data, it probably can be used in pregnancy, but avoiding the first trimester should be considered.
As with pregnancy, there are no reports involving the use of the above drugs during breast-feeding. When there are little or no human data, the risk to a nursing infant can be estimated by considering several factors: indication, duration of therapy, molecular weight, plasma protein binding, elimination half-life, presence of the drug in the systemic circulation, and the most common adverse effects observed in adults.
Using these criteria for the drugs discussed above, there are only 10 that are probably compatible with breast-feeding: glucarpidase, ingenol mebutate, sodium picosulfate, taliglucerase alfa, crofelemer, linaclotide, peginesatide, aclidinium bromide, tafluprost, and ocriplasmin. The remaining drugs are either contraindicated (most of the antineoplastics and tofacitinib if combined with methotrexate) or may cause toxicity in a nursing infant.
Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no relevant financial disclosures. Contact him at [email protected].
In 2012, the Food and Drug Administration approved 39 new molecular entities (i.e., drugs). This was the highest number of approvals in the 2003 to 2012 period. Of the 39, 2 have not yet come onto the market, 3 are highly unlikely to be used in women of reproductive age, and 1 is a four-drug combination for HIV-1 infection.
The remaining 33 agents are classified as anorexiant (1), anticoagulant (1), anticonvulsant (1), antidote (1), antilipemic (1), antineoplastic (11), antituberculosis (1), dermatologic (1), endocrine/metabolic (3), gastrointestinal (4), hematologic (1), immunologic (2), impotence (1), ophthalmic (2), respiratory (1), and urinary tract agent (1).
There is no reported human pregnancy experience for any of these agents. Consequently, the potential risk to the embryo and/or fetus must be estimated based on the indication, mechanism of action, other drugs with a similar mechanism, route of administration, molecular weight, elimination half-life, and animal reproduction data. Some of these drugs have been included in the quarterly updates to the 9th edition of my book "Drugs in Pregnancy and Lactation." The remainder will appear in the 10th edition, scheduled to be released in the spring of 2014.
Lorcaserin (Belviq) is an anorexiant. Because weight loss in pregnancy usually offers no benefit to a pregnant woman, the manufacturer classifies the drug as contraindicated in pregnancy.
A new anticoagulant, apixaban (Eliquis), is used to reduce the risk of stroke in patients with atrial fibrillation. The animal data suggest low risk and, when combined with the indication, the drug should not be withheld because of pregnancy.
The animal data for the anticonvulsant perampanel (Fycompa) suggest risk, but the absence of human pregnancy experience prevents a full assessment of the embryo-fetal risk. If the drug is used in pregnancy, physicians are encouraged to recommend that their patients enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 1-888-233-2334.
The antidote, glucarpidase (Voraxaze), is used to treat toxic levels of methotrexate. Because methotrexate is contraindicated in pregnancy, it appears that there will be few opportunities for use of this drug in a pregnant woman. The same can be said for the antilipemic agent, lomitapide (Juxtapid). Decreasing the levels of lipids and cholesterol offers no benefit in pregnancy. The manufacturer classifies the agent as contraindicated because of the toxicity observed in three animal species.
Among the new antineoplastic agents approved, six are kinase inhibitors. Of these, five are in the subclass of tyrosine kinase inhibitors (trade name; indication): Axitinib (Inlyta; renal cancer), bosutinib (Bosulif; leukemia), cabozantinib (Cometriq; thyroid cancer), ponatinib (Iclusig; leukemia), and ziv-aflibercept (Zaltrap; colorectal cancer). The sixth kinase inhibitor is a multikinase inhibitor: regorafenib (Stivarga; colorectal cancer).
Other new antineoplastics are the antiandrogen enzalutamide (Xtandi; prostate cancer but could be used for other cancers), the proteasome inhibitor carfilzomib (Kyprolis; multiple myeloma), and the protein synthesis inhibitor omacetaxine (Synribo; leukemia). Pertuzumab (Perjeta; breast cancer) is a monoclonal antibody that is given in combination with trastuzumab and docetaxel. Vismodegib (Erivedge; basal cell cancer) is a miscellaneous antineoplastic that has been associated with amenorrhea in clinical trials. Animal data suggest risk of embryo-fetal harm.
All of the above antineoplastics are contraindicated in pregnancy because their mechanisms suggest the potential for embryo-fetal harm. However, if a drug is the best choice for a woman with a severe or a potentially fatal disease, it should not be withheld because the maternal benefit should far outweigh the unknown embryo-fetal risk.
Bedaquiline (Sirturo) is a new antituberculosis agent that can be used in pregnancy because of the low risk in animal studies and its indication. The dermatologic agent, ingenol mebutate (Picato) is used topically for actinic keratosis and appears to be compatible in pregnancy, because blood levels of the drug and two of its metabolites were below the lower limit of quantification (0.1 ng/mL).
The three endocrine/metabolic agents are ivacaftor (Kalydeco; cystic fibrosis), taliglucerase alfa (Elelyso; Gaucher disease), and pasireotide (Signifor; Cushing’s disease). The animal data for ivacaftor suggest low risk. Taliglucerase alfa appears to be compatible in pregnancy because it might reduce the risk of spontaneous abortion and bleeding complications. However, based on animal data, if a pregnant woman takes pasireotide, she should be informed of the potential risk, including abortion, to her embryo and/or fetus.
There are four gastrointestinal agents: crofelemer (Fulyzaq; antidiarrheal), linaclotide (Linzess; laxative), teduglutide (Gattex; short bowel syndrome), and the combination of sodium picosulfate, magnesium oxide, and citric acid (Prepopik; osmotic laxative). All appear to be compatible in pregnancy because of limited, if any, absorption (crofelemer, linaclotide, and sodium picosulfate) or because it is an analogue of a naturally occurring peptide (teduglutide).
The animal data for the hematologic agent, peginesatide (Omontys; anemia in patients with chronic renal disease) suggest risk. The drug has a high molecular weightthat should limit its passage across the placenta, but it still might cross in the third trimester. Because it stimulates erythropoiesis in human red blood cell precursors, it could do the same in the fetus if it crosses.
The two immunologic drugs are teriflunomide (Aubagio; multiple sclerosis) and tofacitinib (Xeljanz; rheumatoid arthritis). Teriflunomide, the principal active metabolite of leflunomide and responsible for leflunomide’s activity, is contraindicated in pregnancy. If a woman conceives while taking this drug, an 11-day procedure for accelerated elimination is recommended because it takes an average of 8 months (and it may be as long as 2 years) to reach plasma concentrations that are considered minimal risk (see package insert for procedure). The animal data for tofacitinib suggest risk. It is contraindicated if combined with methotrexate.
At first glance, it does not appear that the vasodilator avanafil (Stendra; impotence agent) will be used in pregnancy. However, a similar agent, sildenafil, has been used for the treatment of pulmonary arterial hypertension, a high-risk condition in pregnancy. Based on its indication, mechanism of action, and low-risk animal data, avanafil can be used in pregnancy if indicated.
Aclidinium bromide (Tudorza Pressair; bronchodilator) is a respiratory agent used in chronic obstructive pulmonary disease, chronic bronchitis, and emphysema. The animal data suggest low risk. The low plasma concentrations suggest that the drug represents a low, if any, risk in pregnancy.
The two ophthalmic preparations are ocriplasmin (Jetrea; symptomatic vitreomacular adhesions) and tafluprost (Zioptan; glaucoma). Both are probably compatible in pregnancy because of the undetectable or very low systemic concentrations.
The animal data for mirabegron (Myrbetriq; antispasmodic for overactive bladder) suggest low risk. It is an adrenergic agonist that increases bladder capacity. Although there are no human data, it probably can be used in pregnancy, but avoiding the first trimester should be considered.
As with pregnancy, there are no reports involving the use of the above drugs during breast-feeding. When there are little or no human data, the risk to a nursing infant can be estimated by considering several factors: indication, duration of therapy, molecular weight, plasma protein binding, elimination half-life, presence of the drug in the systemic circulation, and the most common adverse effects observed in adults.
Using these criteria for the drugs discussed above, there are only 10 that are probably compatible with breast-feeding: glucarpidase, ingenol mebutate, sodium picosulfate, taliglucerase alfa, crofelemer, linaclotide, peginesatide, aclidinium bromide, tafluprost, and ocriplasmin. The remaining drugs are either contraindicated (most of the antineoplastics and tofacitinib if combined with methotrexate) or may cause toxicity in a nursing infant.
Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no relevant financial disclosures. Contact him at [email protected].
In 2012, the Food and Drug Administration approved 39 new molecular entities (i.e., drugs). This was the highest number of approvals in the 2003 to 2012 period. Of the 39, 2 have not yet come onto the market, 3 are highly unlikely to be used in women of reproductive age, and 1 is a four-drug combination for HIV-1 infection.
The remaining 33 agents are classified as anorexiant (1), anticoagulant (1), anticonvulsant (1), antidote (1), antilipemic (1), antineoplastic (11), antituberculosis (1), dermatologic (1), endocrine/metabolic (3), gastrointestinal (4), hematologic (1), immunologic (2), impotence (1), ophthalmic (2), respiratory (1), and urinary tract agent (1).
There is no reported human pregnancy experience for any of these agents. Consequently, the potential risk to the embryo and/or fetus must be estimated based on the indication, mechanism of action, other drugs with a similar mechanism, route of administration, molecular weight, elimination half-life, and animal reproduction data. Some of these drugs have been included in the quarterly updates to the 9th edition of my book "Drugs in Pregnancy and Lactation." The remainder will appear in the 10th edition, scheduled to be released in the spring of 2014.
Lorcaserin (Belviq) is an anorexiant. Because weight loss in pregnancy usually offers no benefit to a pregnant woman, the manufacturer classifies the drug as contraindicated in pregnancy.
A new anticoagulant, apixaban (Eliquis), is used to reduce the risk of stroke in patients with atrial fibrillation. The animal data suggest low risk and, when combined with the indication, the drug should not be withheld because of pregnancy.
The animal data for the anticonvulsant perampanel (Fycompa) suggest risk, but the absence of human pregnancy experience prevents a full assessment of the embryo-fetal risk. If the drug is used in pregnancy, physicians are encouraged to recommend that their patients enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 1-888-233-2334.
The antidote, glucarpidase (Voraxaze), is used to treat toxic levels of methotrexate. Because methotrexate is contraindicated in pregnancy, it appears that there will be few opportunities for use of this drug in a pregnant woman. The same can be said for the antilipemic agent, lomitapide (Juxtapid). Decreasing the levels of lipids and cholesterol offers no benefit in pregnancy. The manufacturer classifies the agent as contraindicated because of the toxicity observed in three animal species.
Among the new antineoplastic agents approved, six are kinase inhibitors. Of these, five are in the subclass of tyrosine kinase inhibitors (trade name; indication): Axitinib (Inlyta; renal cancer), bosutinib (Bosulif; leukemia), cabozantinib (Cometriq; thyroid cancer), ponatinib (Iclusig; leukemia), and ziv-aflibercept (Zaltrap; colorectal cancer). The sixth kinase inhibitor is a multikinase inhibitor: regorafenib (Stivarga; colorectal cancer).
Other new antineoplastics are the antiandrogen enzalutamide (Xtandi; prostate cancer but could be used for other cancers), the proteasome inhibitor carfilzomib (Kyprolis; multiple myeloma), and the protein synthesis inhibitor omacetaxine (Synribo; leukemia). Pertuzumab (Perjeta; breast cancer) is a monoclonal antibody that is given in combination with trastuzumab and docetaxel. Vismodegib (Erivedge; basal cell cancer) is a miscellaneous antineoplastic that has been associated with amenorrhea in clinical trials. Animal data suggest risk of embryo-fetal harm.
All of the above antineoplastics are contraindicated in pregnancy because their mechanisms suggest the potential for embryo-fetal harm. However, if a drug is the best choice for a woman with a severe or a potentially fatal disease, it should not be withheld because the maternal benefit should far outweigh the unknown embryo-fetal risk.
Bedaquiline (Sirturo) is a new antituberculosis agent that can be used in pregnancy because of the low risk in animal studies and its indication. The dermatologic agent, ingenol mebutate (Picato) is used topically for actinic keratosis and appears to be compatible in pregnancy, because blood levels of the drug and two of its metabolites were below the lower limit of quantification (0.1 ng/mL).
The three endocrine/metabolic agents are ivacaftor (Kalydeco; cystic fibrosis), taliglucerase alfa (Elelyso; Gaucher disease), and pasireotide (Signifor; Cushing’s disease). The animal data for ivacaftor suggest low risk. Taliglucerase alfa appears to be compatible in pregnancy because it might reduce the risk of spontaneous abortion and bleeding complications. However, based on animal data, if a pregnant woman takes pasireotide, she should be informed of the potential risk, including abortion, to her embryo and/or fetus.
There are four gastrointestinal agents: crofelemer (Fulyzaq; antidiarrheal), linaclotide (Linzess; laxative), teduglutide (Gattex; short bowel syndrome), and the combination of sodium picosulfate, magnesium oxide, and citric acid (Prepopik; osmotic laxative). All appear to be compatible in pregnancy because of limited, if any, absorption (crofelemer, linaclotide, and sodium picosulfate) or because it is an analogue of a naturally occurring peptide (teduglutide).
