LORAZEPAM

Fetal Risk Summary

Lorazepam is a benzodiazepine indicated for the treatment of status epilepticus and as a preanesthetic sedative. Reproduction studies have been conducted in mice, rats, and two strains of rabbits (1). Occasional, non-dose-related malformations (reduction of tarsals, tibia, metatarsals, malrotated limbs, gastroschisis, malformed skull, and microphthalmia) were observed in rabbits, but these defects have also randomly occurred in controls. Fetal resorptions and increased fetal loss occurred in rabbits at oral (40 mg/kg) and IV (4 mg/kg) doses and higher (1).

Lorazepam crosses the placenta, achieving cord levels similar to maternal serum concentrations (2,3,4 and 5). Placental transfer is slower than that of diazepam, but high IV doses may produce the “floppy infant” syndrome (3). (See Diazepam for a description of this syndrome.) A case reported in 1996 described an otherwise healthy male infant, who had been exposed throughout gestation to lorazepam (7.5–12.5 mg/day) and clozapine (200–300 mg/day), who developed transient, mild floppy infant syndrome after delivery at 37 weeks' gestation (6). The mother had taken the combination therapy for the treatment of schizophrenia. The hypotonia, attributed to lorazepam because of the absence of such reports in pregnancies exposed to clozapine alone, resolved 5 days after birth.

An abstract published in 1999 found an association between lorazepam and anal atresia (7). Using data from a French pregnancy registry, the investigators reported that among infants exposed to benzodiazepines 5 of 6 cases of anal atresia were exposed to lorazepam (p=0.01) (7).

Lorazepam has been used in labor to potentiate the effects of narcotic analgesics (8). Although not statistically significant, a higher incidence of respiratory depression occurred in the exposed newborn infants.

Breast Feeding Summary

Lorazepam is excreted into breast milk in low concentrations (9,10). In one study, no effects on the nursing infant were reported (9), but the slight delay in establishing feeding was a cause for concern (11). Milk:plasma ratios in four women who had received 3.5 mg orally of lorazepam 4 hours earlier ranged from 0.15 to 0.26 (9). The mean milk concentration was 8.5 ng/mL. In another study, 5 mg of oral lorazepam was given 1 hour before labor induction and the effects on feeding behavior were measured in the newborn infants (12). During the first 48 hours, no significant effect was observed on volume of milk consumed or duration of feeding. The American Academy of Pediatrics considers the effects of lorazepam on the nursing infant to be unknown, but they may be of concern if exposure is prolonged (13).

References

1. Product information. Ativan. Wyeth-Ayerst Pharmaceuticals, 2000.
2. de Groot G, Maes RAA, Defoort P, Thiery M. Placental transfer of lorazepam. IRCS Med Sci 1975;3:290.
3. McBride RJ, Dundee JW, Moore J, Toner W, Howard PJ. A study of the plasma concentrations of lorazepam in mother and neonate. Br J Anaesth 1979;51:971–8.
4. Kanto J, Aaltonen L, Liukko P, Maenpaa K. Transfer of lorazepam and its conjugate across the human placenta. Acta Pharmacol Toxicol (Copenh) 1980;47:130–4.
5. Kanto JH. Use of benzodiazepines during pregnancy, labour and lactation, with particular Reference to pharmacokinetic considerations. Drugs 1982;23:354–80.
6. Di Michele V, Ramenghi LA, Sabatino G. Clozapine and lorazepam administration in pregnancy. Eur Psychiatry 1996;11:214.
7. Bonnot O, Vollset SE, Godet PF, Robert E. Maternal exposure to lorazepam and anal atresia in newborns? Results from a hypothesis generating study of benzodiazepines and malformations (abstract). Teratology 1999;59:439–40.
8. McAuley DM, O'Neill MP, Moore J, Dundee JW. Lorazepam premedication for labour. Br J Obstet Gynaecol 1982;89:149–54.
9. Whitelaw AGL, Cummings AJ, McFadyen IR. Effect of maternal lorazepam on the neonate. Br Med J 1981;282:1106–8.
10. Summerfield RJ, Nielsen MS. Excretion of lorazepam into breast milk. Br J Anaesth 1985;57:1042–3.
11. Johnstone M. Effect of maternal lorazepam on the neonate. Br Med J 1981;282:1973.
12. Johnstone MJ. The effect of lorazepam on neonatal feeding behaviour at term. Pharmatherapeutica 1982;3:259–62.
13. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.