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].