The animal data for the hematologic agent, peginesatide (Omontys; anemia in patients with chronic renal disease) suggest risk. The drug has a high molecular weightthat should limit its passage across the placenta, but it still might cross in the third trimester. Because it stimulates erythropoiesis in human red blood cell precursors, it could do the same in the fetus if it crosses.
The two immunologic drugs are teriflunomide (Aubagio; multiple sclerosis) and tofacitinib (Xeljanz; rheumatoid arthritis). Teriflunomide, the principal active metabolite of leflunomide and responsible for leflunomide’s activity, is contraindicated in pregnancy. If a woman conceives while taking this drug, an 11-day procedure for accelerated elimination is recommended because it takes an average of 8 months (and it may be as long as 2 years) to reach plasma concentrations that are considered minimal risk (see package insert for procedure). The animal data for tofacitinib suggest risk. It is contraindicated if combined with methotrexate.
At first glance, it does not appear that the vasodilator avanafil (Stendra; impotence agent) will be used in pregnancy. However, a similar agent, sildenafil, has been used for the treatment of pulmonary arterial hypertension, a high-risk condition in pregnancy. Based on its indication, mechanism of action, and low-risk animal data, avanafil can be used in pregnancy if indicated.
Aclidinium bromide (Tudorza Pressair; bronchodilator) is a respiratory agent used in chronic obstructive pulmonary disease, chronic bronchitis, and emphysema. The animal data suggest low risk. The low plasma concentrations suggest that the drug represents a low, if any, risk in pregnancy.
The two ophthalmic preparations are ocriplasmin (Jetrea; symptomatic vitreomacular adhesions) and tafluprost (Zioptan; glaucoma). Both are probably compatible in pregnancy because of the undetectable or very low systemic concentrations.
The animal data for mirabegron (Myrbetriq; antispasmodic for overactive bladder) suggest low risk. It is an adrenergic agonist that increases bladder capacity. Although there are no human data, it probably can be used in pregnancy, but avoiding the first trimester should be considered.
As with pregnancy, there are no reports involving the use of the above drugs during breast-feeding. When there are little or no human data, the risk to a nursing infant can be estimated by considering several factors: indication, duration of therapy, molecular weight, plasma protein binding, elimination half-life, presence of the drug in the systemic circulation, and the most common adverse effects observed in adults.
Using these criteria for the drugs discussed above, there are only 10 that are probably compatible with breast-feeding: glucarpidase, ingenol mebutate, sodium picosulfate, taliglucerase alfa, crofelemer, linaclotide, peginesatide, aclidinium bromide, tafluprost, and ocriplasmin. The remaining drugs are either contraindicated (most of the antineoplastics and tofacitinib if combined with methotrexate) or may cause toxicity in a nursing infant.
Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no relevant financial disclosures. Contact him at [email protected].
Over-the-counter H1-antihistamines
H1-antihistamines are commonly used by pregnant and lactating women. New information suggests that their mechanism of action is different from the initial characterization that they were competitive antagonists of H1-histamine receptors. On the cellular surface, both active and inactive H1-receptors exist in equilibrium, responding to histamines (agonists) and inverse agonists (antihistamines). Antihistamines bind and stabilize the inactive receptors, shifting the equilibrium to the inactive state and preventing or reducing the physiologic effects of histamine (Clin. Exp. Allergy 2002;32:489-98).
Antihistamines can be classified as either first-generation (nonselective) or second-generation (peripherally selective) agents. First-generation antihistamines bind nonselectively to central and peripheral inactive H1-receptors. They have various indications, including allergic rhinitis (hay fever), allergic conjunctivitis, urticaria/angioedema, vasomotor rhinitis, sneezing, asthma, and hypersensitivity reactions. The four first-generation oral agents available over-the-counter (OTC) can be further classified, based on their chemical composition, into two groups: alkylamines (chlorpheniramine) and ethanolamines (clemastine, diphenhydramine, and doxylamine). This latter group has marked sedative properties, as well as anticholinergic and antiemetic actions.
Chlorpheniramine
Brands include Aller-Chlor, Allergy Relief, Chlo-Amine, Chlor-Trimeton, and Efidac 24. More than 1,100 first-trimester exposures to this agent have been reported. In these cases, the number of congenital anomalies was not increased over the expected background risk (Collaborative Perinatal Project 1977 [CPP]; and Michigan Medicaid Data 1993 [MMD]).
Clemastine
Brands include Dayhist-1 and Tavist Allergy. More than 2,800 first-trimester exposures to clemastine have been reported. No increased risk of teratogenicity was noted in one study involving 1,230 exposures (J. Matern. Fetal Neonat. Med. 2002;11:146-52). In contrast, among the 1,617 exposures in the MMD, a possible association with limb reduction defects (5 observed/1.9 expected) was discovered, but a causal association cannot be determined from these data.
Diphenhydramine
Brands include AllerMax, Altaryl Children’s Allergy, Banophen, Benadryl, Diphenhist, Dormin, Genahist, Miles Nervine, Nytol, Siladryl, Sleep-eze 3, Sleepwell 2-nite, and Sominex. Commonly used to promote sleep, as well as to treat nausea and allergies, more than 2,300 first-trimester exposures have been reported in the literature.
Several possible associations with congenital defects have been observed in some of these reports, such as those from the CPP and MMD, but many other studies have not found these associations (Drugs in Pregnancy and Lactation, 9th ed. Riverwoods, Ill.: Wolters Kluwer Health, 2011). Withdrawal was observed in one infant whose mother took diphenhydramine 150 mg/day throughout pregnancy (J. Pediatr. 1974;85:580). A potential drug interaction, resulting in stillbirth, occurred when a mother took 50 mg of the antihistamine for itching and then, 1.5 hours later, a 30-mg dose of temazepam for sleep. Violent fetal movements occurred 3 hours later, followed in 4 hours by the stillbirth of a term female infant. The interaction was confirmed in rabbits with a fetal mortality rate of 81% (N. Engl. J. Med. 1985;313:1417-8).
Doxylamine
Brands include Unisom Nighttime Sleep Aid. This agent is a potent antiemetic and sedative and may be one of the most studied drugs in human pregnancy. Although some studies found associations with various defects, most studies have not (Drugs in Pregnancy and Lactation, 9th ed. Riverwoods, Ill.: Wolters Kluwer Health, 2011). These results suggest that other exposures, conditions, or chance were involved in the positive studies, and doxylamine is considered safe to use in pregnancy. The combination of doxylamine and pyridoxine (vitamin B6) is recommended as a first-line therapy for nausea and vomiting of pregnancy (ACOG Practice Bulletin no. 52. Nausea and vomiting of pregnancy. April 2004. Obstet. Gynecol. 2004;103:803-15). The combination has been available for years as Diclectin in Canada but, in the United States, could only be obtained as individual OTC components. In April 2013, the doxylamine-pyridoxine combination (Diclegis) was approved by the U.S. Food and Drug Administration.
Second-generation antihistamines are selective for peripheral inactive H1-receptors and, as a group, are less sedating. These agents are used for allergic rhinitis, sinusitis, seasonal allergic rhinitis, and chronic idiopathic urticaria, The three OTC agents in this class also can be divided into two subgroups: piperazines (cetirizine) and piperidines (fexofenadine and loratadine).
Cetirizine
It comes in various generic and Zyrtec formulations. Cetirizine is a human metabolite of hydroxyzine. Although the human pregnancy experience is limited (about 120 cases), there is no evidence that it is a significant risk to the embryo and/or fetus. In one report, pregnant women using the drug for allergies had a lower rate of nausea and vomiting than a control group (Ann. Pharmacother. 2000;34:1486-7).
Fexofenadine
There are various generic and Allegra formulations. There are no reports describing the use of this agent in human pregnancy. Animal data suggest moderate risk based on dose-related embryo and fetal toxicity in rats. The use of other antihistamines is recommended.
Loratadine
There are various generic and Claritin and Alavert formulations. The limited human data have generally shown no risk of teratogenicity. A Swedish study reported that exposure during pregnancy doubled the incidence of hypospadias (Int. J. Risk Saf. Med. 2001;14:115-9). However, a later study using data from the U.S. National Birth Defects Prevention Study found no association between loratadine and hypospadias (MMWR 2004;53:219-21).
In summary, the available evidence, both animal and human, indicates that as a class, H1-antihistamines represent a low risk to the embryo and fetus. Because there are no reports for fexofenadine, other antihistamines might be a better choice. Although not discussed here, H1-antihistamines are common components of upper respiratory formulations that contain decongestants, expectorants, or analgesics. Depending on the stage of gestation when used, these combinations may have a risk of maternal or fetal harm.
Breastfeeding
All of the above H1-antihistamines are probably excreted into breast milk. Although published reports are rare, the first-generation agents have caused irritability or drowsiness in nursing infants. Fortunately, the second-generation agents have not been reported to cause these effects in a nursing neonate. Nevertheless, recommended doses of all of these agents are probably compatible with nursing full-term infants, but exposing preterm infants should be avoided.
Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He said he had no relevant financial disclosures. Contact him at [email protected]. View more Drugs, Pregnancy, and Lactation columns by clicking here.
H1-antihistamines are commonly used by pregnant and lactating women. New information suggests that their mechanism of action is different from the initial characterization that they were competitive antagonists of H1-histamine receptors. On the cellular surface, both active and inactive H1-receptors exist in equilibrium, responding to histamines (agonists) and inverse agonists (antihistamines). Antihistamines bind and stabilize the inactive receptors, shifting the equilibrium to the inactive state and preventing or reducing the physiologic effects of histamine (Clin. Exp. Allergy 2002;32:489-98).
Antihistamines can be classified as either first-generation (nonselective) or second-generation (peripherally selective) agents. First-generation antihistamines bind nonselectively to central and peripheral inactive H1-receptors. They have various indications, including allergic rhinitis (hay fever), allergic conjunctivitis, urticaria/angioedema, vasomotor rhinitis, sneezing, asthma, and hypersensitivity reactions. The four first-generation oral agents available over-the-counter (OTC) can be further classified, based on their chemical composition, into two groups: alkylamines (chlorpheniramine) and ethanolamines (clemastine, diphenhydramine, and doxylamine). This latter group has marked sedative properties, as well as anticholinergic and antiemetic actions.
Chlorpheniramine
Brands include Aller-Chlor, Allergy Relief, Chlo-Amine, Chlor-Trimeton, and Efidac 24. More than 1,100 first-trimester exposures to this agent have been reported. In these cases, the number of congenital anomalies was not increased over the expected background risk (Collaborative Perinatal Project 1977 [CPP]; and Michigan Medicaid Data 1993 [MMD]).
Clemastine
Brands include Dayhist-1 and Tavist Allergy. More than 2,800 first-trimester exposures to clemastine have been reported. No increased risk of teratogenicity was noted in one study involving 1,230 exposures (J. Matern. Fetal Neonat. Med. 2002;11:146-52). In contrast, among the 1,617 exposures in the MMD, a possible association with limb reduction defects (5 observed/1.9 expected) was discovered, but a causal association cannot be determined from these data.
Diphenhydramine
Brands include AllerMax, Altaryl Children’s Allergy, Banophen, Benadryl, Diphenhist, Dormin, Genahist, Miles Nervine, Nytol, Siladryl, Sleep-eze 3, Sleepwell 2-nite, and Sominex. Commonly used to promote sleep, as well as to treat nausea and allergies, more than 2,300 first-trimester exposures have been reported in the literature.
Several possible associations with congenital defects have been observed in some of these reports, such as those from the CPP and MMD, but many other studies have not found these associations (Drugs in Pregnancy and Lactation, 9th ed. Riverwoods, Ill.: Wolters Kluwer Health, 2011). Withdrawal was observed in one infant whose mother took diphenhydramine 150 mg/day throughout pregnancy (J. Pediatr. 1974;85:580). A potential drug interaction, resulting in stillbirth, occurred when a mother took 50 mg of the antihistamine for itching and then, 1.5 hours later, a 30-mg dose of temazepam for sleep. Violent fetal movements occurred 3 hours later, followed in 4 hours by the stillbirth of a term female infant. The interaction was confirmed in rabbits with a fetal mortality rate of 81% (N. Engl. J. Med. 1985;313:1417-8).
Doxylamine
Brands include Unisom Nighttime Sleep Aid. This agent is a potent antiemetic and sedative and may be one of the most studied drugs in human pregnancy. Although some studies found associations with various defects, most studies have not (Drugs in Pregnancy and Lactation, 9th ed. Riverwoods, Ill.: Wolters Kluwer Health, 2011). These results suggest that other exposures, conditions, or chance were involved in the positive studies, and doxylamine is considered safe to use in pregnancy. The combination of doxylamine and pyridoxine (vitamin B6) is recommended as a first-line therapy for nausea and vomiting of pregnancy (ACOG Practice Bulletin no. 52. Nausea and vomiting of pregnancy. April 2004. Obstet. Gynecol. 2004;103:803-15). The combination has been available for years as Diclectin in Canada but, in the United States, could only be obtained as individual OTC components. In April 2013, the doxylamine-pyridoxine combination (Diclegis) was approved by the U.S. Food and Drug Administration.
