Commentary

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.

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