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Can we use anxiolytics during pregnancy without anxiety?: In moderation

Antonio Addis, PHARMD; Lisa R. Dolovich, PHARMD; Thomas R. Einarson, PHD; Gideon Koren, MD, FRCPC

March, 2000

ABSTRACT

QUESTION

One of my patients suffers from anxiety and was using lorazepam to treat it. When she became pregnant, she stopped the medication immediately, but now she is worried about the potential effect on the baby because she was using the drug just after conception. Is this class of drugs safe during pregnancy? What should she do if she needs antianxiety treatment during the rest of her pregnancy?

ANSWER

Evidence to date from cohort studies did not identify a notable association between use of benzodiazepines and increased risk of major malformations, including oral cleft. In contrast, data from case-control studies show a slightly increased risk of oral cleft. Hence, level 2 ultrasonography is recommended to rule out visible forms of cleft lip. Using benzodiazepines late in pregnancy could cause withdrawal syndrome in newborns.


Benzodiazepines (BZDs) are commonly used for anxiety and insomnia, even by pregnant women. A recent study found that 2% of pregnant women in the United States who were receiving Medicaid benefits filled one or more prescriptions for BZDs during pregnancy.1 An international drug use study has shown that BZDs account for the greatest number (85%) of psychotropic agents used during pregnancy.2 Because about half of pregnancies are unplanned,3 many women could inadvertently expose fetuses to BZDs during the first trimester.

Antepartum exposure to BZDs has been associated with teratogenic effects (facial cleft, skeletal anomalies) in some animal studies4,5 but not others.6-7 Risk for cleft palate in the general population is approximately 0.06%.8 Early human case-control studies suggested that maternal exposure to BZDs increases risk of fetal cleft lip and cleft palate.9,10 Subsequent reports have implicated BZDs in other major malformations,11-13 abnormal neurodevelopment,11,14,15 and an irreproducible congenital benzodiazepine syndrome similar to fetal alcohol syndrome.11,16-17

Unfortunately, these studies were not designed to control for confounding factors that could influence results. Several prospective cohort studies involving hundreds of women using BZDs during pregnancy and an equal number of controls failed to show increased risk of malformations after BZD use during the first trimester.

The contradictory results mentioned above have led to considerable controversy surrounding use of BZDs during pregnancy. Nevertheless, it seemed clear that, even if it existed, the risk of malformations in newborns exposed to BZDs during the first trimester was marginal. To investigate this issue, Motherisk conducted a meta-analysis of all data on exposure to BZDs during the first trimester.18

Motherisk's meta-analysis

Motherisk considered 13 studies that examined major malformations, 11 that examined oral cleft alone, and three that examined other specific malformations. Exposure was ascertained mainly through interviewing the mothers (61%), and outcome was confirmed mainly through examination by a physician, records (44%), or malformation registries (30%). Various BZDs were used or prescribed, although 48% of the studies examined use of chlorodiazepoxide or diazepam only.

Data pooled from seven cohort studies did not show an association between fetal exposure to BZDs during pregnancy and major malformations (Table1). A combination of four case-control studies, however, showed that major malformations were associated with use of BZDs during pregnancy (Table1). Data pooled from three cohort studies showed no association between fetal exposure to BZDs during pregnancy and oral cleft (Table2), but analysis of six case-control studies produced a significant odds ratio for oral cleft.

Discussion

Data from cohort studies showed no significant association between BZDs during the first trimester and either major malformations or oral cleft alone. Data from case-control studies, however, showed a small but significant increased risk for these outcomes. This finding might reflect the substantially higher sensitivity of case-control studies for examining risk of specific malformations.

Tests of heterogeneity also showed that the cohort studies were homogeneous for both major malformations and oral cleft, whereas the case-control studies for oral cleft were heterogeneous, which decreases the reliability of the marginally significant results. Even when a "worst case scenario" is assumed, BZDs do not seem to be major human teratogens but, because some cases of cleft lip can be visualized by fetal ultrasound, level 2 ultrasonography should be used to rule out this malformation.