Second-generation antihistamines are selective for peripheral inactive H1-receptors and, as a group, are less sedating. These agents are used for allergic rhinitis, sinusitis, seasonal allergic rhinitis, and chronic idiopathic urticaria, The three OTC agents in this class also can be divided into two subgroups: piperazines (cetirizine) and piperidines (fexofenadine and loratadine).
Cetirizine
It comes in various generic and Zyrtec formulations. Cetirizine is a human metabolite of hydroxyzine. Although the human pregnancy experience is limited (about 120 cases), there is no evidence that it is a significant risk to the embryo and/or fetus. In one report, pregnant women using the drug for allergies had a lower rate of nausea and vomiting than a control group (Ann. Pharmacother. 2000;34:1486-7).
Fexofenadine
There are various generic and Allegra formulations. There are no reports describing the use of this agent in human pregnancy. Animal data suggest moderate risk based on dose-related embryo and fetal toxicity in rats. The use of other antihistamines is recommended.
Loratadine
There are various generic and Claritin and Alavert formulations. The limited human data have generally shown no risk of teratogenicity. A Swedish study reported that exposure during pregnancy doubled the incidence of hypospadias (Int. J. Risk Saf. Med. 2001;14:115-9). However, a later study using data from the U.S. National Birth Defects Prevention Study found no association between loratadine and hypospadias (MMWR 2004;53:219-21).
In summary, the available evidence, both animal and human, indicates that as a class, H1-antihistamines represent a low risk to the embryo and fetus. Because there are no reports for fexofenadine, other antihistamines might be a better choice. Although not discussed here, H1-antihistamines are common components of upper respiratory formulations that contain decongestants, expectorants, or analgesics. Depending on the stage of gestation when used, these combinations may have a risk of maternal or fetal harm.
Breastfeeding
All of the above H1-antihistamines are probably excreted into breast milk. Although published reports are rare, the first-generation agents have caused irritability or drowsiness in nursing infants. Fortunately, the second-generation agents have not been reported to cause these effects in a nursing neonate. Nevertheless, recommended doses of all of these agents are probably compatible with nursing full-term infants, but exposing preterm infants should be avoided.
Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He said he had no relevant financial disclosures. Contact him at [email protected]. View more Drugs, Pregnancy, and Lactation columns by clicking here.
H1-antihistamines are commonly used by pregnant and lactating women. New information suggests that their mechanism of action is different from the initial characterization that they were competitive antagonists of H1-histamine receptors. On the cellular surface, both active and inactive H1-receptors exist in equilibrium, responding to histamines (agonists) and inverse agonists (antihistamines). Antihistamines bind and stabilize the inactive receptors, shifting the equilibrium to the inactive state and preventing or reducing the physiologic effects of histamine (Clin. Exp. Allergy 2002;32:489-98).
Antihistamines can be classified as either first-generation (nonselective) or second-generation (peripherally selective) agents. First-generation antihistamines bind nonselectively to central and peripheral inactive H1-receptors. They have various indications, including allergic rhinitis (hay fever), allergic conjunctivitis, urticaria/angioedema, vasomotor rhinitis, sneezing, asthma, and hypersensitivity reactions. The four first-generation oral agents available over-the-counter (OTC) can be further classified, based on their chemical composition, into two groups: alkylamines (chlorpheniramine) and ethanolamines (clemastine, diphenhydramine, and doxylamine). This latter group has marked sedative properties, as well as anticholinergic and antiemetic actions.
Chlorpheniramine
Brands include Aller-Chlor, Allergy Relief, Chlo-Amine, Chlor-Trimeton, and Efidac 24. More than 1,100 first-trimester exposures to this agent have been reported. In these cases, the number of congenital anomalies was not increased over the expected background risk (Collaborative Perinatal Project 1977 [CPP]; and Michigan Medicaid Data 1993 [MMD]).
Clemastine
Brands include Dayhist-1 and Tavist Allergy. More than 2,800 first-trimester exposures to clemastine have been reported. No increased risk of teratogenicity was noted in one study involving 1,230 exposures (J. Matern. Fetal Neonat. Med. 2002;11:146-52). In contrast, among the 1,617 exposures in the MMD, a possible association with limb reduction defects (5 observed/1.9 expected) was discovered, but a causal association cannot be determined from these data.
Diphenhydramine
Brands include AllerMax, Altaryl Children’s Allergy, Banophen, Benadryl, Diphenhist, Dormin, Genahist, Miles Nervine, Nytol, Siladryl, Sleep-eze 3, Sleepwell 2-nite, and Sominex. Commonly used to promote sleep, as well as to treat nausea and allergies, more than 2,300 first-trimester exposures have been reported in the literature.
Several possible associations with congenital defects have been observed in some of these reports, such as those from the CPP and MMD, but many other studies have not found these associations (Drugs in Pregnancy and Lactation, 9th ed. Riverwoods, Ill.: Wolters Kluwer Health, 2011). Withdrawal was observed in one infant whose mother took diphenhydramine 150 mg/day throughout pregnancy (J. Pediatr. 1974;85:580). A potential drug interaction, resulting in stillbirth, occurred when a mother took 50 mg of the antihistamine for itching and then, 1.5 hours later, a 30-mg dose of temazepam for sleep. Violent fetal movements occurred 3 hours later, followed in 4 hours by the stillbirth of a term female infant. The interaction was confirmed in rabbits with a fetal mortality rate of 81% (N. Engl. J. Med. 1985;313:1417-8).
Doxylamine
Brands include Unisom Nighttime Sleep Aid. This agent is a potent antiemetic and sedative and may be one of the most studied drugs in human pregnancy. Although some studies found associations with various defects, most studies have not (Drugs in Pregnancy and Lactation, 9th ed. Riverwoods, Ill.: Wolters Kluwer Health, 2011). These results suggest that other exposures, conditions, or chance were involved in the positive studies, and doxylamine is considered safe to use in pregnancy. The combination of doxylamine and pyridoxine (vitamin B6) is recommended as a first-line therapy for nausea and vomiting of pregnancy (ACOG Practice Bulletin no. 52. Nausea and vomiting of pregnancy. April 2004. Obstet. Gynecol. 2004;103:803-15). The combination has been available for years as Diclectin in Canada but, in the United States, could only be obtained as individual OTC components. In April 2013, the doxylamine-pyridoxine combination (Diclegis) was approved by the U.S. Food and Drug Administration.
Second-generation antihistamines are selective for peripheral inactive H1-receptors and, as a group, are less sedating. These agents are used for allergic rhinitis, sinusitis, seasonal allergic rhinitis, and chronic idiopathic urticaria, The three OTC agents in this class also can be divided into two subgroups: piperazines (cetirizine) and piperidines (fexofenadine and loratadine).
Cetirizine
It comes in various generic and Zyrtec formulations. Cetirizine is a human metabolite of hydroxyzine. Although the human pregnancy experience is limited (about 120 cases), there is no evidence that it is a significant risk to the embryo and/or fetus. In one report, pregnant women using the drug for allergies had a lower rate of nausea and vomiting than a control group (Ann. Pharmacother. 2000;34:1486-7).
Fexofenadine
There are various generic and Allegra formulations. There are no reports describing the use of this agent in human pregnancy. Animal data suggest moderate risk based on dose-related embryo and fetal toxicity in rats. The use of other antihistamines is recommended.
Loratadine
There are various generic and Claritin and Alavert formulations. The limited human data have generally shown no risk of teratogenicity. A Swedish study reported that exposure during pregnancy doubled the incidence of hypospadias (Int. J. Risk Saf. Med. 2001;14:115-9). However, a later study using data from the U.S. National Birth Defects Prevention Study found no association between loratadine and hypospadias (MMWR 2004;53:219-21).
In summary, the available evidence, both animal and human, indicates that as a class, H1-antihistamines represent a low risk to the embryo and fetus. Because there are no reports for fexofenadine, other antihistamines might be a better choice. Although not discussed here, H1-antihistamines are common components of upper respiratory formulations that contain decongestants, expectorants, or analgesics. Depending on the stage of gestation when used, these combinations may have a risk of maternal or fetal harm.
Breastfeeding
All of the above H1-antihistamines are probably excreted into breast milk. Although published reports are rare, the first-generation agents have caused irritability or drowsiness in nursing infants. Fortunately, the second-generation agents have not been reported to cause these effects in a nursing neonate. Nevertheless, recommended doses of all of these agents are probably compatible with nursing full-term infants, but exposing preterm infants should be avoided.
Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He said he had no relevant financial disclosures. Contact him at [email protected]. View more Drugs, Pregnancy, and Lactation columns by clicking here.
Anesthetic Agents
Local and general anesthetic agents are commonly used in pregnancy, especially for epidural or combined spinal epidural analgesia at delivery. Although surgery requiring general anesthesia is less common, such use is still relatively frequent.
Local anesthetics are given by injection or topically, and include benzocaine, bupivacaine (Marcaine, Sensorcaine), chloroprocaine (Nesacaine), camphor, dibucaine (Nupercainal), levobupivacaine (Chirocaine), lidocaine (Xylocaine, Octocaine), mepivacaine (Carbocaine, Polocaine), pramoxine, prilocaine (Citanest), procaine (Novocaine), ropivacaine (Naropin), and tetracaine (Pontocaine). For neuraxial analgesia, low doses of bupivacaine, lidocaine, or ropivacaine – with or without a small dose of an opioid such as fentanyl – are commonly used. Use of injectable anesthetics for dental procedures also is common in pregnancy. Maternal toxicity involving the central nervous and cardiovascular systems may result from inadvertent intravenous administration or excessive doses.
Topical anesthetics are commonly used in dermatologic products; many are over-the-counter (OTC) products with multiple trade names not listed here. Such agents include benzocaine, butamben, cocaine, dibucaine, lidocaine, pramoxine, prilocaine, tetracaine, and dyclonine (a bactericidal and fungicidal local anesthetic used in lozenges and throat sprays for sore throats). The three topical cocaine products are controlled substances. Because of rapid absorption that can produce toxicity in the user, they are best avoided in pregnancy. Ethyl chloride (chloroethane) is a refrigerant used as a topical anesthetic. Although there are no reports of its use in pregnancy, the low absorption suggests that it is safe.
Benzocaine and pramoxine are available in OTC preparations for anorectal indications, such as hemorrhoids. The human pregnancy data are limited, but because there are more than 50 such products and hemorrhoids are common in pregnancy, these agents appear to be widely used in pregnancy. Systemic absorption may occur from mucous membranes or from damaged skin with the amount absorbed dependent on the dose.
The local anesthetics available for ophthalmic use are lidocaine (Akten), proparacaine (Alcaine, Ophthetic, Paracaine), proparacaine combined with fluorescein (Flucaine, Fluoracaine, Flurate, Fluress, Flurox), and tetracaine (Altacaine, Tetcaine).
In the above situations, with the exception of cocaine, the risk of any aspect of developmental toxicity from appropriate doses and administration of local anesthetics appears to be rare or nonexistent.
General anesthetics can be classified as injectable, gases, or volatile liquids. The injectable agents include droperidol (Inapsine), etomidate (Amidate), fospropofol (Lusedra), ketamine (Ketalar), methohexital (Brevital), midazolam (Versed), propofol (Diprivan), and sodium thiopental (Pentothal). The volatile liquids include desflurane (Suprane), enflurane (Ethrane), halothane (Fluothane), isoflurane (Forane), methoxyflurane (Penthrane), and sevoflurane (Ultane). All of the agents in these two categories of general anesthetics have the potential to cause neonatal depression or adverse neurobehavioral effects if used close to birth. For most agents, developmental toxicity during other periods of gestation, including organogenesis, has not been reported, but the human pregnancy experience is either absent or very limited. Moreover, the animal reproduction data, when these agents were used alone, were reassuring.
Because nitrous oxide is a gas, concerns have been raised about the potential for adverse effects on the embryo-fetus, as well as the potential effects on women of reproductive potential working in surgical areas. Moreover, when used for surgery, nitrous oxide is always combined with other general anesthetic agents. In animals, the gas is an embryo-fetal toxin (growth restriction, structural anomalies, and death), but the maternal exposures were sometimes high and prolonged. Long-lasting effects reported in animals include permanent brain damage resulting in abnormal behavior effects in motor development and general activity.
In humans, reports have described spontaneous abortions, infertility, and decreased birth weight in exposed pregnancies and in women of reproductive potential working in surgical areas and dental offices. Many of these retrospective reports were subject to self-reporting and/or recall bias, as well as confounders such as lack of information on exposure dose, type of anesthesia, use of other drugs, maternal age, and smoking. Scavenging and ventilating surgical rooms will lessen the exposure of personnel, but will not completely free the area of waste gases. Fortunately, the data do not support an association between acute or chronic nitrous oxide exposure and structural anomalies, but the news for neurotoxicity is troubling.
