What are the effects of benzodiazepines (BZDs) on pregnancy?

From the Guidelines

Benzodiazepines should be avoided during pregnancy, especially in the first trimester, due to the potential risks of oral clefts and other complications. The use of benzodiazepines during pregnancy has been associated with a small increased risk of oral clefts, with a 2-fold increased risk reported in some studies 1. Additionally, third-trimester use can cause neonatal withdrawal syndrome, respiratory depression, hypotonia, and feeding difficulties in newborns.

Recommendations for Benzodiazepine Use in Pregnancy

• If absolutely necessary for severe anxiety or seizure disorders, lorazepam or clonazepam at the lowest effective dose for the shortest duration are preferred options.
• Non-pharmacological approaches like cognitive behavioral therapy should be first-line for anxiety during pregnancy.
• If medication is needed for anxiety, SSRIs like sertraline (50-200 mg daily) are generally considered safer alternatives.
• For pregnant women already taking benzodiazepines, abrupt discontinuation should be avoided due to withdrawal risks; instead, a slow taper under medical supervision is recommended.
• For women requiring benzodiazepines during pregnancy, additional fetal monitoring may be recommended, and pediatricians should be informed about maternal benzodiazepine use before delivery to monitor for and manage potential neonatal complications.

Key Considerations

• The risk of fetal sedation or respiratory depression should be discussed with an obstetrician, and the need for periprocedural fetal monitoring should be considered 1.
• Guidelines suggest that meperidine and fentanyl appear to be safe in humans during pregnancy, and midazolam is preferred over other benzodiazepines if sedation is necessary 1.

From the FDA Drug Label

There are no adequate and well-controlled studies of clonazepam in pregnant women. Available human data on the risk of teratogenicity are inconclusive Administration of benzodiazepines immediately prior to or during childbirth can result in a syndrome of hypothermia, hypotonia, respiratory depression, and difficulty feeding In addition, infants born to mothers who have taken benzodiazepines during the later stages of pregnancy can develop dependence, and subsequently withdrawal, during the postnatal period. Although all of these anomalies were not present in the concurrent control group, they have been reported to occur randomly in historical controls At doses of 40 mg/kg and higher, there was evidence of fetal resorption and increased fetal loss in rabbits which was not seen at lower doses. However, an increased risk of congenital malformations associated with the use of minor tranquilizers (chlordiazepoxide, diazepam, and meprobamate) during the first trimester of pregnancy has been suggested in several studies.

Benzodiazepines in pregnancy should be used with caution. The FDA drug labels do not provide conclusive evidence on the safety of benzodiazepines during pregnancy.

• Teratogenicity: Available human data are inconclusive.
• Neonatal effects: Administration of benzodiazepines during pregnancy can result in hypothermia, hypotonia, respiratory depression, and difficulty feeding in newborns.
• Dependence and withdrawal: Infants born to mothers who have taken benzodiazepines during pregnancy can develop dependence and withdrawal symptoms.
• Fetal risk: Animal studies suggest an increased risk of fetal resorption and fetal loss at high doses.
• Clinical consideration: The use of benzodiazepines during the first trimester of pregnancy should be avoided unless the benefits outweigh the risks 2 3.

From the Research

Benzodiazepines in Pregnancy: Risks and Considerations

• The use of benzodiazepines during pregnancy has been associated with an increased risk of miscarriage, with an odds ratio of 1.69 4.
• Studies have shown that benzodiazepine exposure during the first trimester of pregnancy may not be associated with an increasing risk of congenital major malformations 5.
• However, the use of benzodiazepines during pregnancy has been linked to preterm delivery and low birth weight 6.
• Short-term neonatal effects of benzodiazepine exposure include hypotonia, depression, and withdrawal symptoms 6.
• Long-term sequelae of benzodiazepine exposure during pregnancy are poorly understood 6.

Safety of Specific Benzodiazepines

• Diazepam and chlordiazepoxide are considered to be relatively safe during pregnancy 7, 5.
• Alprazolam should be avoided during pregnancy and lactation due to potential risks 7.
• Clonazepam, lorazepam, and other benzodiazepines may also pose risks during pregnancy, although the evidence is limited 8.

Recommendations for Benzodiazepine Use During Pregnancy

• Benzodiazepines should be used at the lowest effective dosage for the shortest possible duration 7.
• High peak concentrations should be avoided by dividing the daily dosage into two or three doses 7.
• Physicians should carefully weigh the potential benefits of benzodiazepine therapy against the risks to the fetus 7.
• Alternative strategies for anxiety management during pregnancy should be considered 6.