References

  1. Bergman U, Rosa FW, Baum C, Wiholm BE, Faich GA. Effects of exposure to benzodiazepine during fetal life. Lancet 1992;340:694-6.
  2. Marchetti F, Romero M, Bonati M, Tognoni G, CGDUP. Use of psychotropic drugs during pregnancy. Eur J Clin Pharmacol 1993;45:495-501.
  3. Skrabanek P. Smoking and statistical overkill. Lancet 1992;340:1208-9.
  4. Miller RP, Becker BA. Teratogenicity of oral diazepam and diphenylhy-dantoin in mice. Toxicol Appl Pharmacol 1975;32:53-61.
  5. Walker BE, Patterson A. Induction of cleft palate in mice by tranquillizers and barbiturates. Teratology 1974;10:159-63.
  6. Beall JR. Study of the teratogenic potential of oral diazepam and SCH 12041. Can Med Assoc J 1972;106:1061.
  7. Chesley S, Lumpkin M, Schatzki A, Galpern WR, Greenblatt DJ, Shader RI, et al. Prenatal exposure to benzodiazepine. I. Prenatal exposure to lorazepam in mice alters open-field activity and GABA receptor function. Neuropharmacology 1991;30:53-8.
  8. Heinonen OP, Sloane D, Shapiro S. Birth defects and drugs in pregnancy: maternal drug exposure and congenital malformations. Littleton, Mass: Publishing Sciences Group; 1977.
  9. Saxen I, Saxen L. Association between maternal intake of diazepam and oral clefts. Lancet 1975;2:498.
  10. Saxen I, Lahti A. Cleft lip and palate in Finland: incidence, secular, seasonal, and geographical variations. Teratology 1974;9:217-24.
  11. Laegreid L, Olegard R, Walstrom J, Conradi N. Teratogenic effects of benzodiazepine use during pregnancy. J Pediatr 1989;114:126-31.
  12. Safra MJ, Oakley GP. Association between cleft lip with or without cleft palate and prenatal exposure to diazepam. Lancet 1975;2:478 80.
  13. Milkovich L, van den Berg BJ. Effects of prenatal meprobamate and chlordiazepoxide hydrochloride on human embryonic and fetal development. N Engl J Med 1974;291:1268-71.
  14. Laegreid L, Hagberg G, Lundberg A. Neurodevelopment in late infancy after prenatal exposure to benzodiazepines a prospective study. Neuropediatrics 1992;23:60-7.
  15. Viggedal G, Hagberg BS, Laegreid L, Aronsson M. Mental development in late infancy after prenatal exposure to benzodiazepines a prospective study. J Child Psychol Psychiatry 1993;34:295-305.
  16. Laegreid L, Olegard R, Wahlstrom J, Conradi N. Abnormalities in children exposed to benzodiazepines in utero. Lancet 1987;1:108-9.
  17. Laegreid L, Olegard R, Conradi N, Hagberg G, Wahlstrom J, Abrahamsson L. Congenital malformations and maternal consumption of benzodiazepines: a case-control study. Dev Med Child Neurol 1990;32:432-41.
  18. Dolovich L, Addis A, Vaillancourt JMR, Power JDB, Koren G, Einarson TR. Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies BMJ 1998:317:839-43.
  19. Winship KA, Cahal DA, Weber JP, Griffin JP. Maternal drug histories and central nervous system anomalies.Arch Dis Child 1984;59:1052-60.
  20. Crombie DL, Pinsent RJ, Fleming DM, Rumeau-Rouquette C, Goujard J, Huel G. Fetal effects of tranquilizers in pregnancy. N Engl J Med 1975;293:198-9.
  21. Hartz SC, Heinonen OP, Shapiro S, Siskind V, Slone D. Antenatal exposure to meprobamate and chlordiazepoxide in relation to malformations, mental development, and childhood mortality. N Engl J Med 1975;292:726-8.
  22. Kullander S, Kallen B. A prospective study of drugs and pregnancy. I. Psychopharmaca. Acta Obstet Gynecol Scand 1976;55:25-33.
  23. Pastuszak A, Milich V, Chan S, Chu J, Koren G. Prospective assessment of pregnancy outcome following first trimester exposure to benzodiazepines. Can J Clin Pharmacol 1996;3:167-71.
  24. Ornoy A, Moerman L, Lukashova I, Arnon J. The outcome of children exposed in utero to benzodiazepines. Teratology 1997;55:102A.
  25. Greenberg G, Inman WH, Weatherall JA, Adelstein AM, Haskey JC. Maternal drug histories and congenital abnormalities. BMJ 1977;2:853-6.
  26. Bracken MB, Holford TR. Exposure to prescribed drugs in pregnancy and association with congenital malformations. Obstet Gynecol 1981;58:336-44.
  27. Noya CA. Epidemiological study on congenital malformations. Rev Cubana Hig Epidemiol 1981;19:200-10.
  28. Shiono PH, Mills JL. Oral clefts and diazepam use during pregnancy. N Engl J Med 1984;311:919-20.
  29. Rosenberg L, Mitchell AA, Parsells JL, Pashayan H, Louik C, Shapiro S. Lack of relation of oral clefts to diazepam use during pregnancy. N Engl J Med 1983;309:1282-5.
  30. Czeizel A. Lack of evidence of teratogenicity of benzodiazepine drugs in Hungary. Reprod Toxicol 1987-88;1:183-8.
  31. Rodriguez PE, Salvador PJ, Garcia AF, Martinez FM. Relationship between benzodiazepine ingestion during pregnancy and oral clefts in the newborn: a case-control study. Med Clin 1986;87:741-3.