A 2004 study compared 40 children (ages 5–13 years) born to female physicians and nurses who were exposed to waste anesthetic gases (specific agents not identified) with 40 nonexposed controls matched for age, gender, and maternal occupation. The developmental milestones in the two groups were similar, but the exposed children had significantly lower gross motor ability and more evidence of inattention/hyperactivity. Moreover, the level of exposure was significantly and negatively correlated with fine motor ability and IQ performance (Birth Defects Res. A. Clin. Mol. Teratol. 2004;70:476–82). This study supported the hypothesis that occupational exposure to waste anesthetic gases during pregnancy might be a risk factor for minor neurological deficits in the offspring. Although more data are needed, women of reproductive potential working in surgical areas should consider decreasing or eliminating their exposure to anesthetic gases if pregnancy is a possibility. Moreover, postponing elective surgery until after pregnancy or, at least, after the period of organogenesis, also should be considered. Pregnancy tests should be conducted in any woman of reproductive potential before surgery.
Although the data are very limited, small amounts of some local anesthetics such as lidocaine are excreted into breast milk. Because the amounts in the maternal circulation are usually very low, any exposure of a nursing infant probably is clinically insignificant. Mothers exposed to general anesthetics will not be capable of nursing for several hours, thus allowing clearance of the agents from their circulation.
Local and general anesthetic agents are commonly used in pregnancy, especially for epidural or combined spinal epidural analgesia at delivery. Although surgery requiring general anesthesia is less common, such use is still relatively frequent.
Local anesthetics are given by injection or topically, and include benzocaine, bupivacaine (Marcaine, Sensorcaine), chloroprocaine (Nesacaine), camphor, dibucaine (Nupercainal), levobupivacaine (Chirocaine), lidocaine (Xylocaine, Octocaine), mepivacaine (Carbocaine, Polocaine), pramoxine, prilocaine (Citanest), procaine (Novocaine), ropivacaine (Naropin), and tetracaine (Pontocaine). For neuraxial analgesia, low doses of bupivacaine, lidocaine, or ropivacaine – with or without a small dose of an opioid such as fentanyl – are commonly used. Use of injectable anesthetics for dental procedures also is common in pregnancy. Maternal toxicity involving the central nervous and cardiovascular systems may result from inadvertent intravenous administration or excessive doses.
Topical anesthetics are commonly used in dermatologic products; many are over-the-counter (OTC) products with multiple trade names not listed here. Such agents include benzocaine, butamben, cocaine, dibucaine, lidocaine, pramoxine, prilocaine, tetracaine, and dyclonine (a bactericidal and fungicidal local anesthetic used in lozenges and throat sprays for sore throats). The three topical cocaine products are controlled substances. Because of rapid absorption that can produce toxicity in the user, they are best avoided in pregnancy. Ethyl chloride (chloroethane) is a refrigerant used as a topical anesthetic. Although there are no reports of its use in pregnancy, the low absorption suggests that it is safe.
Benzocaine and pramoxine are available in OTC preparations for anorectal indications, such as hemorrhoids. The human pregnancy data are limited, but because there are more than 50 such products and hemorrhoids are common in pregnancy, these agents appear to be widely used in pregnancy. Systemic absorption may occur from mucous membranes or from damaged skin with the amount absorbed dependent on the dose.
The local anesthetics available for ophthalmic use are lidocaine (Akten), proparacaine (Alcaine, Ophthetic, Paracaine), proparacaine combined with fluorescein (Flucaine, Fluoracaine, Flurate, Fluress, Flurox), and tetracaine (Altacaine, Tetcaine).
In the above situations, with the exception of cocaine, the risk of any aspect of developmental toxicity from appropriate doses and administration of local anesthetics appears to be rare or nonexistent.
General anesthetics can be classified as injectable, gases, or volatile liquids. The injectable agents include droperidol (Inapsine), etomidate (Amidate), fospropofol (Lusedra), ketamine (Ketalar), methohexital (Brevital), midazolam (Versed), propofol (Diprivan), and sodium thiopental (Pentothal). The volatile liquids include desflurane (Suprane), enflurane (Ethrane), halothane (Fluothane), isoflurane (Forane), methoxyflurane (Penthrane), and sevoflurane (Ultane). All of the agents in these two categories of general anesthetics have the potential to cause neonatal depression or adverse neurobehavioral effects if used close to birth. For most agents, developmental toxicity during other periods of gestation, including organogenesis, has not been reported, but the human pregnancy experience is either absent or very limited. Moreover, the animal reproduction data, when these agents were used alone, were reassuring.
Because nitrous oxide is a gas, concerns have been raised about the potential for adverse effects on the embryo-fetus, as well as the potential effects on women of reproductive potential working in surgical areas. Moreover, when used for surgery, nitrous oxide is always combined with other general anesthetic agents. In animals, the gas is an embryo-fetal toxin (growth restriction, structural anomalies, and death), but the maternal exposures were sometimes high and prolonged. Long-lasting effects reported in animals include permanent brain damage resulting in abnormal behavior effects in motor development and general activity.
In humans, reports have described spontaneous abortions, infertility, and decreased birth weight in exposed pregnancies and in women of reproductive potential working in surgical areas and dental offices. Many of these retrospective reports were subject to self-reporting and/or recall bias, as well as confounders such as lack of information on exposure dose, type of anesthesia, use of other drugs, maternal age, and smoking. Scavenging and ventilating surgical rooms will lessen the exposure of personnel, but will not completely free the area of waste gases. Fortunately, the data do not support an association between acute or chronic nitrous oxide exposure and structural anomalies, but the news for neurotoxicity is troubling.
A 2004 study compared 40 children (ages 5–13 years) born to female physicians and nurses who were exposed to waste anesthetic gases (specific agents not identified) with 40 nonexposed controls matched for age, gender, and maternal occupation. The developmental milestones in the two groups were similar, but the exposed children had significantly lower gross motor ability and more evidence of inattention/hyperactivity. Moreover, the level of exposure was significantly and negatively correlated with fine motor ability and IQ performance (Birth Defects Res. A. Clin. Mol. Teratol. 2004;70:476–82). This study supported the hypothesis that occupational exposure to waste anesthetic gases during pregnancy might be a risk factor for minor neurological deficits in the offspring. Although more data are needed, women of reproductive potential working in surgical areas should consider decreasing or eliminating their exposure to anesthetic gases if pregnancy is a possibility. Moreover, postponing elective surgery until after pregnancy or, at least, after the period of organogenesis, also should be considered. Pregnancy tests should be conducted in any woman of reproductive potential before surgery.
Although the data are very limited, small amounts of some local anesthetics such as lidocaine are excreted into breast milk. Because the amounts in the maternal circulation are usually very low, any exposure of a nursing infant probably is clinically insignificant. Mothers exposed to general anesthetics will not be capable of nursing for several hours, thus allowing clearance of the agents from their circulation.
Local and general anesthetic agents are commonly used in pregnancy, especially for epidural or combined spinal epidural analgesia at delivery. Although surgery requiring general anesthesia is less common, such use is still relatively frequent.
Local anesthetics are given by injection or topically, and include benzocaine, bupivacaine (Marcaine, Sensorcaine), chloroprocaine (Nesacaine), camphor, dibucaine (Nupercainal), levobupivacaine (Chirocaine), lidocaine (Xylocaine, Octocaine), mepivacaine (Carbocaine, Polocaine), pramoxine, prilocaine (Citanest), procaine (Novocaine), ropivacaine (Naropin), and tetracaine (Pontocaine). For neuraxial analgesia, low doses of bupivacaine, lidocaine, or ropivacaine – with or without a small dose of an opioid such as fentanyl – are commonly used. Use of injectable anesthetics for dental procedures also is common in pregnancy. Maternal toxicity involving the central nervous and cardiovascular systems may result from inadvertent intravenous administration or excessive doses.
Topical anesthetics are commonly used in dermatologic products; many are over-the-counter (OTC) products with multiple trade names not listed here. Such agents include benzocaine, butamben, cocaine, dibucaine, lidocaine, pramoxine, prilocaine, tetracaine, and dyclonine (a bactericidal and fungicidal local anesthetic used in lozenges and throat sprays for sore throats). The three topical cocaine products are controlled substances. Because of rapid absorption that can produce toxicity in the user, they are best avoided in pregnancy. Ethyl chloride (chloroethane) is a refrigerant used as a topical anesthetic. Although there are no reports of its use in pregnancy, the low absorption suggests that it is safe.
Benzocaine and pramoxine are available in OTC preparations for anorectal indications, such as hemorrhoids. The human pregnancy data are limited, but because there are more than 50 such products and hemorrhoids are common in pregnancy, these agents appear to be widely used in pregnancy. Systemic absorption may occur from mucous membranes or from damaged skin with the amount absorbed dependent on the dose.
The local anesthetics available for ophthalmic use are lidocaine (Akten), proparacaine (Alcaine, Ophthetic, Paracaine), proparacaine combined with fluorescein (Flucaine, Fluoracaine, Flurate, Fluress, Flurox), and tetracaine (Altacaine, Tetcaine).
In the above situations, with the exception of cocaine, the risk of any aspect of developmental toxicity from appropriate doses and administration of local anesthetics appears to be rare or nonexistent.
General anesthetics can be classified as injectable, gases, or volatile liquids. The injectable agents include droperidol (Inapsine), etomidate (Amidate), fospropofol (Lusedra), ketamine (Ketalar), methohexital (Brevital), midazolam (Versed), propofol (Diprivan), and sodium thiopental (Pentothal). The volatile liquids include desflurane (Suprane), enflurane (Ethrane), halothane (Fluothane), isoflurane (Forane), methoxyflurane (Penthrane), and sevoflurane (Ultane). All of the agents in these two categories of general anesthetics have the potential to cause neonatal depression or adverse neurobehavioral effects if used close to birth. For most agents, developmental toxicity during other periods of gestation, including organogenesis, has not been reported, but the human pregnancy experience is either absent or very limited. Moreover, the animal reproduction data, when these agents were used alone, were reassuring.
Because nitrous oxide is a gas, concerns have been raised about the potential for adverse effects on the embryo-fetus, as well as the potential effects on women of reproductive potential working in surgical areas. Moreover, when used for surgery, nitrous oxide is always combined with other general anesthetic agents. In animals, the gas is an embryo-fetal toxin (growth restriction, structural anomalies, and death), but the maternal exposures were sometimes high and prolonged. Long-lasting effects reported in animals include permanent brain damage resulting in abnormal behavior effects in motor development and general activity.
In humans, reports have described spontaneous abortions, infertility, and decreased birth weight in exposed pregnancies and in women of reproductive potential working in surgical areas and dental offices. Many of these retrospective reports were subject to self-reporting and/or recall bias, as well as confounders such as lack of information on exposure dose, type of anesthesia, use of other drugs, maternal age, and smoking. Scavenging and ventilating surgical rooms will lessen the exposure of personnel, but will not completely free the area of waste gases. Fortunately, the data do not support an association between acute or chronic nitrous oxide exposure and structural anomalies, but the news for neurotoxicity is troubling.
A 2004 study compared 40 children (ages 5–13 years) born to female physicians and nurses who were exposed to waste anesthetic gases (specific agents not identified) with 40 nonexposed controls matched for age, gender, and maternal occupation. The developmental milestones in the two groups were similar, but the exposed children had significantly lower gross motor ability and more evidence of inattention/hyperactivity. Moreover, the level of exposure was significantly and negatively correlated with fine motor ability and IQ performance (Birth Defects Res. A. Clin. Mol. Teratol. 2004;70:476–82). This study supported the hypothesis that occupational exposure to waste anesthetic gases during pregnancy might be a risk factor for minor neurological deficits in the offspring. Although more data are needed, women of reproductive potential working in surgical areas should consider decreasing or eliminating their exposure to anesthetic gases if pregnancy is a possibility. Moreover, postponing elective surgery until after pregnancy or, at least, after the period of organogenesis, also should be considered. Pregnancy tests should be conducted in any woman of reproductive potential before surgery.
Although the data are very limited, small amounts of some local anesthetics such as lidocaine are excreted into breast milk. Because the amounts in the maternal circulation are usually very low, any exposure of a nursing infant probably is clinically insignificant. Mothers exposed to general anesthetics will not be capable of nursing for several hours, thus allowing clearance of the agents from their circulation.
Cigarette Smoking Cessation
The rate of cigarette smoking during pregnancy has declined to about 11%, but the prevalence is higher in younger (under 20 years) and older (over 35 years) women.
Smoking is a significant cause of embryonic, fetal, neonatal, infantile, and adolescent toxicity that includes growth restriction, a small increased risk for some birth defects, functional-neurobehavioral deficits, and death. In the 8th edition of “Drugs in Pregnancy and Lactation,” smoking is cited as a major cause of premature birth, placental abruption, placenta previa, and premature rupture of the membranes (Philadelphia: Lippincott Williams & Wilkins, 2008). Because of the dose-effect relationship between smoking and these toxicities, pregnant women should try to stop, or at least reduce, smoking.
The primary intervention strategy is nonpharmacologic: counseling, acupuncture, and hypnotherapy. A 2005 American College of Obstetricians and Gynecologists Committee Opinion detailed an intervention known as the 5 A's: Ask, Advise, Assess, Assist, and Arrange (Obstet. Gynecol. 2005;106:883–8), which also provided resources for smoking cessation. The few studies conducted with acupuncture and hypnotherapy have not clearly shown these therapies to be more effective than placebo; larger and better-designed studies are warranted (Clin. Obstet. Gynecol. 2008;51:419–35).
Pharmacologic therapy may be required if counseling is not successful. Such interventions include varenicline (Chantix); nicotine replacement therapy (NRT) with patches, gum, lozenges, inhalers, and nasal sprays); antidepressants, such as bupropion (Zyban, Wellbutrin); and nonspecific therapies.
The Food and Drug Administration approved varenicline for smoking cessation in 2006. Its mechanism is unique in that it prevents nicotine from binding to nicotinic acetylcholine receptors. Reproduction studies in animals are reassuring, but there are no human pregnancy data. Nevertheless, if a woman requires this therapy, the risk-to-benefit ratio appears to favor use of the drug.
The use of NRT in pregnancy is controversial. Nicotine is the primary chemical derived from smoking and it is a toxin, and since smoking is known to increase the risk of developmental toxicity, the same could occur with NRT. Although nicotine patches produce nicotine serum levels that are similar to smoking, they prevent exposure to other toxins, such as carbon monoxide, cyanide, dioxin, cadmium, thiosulfate, and the more than 3,000 other compounds identified in cigarette smoke. Removing the patch at night before going to sleep will reduce nicotine serum levels for part of the day. Nicotine gum, lozenges, inhaler, and nasal spray produce lower maternal nicotine serum levels but they may cause adverse effects such as poor taste and throat and nasal irritation and reduce compliance.
One study found a nonsignificant increase overall in birth defects in babies of women using NRT (Obstet. Gynecol. 2006;107:51–7). But there were significant increases in cleft lip and defects of the digestive tract and cardiovascular system. The data suggested an increased risk of defects but the authors could not prove or exclude causality.
Bupropion is approved by the FDA for smoking cessation and seems to be effective in reducing withdrawal, weight gain, and cravings. Adverse effects, such as insomnia, dry mouth, and an increased risk of seizures, can be problems, but the drug is more effective than NRT and does not expose the mother or the embryo-fetus to nicotine. The bupropion birth defect registry (now closed) collected data from 1997 to late 2007. It reviewed 1,005 prospective pregnancy outcomes and was able to exclude a major teratogenic effect. However, it was not designed to exclude an increase in the risk of specific defects.
Nonspecific therapies include the antihypertensive/central analgesic clonidine, narcotic antagonists naloxone and naltrexone, and melatonin. They've not been effective against smoking. Melatonin has not been studied in pregnancy or lactation and should be avoided.
Smoking decreases the duration of breastfeeding and exposes the nursing infant to nicotine and other toxins. If a mother can't stop smoking, she should at least not smoke around the infant or while nursing. The risks of using NRT during lactation are unclear because they have not been defined. Varenicline is probably excreted into milk and could cause adverse effects in the infant. Bupropion is excreted into milk and, in the case of one infant exposed via breast milk, no adverse effects were observed.
Counseling is the preferred treatment for smoking cessation. Bupropion would be my first choice for pharmacologic therapy, followed by varenicline, then NRT (avoid NRT in the first trimester.
The rate of cigarette smoking during pregnancy has declined to about 11%, but the prevalence is higher in younger (under 20 years) and older (over 35 years) women.
Smoking is a significant cause of embryonic, fetal, neonatal, infantile, and adolescent toxicity that includes growth restriction, a small increased risk for some birth defects, functional-neurobehavioral deficits, and death. In the 8th edition of “Drugs in Pregnancy and Lactation,” smoking is cited as a major cause of premature birth, placental abruption, placenta previa, and premature rupture of the membranes (Philadelphia: Lippincott Williams & Wilkins, 2008). Because of the dose-effect relationship between smoking and these toxicities, pregnant women should try to stop, or at least reduce, smoking.
The primary intervention strategy is nonpharmacologic: counseling, acupuncture, and hypnotherapy. A 2005 American College of Obstetricians and Gynecologists Committee Opinion detailed an intervention known as the 5 A's: Ask, Advise, Assess, Assist, and Arrange (Obstet. Gynecol. 2005;106:883–8), which also provided resources for smoking cessation. The few studies conducted with acupuncture and hypnotherapy have not clearly shown these therapies to be more effective than placebo; larger and better-designed studies are warranted (Clin. Obstet. Gynecol. 2008;51:419–35).
Pharmacologic therapy may be required if counseling is not successful. Such interventions include varenicline (Chantix); nicotine replacement therapy (NRT) with patches, gum, lozenges, inhalers, and nasal sprays); antidepressants, such as bupropion (Zyban, Wellbutrin); and nonspecific therapies.
The Food and Drug Administration approved varenicline for smoking cessation in 2006. Its mechanism is unique in that it prevents nicotine from binding to nicotinic acetylcholine receptors. Reproduction studies in animals are reassuring, but there are no human pregnancy data. Nevertheless, if a woman requires this therapy, the risk-to-benefit ratio appears to favor use of the drug.
The use of NRT in pregnancy is controversial. Nicotine is the primary chemical derived from smoking and it is a toxin, and since smoking is known to increase the risk of developmental toxicity, the same could occur with NRT. Although nicotine patches produce nicotine serum levels that are similar to smoking, they prevent exposure to other toxins, such as carbon monoxide, cyanide, dioxin, cadmium, thiosulfate, and the more than 3,000 other compounds identified in cigarette smoke. Removing the patch at night before going to sleep will reduce nicotine serum levels for part of the day. Nicotine gum, lozenges, inhaler, and nasal spray produce lower maternal nicotine serum levels but they may cause adverse effects such as poor taste and throat and nasal irritation and reduce compliance.
One study found a nonsignificant increase overall in birth defects in babies of women using NRT (Obstet. Gynecol. 2006;107:51–7). But there were significant increases in cleft lip and defects of the digestive tract and cardiovascular system. The data suggested an increased risk of defects but the authors could not prove or exclude causality.
Bupropion is approved by the FDA for smoking cessation and seems to be effective in reducing withdrawal, weight gain, and cravings. Adverse effects, such as insomnia, dry mouth, and an increased risk of seizures, can be problems, but the drug is more effective than NRT and does not expose the mother or the embryo-fetus to nicotine. The bupropion birth defect registry (now closed) collected data from 1997 to late 2007. It reviewed 1,005 prospective pregnancy outcomes and was able to exclude a major teratogenic effect. However, it was not designed to exclude an increase in the risk of specific defects.
Nonspecific therapies include the antihypertensive/central analgesic clonidine, narcotic antagonists naloxone and naltrexone, and melatonin. They've not been effective against smoking. Melatonin has not been studied in pregnancy or lactation and should be avoided.
Smoking decreases the duration of breastfeeding and exposes the nursing infant to nicotine and other toxins. If a mother can't stop smoking, she should at least not smoke around the infant or while nursing. The risks of using NRT during lactation are unclear because they have not been defined. Varenicline is probably excreted into milk and could cause adverse effects in the infant. Bupropion is excreted into milk and, in the case of one infant exposed via breast milk, no adverse effects were observed.
Counseling is the preferred treatment for smoking cessation. Bupropion would be my first choice for pharmacologic therapy, followed by varenicline, then NRT (avoid NRT in the first trimester.
The rate of cigarette smoking during pregnancy has declined to about 11%, but the prevalence is higher in younger (under 20 years) and older (over 35 years) women.
Smoking is a significant cause of embryonic, fetal, neonatal, infantile, and adolescent toxicity that includes growth restriction, a small increased risk for some birth defects, functional-neurobehavioral deficits, and death. In the 8th edition of “Drugs in Pregnancy and Lactation,” smoking is cited as a major cause of premature birth, placental abruption, placenta previa, and premature rupture of the membranes (Philadelphia: Lippincott Williams & Wilkins, 2008). Because of the dose-effect relationship between smoking and these toxicities, pregnant women should try to stop, or at least reduce, smoking.
The primary intervention strategy is nonpharmacologic: counseling, acupuncture, and hypnotherapy. A 2005 American College of Obstetricians and Gynecologists Committee Opinion detailed an intervention known as the 5 A's: Ask, Advise, Assess, Assist, and Arrange (Obstet. Gynecol. 2005;106:883–8), which also provided resources for smoking cessation. The few studies conducted with acupuncture and hypnotherapy have not clearly shown these therapies to be more effective than placebo; larger and better-designed studies are warranted (Clin. Obstet. Gynecol. 2008;51:419–35).
Pharmacologic therapy may be required if counseling is not successful. Such interventions include varenicline (Chantix); nicotine replacement therapy (NRT) with patches, gum, lozenges, inhalers, and nasal sprays); antidepressants, such as bupropion (Zyban, Wellbutrin); and nonspecific therapies.
The Food and Drug Administration approved varenicline for smoking cessation in 2006. Its mechanism is unique in that it prevents nicotine from binding to nicotinic acetylcholine receptors. Reproduction studies in animals are reassuring, but there are no human pregnancy data. Nevertheless, if a woman requires this therapy, the risk-to-benefit ratio appears to favor use of the drug.
The use of NRT in pregnancy is controversial. Nicotine is the primary chemical derived from smoking and it is a toxin, and since smoking is known to increase the risk of developmental toxicity, the same could occur with NRT. Although nicotine patches produce nicotine serum levels that are similar to smoking, they prevent exposure to other toxins, such as carbon monoxide, cyanide, dioxin, cadmium, thiosulfate, and the more than 3,000 other compounds identified in cigarette smoke. Removing the patch at night before going to sleep will reduce nicotine serum levels for part of the day. Nicotine gum, lozenges, inhaler, and nasal spray produce lower maternal nicotine serum levels but they may cause adverse effects such as poor taste and throat and nasal irritation and reduce compliance.
One study found a nonsignificant increase overall in birth defects in babies of women using NRT (Obstet. Gynecol. 2006;107:51–7). But there were significant increases in cleft lip and defects of the digestive tract and cardiovascular system. The data suggested an increased risk of defects but the authors could not prove or exclude causality.
Bupropion is approved by the FDA for smoking cessation and seems to be effective in reducing withdrawal, weight gain, and cravings. Adverse effects, such as insomnia, dry mouth, and an increased risk of seizures, can be problems, but the drug is more effective than NRT and does not expose the mother or the embryo-fetus to nicotine. The bupropion birth defect registry (now closed) collected data from 1997 to late 2007. It reviewed 1,005 prospective pregnancy outcomes and was able to exclude a major teratogenic effect. However, it was not designed to exclude an increase in the risk of specific defects.
Nonspecific therapies include the antihypertensive/central analgesic clonidine, narcotic antagonists naloxone and naltrexone, and melatonin. They've not been effective against smoking. Melatonin has not been studied in pregnancy or lactation and should be avoided.
Smoking decreases the duration of breastfeeding and exposes the nursing infant to nicotine and other toxins. If a mother can't stop smoking, she should at least not smoke around the infant or while nursing. The risks of using NRT during lactation are unclear because they have not been defined. Varenicline is probably excreted into milk and could cause adverse effects in the infant. Bupropion is excreted into milk and, in the case of one infant exposed via breast milk, no adverse effects were observed.
Counseling is the preferred treatment for smoking cessation. Bupropion would be my first choice for pharmacologic therapy, followed by varenicline, then NRT (avoid NRT in the first trimester.
When Human Data Are Lacking
In 2007, the Food and Drug Administration approved 16 new molecular entities and several new biologics. None of these agents have human pregnancy experience, but some will be prescribed to women of reproductive age and exposure in early gestation is inevitable.
There also are situations when a woman's condition requires drug therapy, regardless of pregnancy. New antineoplastics are indicated when other therapies have failed to fit into this category, such as ixabepilone (Ixempra) and lapatinib (Tykerb), for breast cancer; nilotinib (Tasigna), for leukemia; and temsirolimus (Torisel), for advanced renal cancer.
Regardless of the circumstances, clinicians caring for women of reproductive age will be faced with the dilemma of how to counsel patients when there are few or no human pregnancy data. One method, using some of the drugs approved in 2007 as examples, is described here. When an exposure has already occurred, or when the maternal benefit for starting therapy clearly exceeds the fetal risk and there are no other alternatives, the estimation of fetal risk can be based on four questions:
▸ Is there human pregnancy experience for the drug?
▸ Is there human pregnancy experience with other drugs in the same class or with similar mechanisms of action?
▸ Does the drug cross the human placenta?
▸ Does the drug cause developmental toxicity in animals at doses less than or equal to 10 times the human dose?
Timing of the exposure is critical, and must be included in any estimation. Although organogenesis (5–10 weeks) is usually the most vulnerable period and exposure at that time should be avoided if possible, drugs can cause developmental toxicity throughout gestation.
For the new drugs described, the answer to the first question is no.
There are several examples that fit the second question. Aliskiren (Tekturna) is an antihypertensive that acts as a renin inhibitor. Two other classes of drugs acting on the renin-angiotensin system, angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), are known to cause marked fetal toxicity in the second and third trimesters; a similar effect might occur with aliskiren. Nebivolol (Bystolic) is a β-blocker used for hypertension. It has no intrinsic sympathomimetic activity (ISA), so, as with other β-blockers without ISA, its effects may include restricted placental and fetal weights when used during the second half of gestation.