Table 1. Association between prenatal exposure to benzodiazepines and major malformations

Studies Malformed Exposed Malformed Not Exposed Odds Ratio (95% Confidence Interval)
Cohort
Milkovich and van den Berg13 5/86 10/229 1.35 (0.45-4.07)
Crombie et al20 3/300 382/19 143 0.75 (0.24-2.35)
Hartz et al21 11/257 2129/46 233 0.90 (0.49-1.66)
Kullander and Kallen22 2/89 198/5664 0.63 (0.16-2.60)
Laegreid et al14 1/17 1/29 1.75 (0.10-29.92)
Pastuszak et al23 1/106 3/115 0.36 (0.04-3.47)
Ornoy et al24 9/335 10/363 0.97 (0.39-2.43)
Combined effect 0.90 (0.61-1.35)
Case-Control
Greenberg et al25 36/60 800/1612 1.52 (0.9-2.58)
Bracken and Holford26 39/72 1331/4266 2.61 (1.63-4.16)
Noya27 1/24 0/24 3.13 (0.12-80.68)
Laegreid et al17 8/10 10/68 23.20 (4.29-125.55)
Combined effect 3.01 (1.32-6.84)



Table 2. Association between prenatal exposure to benzodiazepines and oral cleft

Studies Malformed Exposed Malformed Not Exposed Odds Ratio (95% Confidence Interval)
Cohort
Shiono and Mills28 1/854 31/32 395 1.22 (0.17-8.89)
Bergman1 0/1354 62/102 985 1.21 (0.17-8.71)
Ornoy et al24 0/335 0/363 1.08 (0.07-17.39)
Combined effect 1.19 (0.34-4.15)
Case-Control
Safra and Oakley12 7/16 42/262 4.07 (1.44- 11.54)
Saxen and Saxen9 27/40 511/1044 2.17 (1.11-4.24)
Rosenberg et al29 13/67 590/3011 0.99 (0.54-1.82)
Rodriguez et al31 8/61 442/7990 2.58 (1.22-5.45)
Czeizel30 48/91 1153/2311 1.12 (0.74-1.71)
Laegreid et al17 2/10 4/68 4.00 (0.63-25.43)
Combined effect 1.79 (1.13-2.82)


Canadian Family Physician 2000;46:549-51.
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