Levocetirizine (Xyzal), the L-isomer of cetirizine (Zyrtec), is an antihistamine. There is no evidence of fetal harm from antihistamines, so the risk from exposure to levocetirizine is probably low. On the other hand, lisdexamfetamine (Vyvanse), which is indicated for attention-deficit/hyperactivity disorder, is a prodrug of dextroamphetamine, a drug known to cause human developmental toxicity.
Package inserts typically provide at least four important factors that help answer the third question: maternal concentration, elimination half-life, plasma protein binding, and molecular weight. For example, a small percentage of nonpregnant adults had measurable plasma concentrations of retapamulin (Altabax), a topical antibiotic, but the levels were very low (less than 1 ng/mL). The elimination half-life is unknown, but the medium molecular weight (518) suggests that the drug will cross the placenta. However, the amounts available for transfer appear to be clinically insignificant.
Although there are no definite methods to interpret animal studies, nearly all drugs known to cause human developmental toxicity also cause such toxicity in at least one animal species
The dose that causes toxicity in animals is critical, as is its relationship to the maximum recommend human dose (MRHD). Guidelines released by the Environmental Protection Agency in 1991 stated that if a drug did not cause developmental toxicity at doses less than or equal to 10 times the human dose based on body surface area (BSA) or systemic exposure (AUC), then the drug could be considered low risk for human fetal toxicity. Conversely, if a drug did cause toxicity at doses less than or equal to 10 times the human dose (in the absence of maternal toxicity), then it could be classified as having risk, but the risk magnitude would be unknown. These conclusions were similar to those reached by a panel convened in 2004 (Birth Defects Res. 2004;70[Part A]:7-12).
The strength of any risk estimation increases if two or more of the responses concur. For example, animal studies with retapamulin found no fetal toxicity after high systemic doses. These results, combined with the low systemic levels, reinforce the estimation that this is a low-risk drug. Conversely, animal studies with aliskiren observed fetal growth restriction. Thus, the estimation that this drug may cause fetal growth restriction is strengthened.
In 2007, the Food and Drug Administration approved 16 new molecular entities and several new biologics. None of these agents have human pregnancy experience, but some will be prescribed to women of reproductive age and exposure in early gestation is inevitable.
There also are situations when a woman's condition requires drug therapy, regardless of pregnancy. New antineoplastics are indicated when other therapies have failed to fit into this category, such as ixabepilone (Ixempra) and lapatinib (Tykerb), for breast cancer; nilotinib (Tasigna), for leukemia; and temsirolimus (Torisel), for advanced renal cancer.
Regardless of the circumstances, clinicians caring for women of reproductive age will be faced with the dilemma of how to counsel patients when there are few or no human pregnancy data. One method, using some of the drugs approved in 2007 as examples, is described here. When an exposure has already occurred, or when the maternal benefit for starting therapy clearly exceeds the fetal risk and there are no other alternatives, the estimation of fetal risk can be based on four questions:
▸ Is there human pregnancy experience for the drug?
▸ Is there human pregnancy experience with other drugs in the same class or with similar mechanisms of action?
▸ Does the drug cross the human placenta?
▸ Does the drug cause developmental toxicity in animals at doses less than or equal to 10 times the human dose?
Timing of the exposure is critical, and must be included in any estimation. Although organogenesis (5–10 weeks) is usually the most vulnerable period and exposure at that time should be avoided if possible, drugs can cause developmental toxicity throughout gestation.
For the new drugs described, the answer to the first question is no.
There are several examples that fit the second question. Aliskiren (Tekturna) is an antihypertensive that acts as a renin inhibitor. Two other classes of drugs acting on the renin-angiotensin system, angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), are known to cause marked fetal toxicity in the second and third trimesters; a similar effect might occur with aliskiren. Nebivolol (Bystolic) is a β-blocker used for hypertension. It has no intrinsic sympathomimetic activity (ISA), so, as with other β-blockers without ISA, its effects may include restricted placental and fetal weights when used during the second half of gestation.
Levocetirizine (Xyzal), the L-isomer of cetirizine (Zyrtec), is an antihistamine. There is no evidence of fetal harm from antihistamines, so the risk from exposure to levocetirizine is probably low. On the other hand, lisdexamfetamine (Vyvanse), which is indicated for attention-deficit/hyperactivity disorder, is a prodrug of dextroamphetamine, a drug known to cause human developmental toxicity.
Package inserts typically provide at least four important factors that help answer the third question: maternal concentration, elimination half-life, plasma protein binding, and molecular weight. For example, a small percentage of nonpregnant adults had measurable plasma concentrations of retapamulin (Altabax), a topical antibiotic, but the levels were very low (less than 1 ng/mL). The elimination half-life is unknown, but the medium molecular weight (518) suggests that the drug will cross the placenta. However, the amounts available for transfer appear to be clinically insignificant.
Although there are no definite methods to interpret animal studies, nearly all drugs known to cause human developmental toxicity also cause such toxicity in at least one animal species
The dose that causes toxicity in animals is critical, as is its relationship to the maximum recommend human dose (MRHD). Guidelines released by the Environmental Protection Agency in 1991 stated that if a drug did not cause developmental toxicity at doses less than or equal to 10 times the human dose based on body surface area (BSA) or systemic exposure (AUC), then the drug could be considered low risk for human fetal toxicity. Conversely, if a drug did cause toxicity at doses less than or equal to 10 times the human dose (in the absence of maternal toxicity), then it could be classified as having risk, but the risk magnitude would be unknown. These conclusions were similar to those reached by a panel convened in 2004 (Birth Defects Res. 2004;70[Part A]:7-12).
The strength of any risk estimation increases if two or more of the responses concur. For example, animal studies with retapamulin found no fetal toxicity after high systemic doses. These results, combined with the low systemic levels, reinforce the estimation that this is a low-risk drug. Conversely, animal studies with aliskiren observed fetal growth restriction. Thus, the estimation that this drug may cause fetal growth restriction is strengthened.
In 2007, the Food and Drug Administration approved 16 new molecular entities and several new biologics. None of these agents have human pregnancy experience, but some will be prescribed to women of reproductive age and exposure in early gestation is inevitable.
There also are situations when a woman's condition requires drug therapy, regardless of pregnancy. New antineoplastics are indicated when other therapies have failed to fit into this category, such as ixabepilone (Ixempra) and lapatinib (Tykerb), for breast cancer; nilotinib (Tasigna), for leukemia; and temsirolimus (Torisel), for advanced renal cancer.
Regardless of the circumstances, clinicians caring for women of reproductive age will be faced with the dilemma of how to counsel patients when there are few or no human pregnancy data. One method, using some of the drugs approved in 2007 as examples, is described here. When an exposure has already occurred, or when the maternal benefit for starting therapy clearly exceeds the fetal risk and there are no other alternatives, the estimation of fetal risk can be based on four questions:
▸ Is there human pregnancy experience for the drug?
▸ Is there human pregnancy experience with other drugs in the same class or with similar mechanisms of action?
▸ Does the drug cross the human placenta?
▸ Does the drug cause developmental toxicity in animals at doses less than or equal to 10 times the human dose?
Timing of the exposure is critical, and must be included in any estimation. Although organogenesis (5–10 weeks) is usually the most vulnerable period and exposure at that time should be avoided if possible, drugs can cause developmental toxicity throughout gestation.
For the new drugs described, the answer to the first question is no.
There are several examples that fit the second question. Aliskiren (Tekturna) is an antihypertensive that acts as a renin inhibitor. Two other classes of drugs acting on the renin-angiotensin system, angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), are known to cause marked fetal toxicity in the second and third trimesters; a similar effect might occur with aliskiren. Nebivolol (Bystolic) is a β-blocker used for hypertension. It has no intrinsic sympathomimetic activity (ISA), so, as with other β-blockers without ISA, its effects may include restricted placental and fetal weights when used during the second half of gestation.
Levocetirizine (Xyzal), the L-isomer of cetirizine (Zyrtec), is an antihistamine. There is no evidence of fetal harm from antihistamines, so the risk from exposure to levocetirizine is probably low. On the other hand, lisdexamfetamine (Vyvanse), which is indicated for attention-deficit/hyperactivity disorder, is a prodrug of dextroamphetamine, a drug known to cause human developmental toxicity.
Package inserts typically provide at least four important factors that help answer the third question: maternal concentration, elimination half-life, plasma protein binding, and molecular weight. For example, a small percentage of nonpregnant adults had measurable plasma concentrations of retapamulin (Altabax), a topical antibiotic, but the levels were very low (less than 1 ng/mL). The elimination half-life is unknown, but the medium molecular weight (518) suggests that the drug will cross the placenta. However, the amounts available for transfer appear to be clinically insignificant.
Although there are no definite methods to interpret animal studies, nearly all drugs known to cause human developmental toxicity also cause such toxicity in at least one animal species
The dose that causes toxicity in animals is critical, as is its relationship to the maximum recommend human dose (MRHD). Guidelines released by the Environmental Protection Agency in 1991 stated that if a drug did not cause developmental toxicity at doses less than or equal to 10 times the human dose based on body surface area (BSA) or systemic exposure (AUC), then the drug could be considered low risk for human fetal toxicity. Conversely, if a drug did cause toxicity at doses less than or equal to 10 times the human dose (in the absence of maternal toxicity), then it could be classified as having risk, but the risk magnitude would be unknown. These conclusions were similar to those reached by a panel convened in 2004 (Birth Defects Res. 2004;70[Part A]:7-12).
The strength of any risk estimation increases if two or more of the responses concur. For example, animal studies with retapamulin found no fetal toxicity after high systemic doses. These results, combined with the low systemic levels, reinforce the estimation that this is a low-risk drug. Conversely, animal studies with aliskiren observed fetal growth restriction. Thus, the estimation that this drug may cause fetal growth restriction is strengthened.
Droperidol and the Black Box Warning
In December 2001, the Food and Drug Administration placed a black box warning on droperidol (Inapsine) because of concerns over QT prolongation and torsades de pointes.
This action took the medical and pharmacy communities by surprise and created tremendous controversy. Although the labeling information always had contained warnings of serious and even life-threatening arrhythmias, droperidol had a 30-year history of safe and effective use in a range of patients.
Since its release in 1970, droperidol had been one of the preferred antiemetics for the prevention and treatment of postoperative nausea and vomiting (PONV) and the treatment of hyperemesis gravidarum (HG). But the agency's action resulted in a marked decrease in its use for both indications.
In the early 1990s, manufacturing problems curtailed the availability of parenteral prochlorperazine, the other preferred antiemetic for these indications. With no other viable alternatives, there was an increase in the use of ondansetron (Zofran), which was expensive, but is now available as a generic.
What remains unresolved is the use of droperidol in clinical situations, in which it is the preferred agent for PONV, including after cesarean section, and for HG.
Several small studies that compared droperidol and ondansetron for PONV found no differences between the two in terms of efficacy and toxicity. However, a large study with more than 2,000 subjects concluded that droperidol (1.25 mg IV) was superior to ondansetron (4 mg IV) for both vomiting and nausea (Anesth. Analg. 1998;86:731–8).
A review of 76 trials of 5,351 patients receiving 24 different droperidol regimens found no serious adverse events (Can. J. Anaesth. 2000;47:537–51). Other studies from California and Montreal reported that droperidol infusions were highly effective in the treatment of HG (Am. J. Obstet. Gynecol. 1996;174:1801–6; J. Soc. Obstet. Gynaecol. Can 2001; 23:133–9). None of these studies found evidence that droperidol was related to torsades de pointes.
A 2005 study of droperidol (0.625–1.25 mg) for antiemetic prophylaxis during general anesthesia in outpatient surgery observed no significant increase in the corrected QT (QTc) interval, compared with saline (Anesthesiology 2005;102:1101–5). A 2007 Mayo Clinic study reported no documented cases of torsades de pointes in the 16,791 patients exposed to droperidol over the 3-year period preceding the black box warning, and the authors concluded the FDA warning for low-dose droperidol was excessive and unnecessary (Anesthesiology 2007;107:531–6).
An editorial voiced the same opinion (N. Engl. J. Med. 2004;350:2511–2). In a small study, 49 women with hyperemesis gravidarum received droperidol 1 mg/hr for 37 hours. The pretreatment QTc interval was 404 milliseconds, compared with 412 milliseconds at 37 hours, a clinically insignificant increase. A 2007 report analyzed data received under the Freedom of Information Act used by the FDA to support their black box warning. After excluding duplicate reports, there were 65 cases of cardiac toxicity possibly caused by droperidol.
Some of these reports appeared to have occurred more than 30 years ago, not merely over the past 4 years as suggested by the FDA. Only two of the cases involved doses commonly used in the United States, one of which was a patient with preexisting cardiovascular disease. In addition, the FDA used European data that involved doses 50–100 times higher than those used in the United States. The authors concluded that it did not appear that drugs such as ondansetron were safer than droperidol with regard to QT interval prolongation (Am. J. Health-Syst. Pharm. 2007;64:1174–86).
For 23 years, my colleagues and I have successfully used droperidol infusions for HG. Before receiving droperidol, patients must have normal concentrations of potassium and magnesium; they are excluded if they have a history of QT prolongation (slow heart rate), congestive heart failure, cardiac arrhythmias, or are taking other drugs known to increase the QT interval.
Because there is a genetic component for QT prolongation, women also are excluded if there is a history of an immediate blood relative (mother, father, or sibling) with QT prolongation or sudden cardiac death secondary to cardiac arrhythmia. Not a single patient has had to be excluded because of personal or family histories, or because of the use of other medications. Nor have we observed any serious adverse effects in the six to seven patients with hyperemesis gravidarum we treat each month.
Considering the strong evidence of safety and efficacy, it is time for the FDA to remove the antiemetic doses of droperidol from the black box warning.
In December 2001, the Food and Drug Administration placed a black box warning on droperidol (Inapsine) because of concerns over QT prolongation and torsades de pointes.
This action took the medical and pharmacy communities by surprise and created tremendous controversy. Although the labeling information always had contained warnings of serious and even life-threatening arrhythmias, droperidol had a 30-year history of safe and effective use in a range of patients.
Since its release in 1970, droperidol had been one of the preferred antiemetics for the prevention and treatment of postoperative nausea and vomiting (PONV) and the treatment of hyperemesis gravidarum (HG). But the agency's action resulted in a marked decrease in its use for both indications.
In the early 1990s, manufacturing problems curtailed the availability of parenteral prochlorperazine, the other preferred antiemetic for these indications. With no other viable alternatives, there was an increase in the use of ondansetron (Zofran), which was expensive, but is now available as a generic.
What remains unresolved is the use of droperidol in clinical situations, in which it is the preferred agent for PONV, including after cesarean section, and for HG.
Several small studies that compared droperidol and ondansetron for PONV found no differences between the two in terms of efficacy and toxicity. However, a large study with more than 2,000 subjects concluded that droperidol (1.25 mg IV) was superior to ondansetron (4 mg IV) for both vomiting and nausea (Anesth. Analg. 1998;86:731–8).
A review of 76 trials of 5,351 patients receiving 24 different droperidol regimens found no serious adverse events (Can. J. Anaesth. 2000;47:537–51). Other studies from California and Montreal reported that droperidol infusions were highly effective in the treatment of HG (Am. J. Obstet. Gynecol. 1996;174:1801–6; J. Soc. Obstet. Gynaecol. Can 2001; 23:133–9). None of these studies found evidence that droperidol was related to torsades de pointes.
A 2005 study of droperidol (0.625–1.25 mg) for antiemetic prophylaxis during general anesthesia in outpatient surgery observed no significant increase in the corrected QT (QTc) interval, compared with saline (Anesthesiology 2005;102:1101–5). A 2007 Mayo Clinic study reported no documented cases of torsades de pointes in the 16,791 patients exposed to droperidol over the 3-year period preceding the black box warning, and the authors concluded the FDA warning for low-dose droperidol was excessive and unnecessary (Anesthesiology 2007;107:531–6).
An editorial voiced the same opinion (N. Engl. J. Med. 2004;350:2511–2). In a small study, 49 women with hyperemesis gravidarum received droperidol 1 mg/hr for 37 hours. The pretreatment QTc interval was 404 milliseconds, compared with 412 milliseconds at 37 hours, a clinically insignificant increase. A 2007 report analyzed data received under the Freedom of Information Act used by the FDA to support their black box warning. After excluding duplicate reports, there were 65 cases of cardiac toxicity possibly caused by droperidol.
Some of these reports appeared to have occurred more than 30 years ago, not merely over the past 4 years as suggested by the FDA. Only two of the cases involved doses commonly used in the United States, one of which was a patient with preexisting cardiovascular disease. In addition, the FDA used European data that involved doses 50–100 times higher than those used in the United States. The authors concluded that it did not appear that drugs such as ondansetron were safer than droperidol with regard to QT interval prolongation (Am. J. Health-Syst. Pharm. 2007;64:1174–86).
For 23 years, my colleagues and I have successfully used droperidol infusions for HG. Before receiving droperidol, patients must have normal concentrations of potassium and magnesium; they are excluded if they have a history of QT prolongation (slow heart rate), congestive heart failure, cardiac arrhythmias, or are taking other drugs known to increase the QT interval.
Because there is a genetic component for QT prolongation, women also are excluded if there is a history of an immediate blood relative (mother, father, or sibling) with QT prolongation or sudden cardiac death secondary to cardiac arrhythmia. Not a single patient has had to be excluded because of personal or family histories, or because of the use of other medications. Nor have we observed any serious adverse effects in the six to seven patients with hyperemesis gravidarum we treat each month.
Considering the strong evidence of safety and efficacy, it is time for the FDA to remove the antiemetic doses of droperidol from the black box warning.
In December 2001, the Food and Drug Administration placed a black box warning on droperidol (Inapsine) because of concerns over QT prolongation and torsades de pointes.
This action took the medical and pharmacy communities by surprise and created tremendous controversy. Although the labeling information always had contained warnings of serious and even life-threatening arrhythmias, droperidol had a 30-year history of safe and effective use in a range of patients.
Since its release in 1970, droperidol had been one of the preferred antiemetics for the prevention and treatment of postoperative nausea and vomiting (PONV) and the treatment of hyperemesis gravidarum (HG). But the agency's action resulted in a marked decrease in its use for both indications.
In the early 1990s, manufacturing problems curtailed the availability of parenteral prochlorperazine, the other preferred antiemetic for these indications. With no other viable alternatives, there was an increase in the use of ondansetron (Zofran), which was expensive, but is now available as a generic.
What remains unresolved is the use of droperidol in clinical situations, in which it is the preferred agent for PONV, including after cesarean section, and for HG.
Several small studies that compared droperidol and ondansetron for PONV found no differences between the two in terms of efficacy and toxicity. However, a large study with more than 2,000 subjects concluded that droperidol (1.25 mg IV) was superior to ondansetron (4 mg IV) for both vomiting and nausea (Anesth. Analg. 1998;86:731–8).
A review of 76 trials of 5,351 patients receiving 24 different droperidol regimens found no serious adverse events (Can. J. Anaesth. 2000;47:537–51). Other studies from California and Montreal reported that droperidol infusions were highly effective in the treatment of HG (Am. J. Obstet. Gynecol. 1996;174:1801–6; J. Soc. Obstet. Gynaecol. Can 2001; 23:133–9). None of these studies found evidence that droperidol was related to torsades de pointes.
A 2005 study of droperidol (0.625–1.25 mg) for antiemetic prophylaxis during general anesthesia in outpatient surgery observed no significant increase in the corrected QT (QTc) interval, compared with saline (Anesthesiology 2005;102:1101–5). A 2007 Mayo Clinic study reported no documented cases of torsades de pointes in the 16,791 patients exposed to droperidol over the 3-year period preceding the black box warning, and the authors concluded the FDA warning for low-dose droperidol was excessive and unnecessary (Anesthesiology 2007;107:531–6).
An editorial voiced the same opinion (N. Engl. J. Med. 2004;350:2511–2). In a small study, 49 women with hyperemesis gravidarum received droperidol 1 mg/hr for 37 hours. The pretreatment QTc interval was 404 milliseconds, compared with 412 milliseconds at 37 hours, a clinically insignificant increase. A 2007 report analyzed data received under the Freedom of Information Act used by the FDA to support their black box warning. After excluding duplicate reports, there were 65 cases of cardiac toxicity possibly caused by droperidol.
Some of these reports appeared to have occurred more than 30 years ago, not merely over the past 4 years as suggested by the FDA. Only two of the cases involved doses commonly used in the United States, one of which was a patient with preexisting cardiovascular disease. In addition, the FDA used European data that involved doses 50–100 times higher than those used in the United States. The authors concluded that it did not appear that drugs such as ondansetron were safer than droperidol with regard to QT interval prolongation (Am. J. Health-Syst. Pharm. 2007;64:1174–86).
For 23 years, my colleagues and I have successfully used droperidol infusions for HG. Before receiving droperidol, patients must have normal concentrations of potassium and magnesium; they are excluded if they have a history of QT prolongation (slow heart rate), congestive heart failure, cardiac arrhythmias, or are taking other drugs known to increase the QT interval.
Because there is a genetic component for QT prolongation, women also are excluded if there is a history of an immediate blood relative (mother, father, or sibling) with QT prolongation or sudden cardiac death secondary to cardiac arrhythmia. Not a single patient has had to be excluded because of personal or family histories, or because of the use of other medications. Nor have we observed any serious adverse effects in the six to seven patients with hyperemesis gravidarum we treat each month.
Considering the strong evidence of safety and efficacy, it is time for the FDA to remove the antiemetic doses of droperidol from the black box warning.
Exposure to Monoclonal Antibodies
Excluding those classified as orphan drugs, there are 10 monoclonal antibodies currently used to treat cancer, asthma, or rheumatoid arthritis. Five are composed of various types of humanized immunoglobulin G (IgG) and two of murine IgG. The approved indications include leukemia, metastatic carcinoma of the colon or rectum, squamous cell carcinoma of the head and neck, non-Hodgkin's lymphoma, metastatic breast cancer, and moderate to severe chronic diseases such as asthma and rheumatoid arthritis.
The antineoplastic agents are alemtuzumab (Campath), bevacizumab (Avastin), cetuximab (Erbitux), gemtuzumab ozogamicin (Mylotarg), ibritumomab tiuxetan (Zevalin), panitumumab (Vectibix), tositumomab and iodine 131 (Bexxar), and trastuzumab (Herceptin). The ninth member of this group, rituximab (Rituxan), is also used as an antirheumatic agent.
Exposure of the embryo and fetus should be expected whenever these antibodies are used in pregnancy. Although their molecular weights are very high, two are known to cross the placenta: Rituxan in humans and Herceptin in monkeys. The transplacental passage of the other antibodies has not been studied, but endogenous IgG crosses the placenta. Moreover, the long elimination half-lives ranging from about 2 to 19 days will place these antibodies at the maternal-fetal interface for prolonged periods. Animal reproduction studies have not been conducted with Bexxar, Campath, Erbitux, or Zevalin. Studies in pregnant animals with Herceptin and Rituxan suggested low risk for humans, whereas the suggested risk was higher for Avastin, Mylotarg, and Vectibix.
Bexxar, Campath, Erbitux, Mylotarg, Zevalin, and Rituxan may cause severe, infusion-related toxicity, including hypotension. Although premedication is used to lessen this effect, this toxicity could have deleterious effects on placental perfusion, resulting in harm to the embryo and fetus.
Human pregnancy data are available only for Herceptin and Rituxan. For Herceptin, the human pregnancy experience is limited to five cases, two of which involved first-trimester exposure. Although no congenital malformations were observed, fetal renal toxicity, as evidenced by oligohydramnios or anhydramnios, was observed in three cases. The toxicity might have been caused by inhibition of human epidermal growth factor receptor 2 (HER-2) in the fetal kidneys. The renal toxicity was reversible, and all five infants developed normally. However, there is potential for other toxicity because HER-2 protein expression is high in many embryonic tissues, such as cardiac and neural tissues.
Six pregnancies have been exposed to Rituxan, including two in the first trimester. No structural anomalies were noted, and all infants appeared to be healthy at birth. One had depletion of B lymphocytes, but B-cell counts returned to normal at about 4 months of age. No increase in infectious disease was noted in any of the infants.
Reports of exposure to Bexxar and Mylotarg during pregnancy are unlikely. Bexxar, indicated for non-Hodgkin's lymphoma, contains radioactive iodine and is contraindicated in pregnancy. Mylotarg, a combination of gemtuzumab (IgG4k) conjugated with the cytotoxic antitumor antibiotic calicheamicin, is indicated for the treatment of patients with CD33-positive acute myeloid leukemia in first relapse who are 60 years of age or older. Mylotarg caused significant developmental toxicity at a small fraction of the human dose in the only experimental animal species tested. The therapeutic regimen for Zevalin, another agent for non-Hodgkin's lymphoma, should preclude its use in pregnancy because it includes two radioactive components as well as Rituxan, and the risk to the embryo and fetus appears to be high.
Omalizumab (Xolair), a monoclonal antibody used for moderate to severe persistent asthma, selectively binds to human IgE and has a half-life of 26 days. It has not been studied in animals or humans, but probably crosses the placenta. Reproduction studies in monkeys suggest that the risk in human pregnancy is low, but the human pregnancy experience is limited. In clinical trials, 29 women became pregnant during treatment with Xolair, which was stopped when pregnancy was diagnosed. Among these patients, there were 4 spontaneous abortions (SABs), 3 elective abortions, 11 normal deliveries, and 11 ongoing pregnancies. The number of SABs, all occurring in the first trimester, is within the expected incidence for recognized pregnancies.
A full assessment of the risk of monoclonal antibodies during pregnancy is not possible because of the very limited or absent human pregnancy data, including a lack of long-term evaluation of exposed offspring. Nevertheless, these agents are used for life-threatening diseases and, if indicated, should not be withheld from a pregnant woman—with the exception of Bexxar, Mylotarg, and possibly Zevalin.
Excluding those classified as orphan drugs, there are 10 monoclonal antibodies currently used to treat cancer, asthma, or rheumatoid arthritis. Five are composed of various types of humanized immunoglobulin G (IgG) and two of murine IgG. The approved indications include leukemia, metastatic carcinoma of the colon or rectum, squamous cell carcinoma of the head and neck, non-Hodgkin's lymphoma, metastatic breast cancer, and moderate to severe chronic diseases such as asthma and rheumatoid arthritis.
The antineoplastic agents are alemtuzumab (Campath), bevacizumab (Avastin), cetuximab (Erbitux), gemtuzumab ozogamicin (Mylotarg), ibritumomab tiuxetan (Zevalin), panitumumab (Vectibix), tositumomab and iodine 131 (Bexxar), and trastuzumab (Herceptin). The ninth member of this group, rituximab (Rituxan), is also used as an antirheumatic agent.
Exposure of the embryo and fetus should be expected whenever these antibodies are used in pregnancy. Although their molecular weights are very high, two are known to cross the placenta: Rituxan in humans and Herceptin in monkeys. The transplacental passage of the other antibodies has not been studied, but endogenous IgG crosses the placenta. Moreover, the long elimination half-lives ranging from about 2 to 19 days will place these antibodies at the maternal-fetal interface for prolonged periods. Animal reproduction studies have not been conducted with Bexxar, Campath, Erbitux, or Zevalin. Studies in pregnant animals with Herceptin and Rituxan suggested low risk for humans, whereas the suggested risk was higher for Avastin, Mylotarg, and Vectibix.
Bexxar, Campath, Erbitux, Mylotarg, Zevalin, and Rituxan may cause severe, infusion-related toxicity, including hypotension. Although premedication is used to lessen this effect, this toxicity could have deleterious effects on placental perfusion, resulting in harm to the embryo and fetus.
Human pregnancy data are available only for Herceptin and Rituxan. For Herceptin, the human pregnancy experience is limited to five cases, two of which involved first-trimester exposure. Although no congenital malformations were observed, fetal renal toxicity, as evidenced by oligohydramnios or anhydramnios, was observed in three cases. The toxicity might have been caused by inhibition of human epidermal growth factor receptor 2 (HER-2) in the fetal kidneys. The renal toxicity was reversible, and all five infants developed normally. However, there is potential for other toxicity because HER-2 protein expression is high in many embryonic tissues, such as cardiac and neural tissues.
Six pregnancies have been exposed to Rituxan, including two in the first trimester. No structural anomalies were noted, and all infants appeared to be healthy at birth. One had depletion of B lymphocytes, but B-cell counts returned to normal at about 4 months of age. No increase in infectious disease was noted in any of the infants.
Reports of exposure to Bexxar and Mylotarg during pregnancy are unlikely. Bexxar, indicated for non-Hodgkin's lymphoma, contains radioactive iodine and is contraindicated in pregnancy. Mylotarg, a combination of gemtuzumab (IgG4k) conjugated with the cytotoxic antitumor antibiotic calicheamicin, is indicated for the treatment of patients with CD33-positive acute myeloid leukemia in first relapse who are 60 years of age or older. Mylotarg caused significant developmental toxicity at a small fraction of the human dose in the only experimental animal species tested. The therapeutic regimen for Zevalin, another agent for non-Hodgkin's lymphoma, should preclude its use in pregnancy because it includes two radioactive components as well as Rituxan, and the risk to the embryo and fetus appears to be high.
Omalizumab (Xolair), a monoclonal antibody used for moderate to severe persistent asthma, selectively binds to human IgE and has a half-life of 26 days. It has not been studied in animals or humans, but probably crosses the placenta. Reproduction studies in monkeys suggest that the risk in human pregnancy is low, but the human pregnancy experience is limited. In clinical trials, 29 women became pregnant during treatment with Xolair, which was stopped when pregnancy was diagnosed. Among these patients, there were 4 spontaneous abortions (SABs), 3 elective abortions, 11 normal deliveries, and 11 ongoing pregnancies. The number of SABs, all occurring in the first trimester, is within the expected incidence for recognized pregnancies.
A full assessment of the risk of monoclonal antibodies during pregnancy is not possible because of the very limited or absent human pregnancy data, including a lack of long-term evaluation of exposed offspring. Nevertheless, these agents are used for life-threatening diseases and, if indicated, should not be withheld from a pregnant woman—with the exception of Bexxar, Mylotarg, and possibly Zevalin.
Excluding those classified as orphan drugs, there are 10 monoclonal antibodies currently used to treat cancer, asthma, or rheumatoid arthritis. Five are composed of various types of humanized immunoglobulin G (IgG) and two of murine IgG. The approved indications include leukemia, metastatic carcinoma of the colon or rectum, squamous cell carcinoma of the head and neck, non-Hodgkin's lymphoma, metastatic breast cancer, and moderate to severe chronic diseases such as asthma and rheumatoid arthritis.
The antineoplastic agents are alemtuzumab (Campath), bevacizumab (Avastin), cetuximab (Erbitux), gemtuzumab ozogamicin (Mylotarg), ibritumomab tiuxetan (Zevalin), panitumumab (Vectibix), tositumomab and iodine 131 (Bexxar), and trastuzumab (Herceptin). The ninth member of this group, rituximab (Rituxan), is also used as an antirheumatic agent.
Exposure of the embryo and fetus should be expected whenever these antibodies are used in pregnancy. Although their molecular weights are very high, two are known to cross the placenta: Rituxan in humans and Herceptin in monkeys. The transplacental passage of the other antibodies has not been studied, but endogenous IgG crosses the placenta. Moreover, the long elimination half-lives ranging from about 2 to 19 days will place these antibodies at the maternal-fetal interface for prolonged periods. Animal reproduction studies have not been conducted with Bexxar, Campath, Erbitux, or Zevalin. Studies in pregnant animals with Herceptin and Rituxan suggested low risk for humans, whereas the suggested risk was higher for Avastin, Mylotarg, and Vectibix.
Bexxar, Campath, Erbitux, Mylotarg, Zevalin, and Rituxan may cause severe, infusion-related toxicity, including hypotension. Although premedication is used to lessen this effect, this toxicity could have deleterious effects on placental perfusion, resulting in harm to the embryo and fetus.
Human pregnancy data are available only for Herceptin and Rituxan. For Herceptin, the human pregnancy experience is limited to five cases, two of which involved first-trimester exposure. Although no congenital malformations were observed, fetal renal toxicity, as evidenced by oligohydramnios or anhydramnios, was observed in three cases. The toxicity might have been caused by inhibition of human epidermal growth factor receptor 2 (HER-2) in the fetal kidneys. The renal toxicity was reversible, and all five infants developed normally. However, there is potential for other toxicity because HER-2 protein expression is high in many embryonic tissues, such as cardiac and neural tissues.
Six pregnancies have been exposed to Rituxan, including two in the first trimester. No structural anomalies were noted, and all infants appeared to be healthy at birth. One had depletion of B lymphocytes, but B-cell counts returned to normal at about 4 months of age. No increase in infectious disease was noted in any of the infants.
Reports of exposure to Bexxar and Mylotarg during pregnancy are unlikely. Bexxar, indicated for non-Hodgkin's lymphoma, contains radioactive iodine and is contraindicated in pregnancy. Mylotarg, a combination of gemtuzumab (IgG4k) conjugated with the cytotoxic antitumor antibiotic calicheamicin, is indicated for the treatment of patients with CD33-positive acute myeloid leukemia in first relapse who are 60 years of age or older. Mylotarg caused significant developmental toxicity at a small fraction of the human dose in the only experimental animal species tested. The therapeutic regimen for Zevalin, another agent for non-Hodgkin's lymphoma, should preclude its use in pregnancy because it includes two radioactive components as well as Rituxan, and the risk to the embryo and fetus appears to be high.
Omalizumab (Xolair), a monoclonal antibody used for moderate to severe persistent asthma, selectively binds to human IgE and has a half-life of 26 days. It has not been studied in animals or humans, but probably crosses the placenta. Reproduction studies in monkeys suggest that the risk in human pregnancy is low, but the human pregnancy experience is limited. In clinical trials, 29 women became pregnant during treatment with Xolair, which was stopped when pregnancy was diagnosed. Among these patients, there were 4 spontaneous abortions (SABs), 3 elective abortions, 11 normal deliveries, and 11 ongoing pregnancies. The number of SABs, all occurring in the first trimester, is within the expected incidence for recognized pregnancies.
A full assessment of the risk of monoclonal antibodies during pregnancy is not possible because of the very limited or absent human pregnancy data, including a lack of long-term evaluation of exposed offspring. Nevertheless, these agents are used for life-threatening diseases and, if indicated, should not be withheld from a pregnant woman—with the exception of Bexxar, Mylotarg, and possibly Zevalin.
Pregnancy Registries
Pregnancy registries are valuable sources of information, and for many drugs and vaccines they are the primary source of human pregnancy experience. The strengths of these registries are their prospective nature—women are enrolled before the outcome is known—and enrollment is over a wide geographical area. Typically, two types of pregnancy outcomes are obtained: outcomes with birth defects and outcomes without known birth defects. The latter comprises live births, fetal deaths, and spontaneous abortions.
Registries can identify early signals of teratogenicity, but they have several limitations. They depend on voluntary reporting, which results in selection bias, and they are not representative of target populations. Pregnancies that are lost to follow-up may have had different outcomes than those with documented outcomes. Furthermore, registries lack details on elective terminations and fetal deaths without birth defects, and all spontaneous abortions. Finally, with some exceptions, they usually lack control groups.
Because the total number of exposed pregnancies is unknown, data from a registry cannot be used to calculate prevalence of an outcome, but the data can be used to estimate the proportion of birth defects. Some registries also collect data on retrospective reports, which are less representative of the target population because they can be biased toward the reporting of more unusual and severe outcomes. However, they may be helpful in detecting unusual patterns of birth defects.
A complete list of pregnancy registries is available on the Food and Drug Administration Web site, which provides additional details on the registries, such as fax numbers, links to other Web sites, and mailing addresses (www.fda.gov/womens/registries
Because the strength of a registry is based on numbers, I encourage health care professionals to enroll appropriate patients in these registries whenever possible.
Pregnancy registries are valuable sources of information, and for many drugs and vaccines they are the primary source of human pregnancy experience. The strengths of these registries are their prospective nature—women are enrolled before the outcome is known—and enrollment is over a wide geographical area. Typically, two types of pregnancy outcomes are obtained: outcomes with birth defects and outcomes without known birth defects. The latter comprises live births, fetal deaths, and spontaneous abortions.
Registries can identify early signals of teratogenicity, but they have several limitations. They depend on voluntary reporting, which results in selection bias, and they are not representative of target populations. Pregnancies that are lost to follow-up may have had different outcomes than those with documented outcomes. Furthermore, registries lack details on elective terminations and fetal deaths without birth defects, and all spontaneous abortions. Finally, with some exceptions, they usually lack control groups.
Because the total number of exposed pregnancies is unknown, data from a registry cannot be used to calculate prevalence of an outcome, but the data can be used to estimate the proportion of birth defects. Some registries also collect data on retrospective reports, which are less representative of the target population because they can be biased toward the reporting of more unusual and severe outcomes. However, they may be helpful in detecting unusual patterns of birth defects.
A complete list of pregnancy registries is available on the Food and Drug Administration Web site, which provides additional details on the registries, such as fax numbers, links to other Web sites, and mailing addresses (www.fda.gov/womens/registries
Because the strength of a registry is based on numbers, I encourage health care professionals to enroll appropriate patients in these registries whenever possible.
Pregnancy registries are valuable sources of information, and for many drugs and vaccines they are the primary source of human pregnancy experience. The strengths of these registries are their prospective nature—women are enrolled before the outcome is known—and enrollment is over a wide geographical area. Typically, two types of pregnancy outcomes are obtained: outcomes with birth defects and outcomes without known birth defects. The latter comprises live births, fetal deaths, and spontaneous abortions.
Registries can identify early signals of teratogenicity, but they have several limitations. They depend on voluntary reporting, which results in selection bias, and they are not representative of target populations. Pregnancies that are lost to follow-up may have had different outcomes than those with documented outcomes. Furthermore, registries lack details on elective terminations and fetal deaths without birth defects, and all spontaneous abortions. Finally, with some exceptions, they usually lack control groups.
Because the total number of exposed pregnancies is unknown, data from a registry cannot be used to calculate prevalence of an outcome, but the data can be used to estimate the proportion of birth defects. Some registries also collect data on retrospective reports, which are less representative of the target population because they can be biased toward the reporting of more unusual and severe outcomes. However, they may be helpful in detecting unusual patterns of birth defects.
A complete list of pregnancy registries is available on the Food and Drug Administration Web site, which provides additional details on the registries, such as fax numbers, links to other Web sites, and mailing addresses (www.fda.gov/womens/registries
Because the strength of a registry is based on numbers, I encourage health care professionals to enroll appropriate patients in these registries whenever possible.