Pregnancy and Neonatal Outcomes After Exposure to Alprazolam in Pregnancy

Hyunji Lee, Jae-Whoan Koh, Young-Ah Kim, Kyoung-Chul Chun, Jung Yeol Han, Jong Hee Hwang, June-Seek Choi, Sung Hong Joo, Hye-Young Kwon, Hyunji Lee, Jae-Whoan Koh, Young-Ah Kim, Kyoung-Chul Chun, Jung Yeol Han, Jong Hee Hwang, June-Seek Choi, Sung Hong Joo, Hye-Young Kwon

Abstract

Alprazolam is a commonly prescribed benzodiazepine for anxiety or panic disorder, even in pregnant women. Information on the safety of alprazolam during pregnancy is insufficient. We aimed to evaluate pregnancy and neonatal outcomes after exposure to alprazolam during pregnancy. A prospective study was conducted on 725 pregnancies from January 2000 to December 2019. Participants were recruited through the Korean Mother-Safe Program, a service providing information on drug-induced teratogenic risk during pregnancy and breastfeeding. Exposed (N = 96) and non-exposed (N = 629) women to alprazolam during pregnancy were selected and followed-up until delivery. Pregnancy outcomes, including spontaneous abortion, still birth, low birth weight (LBW), preterm birth, Apgar score (at 1 and 5 min), and malformations were measured and compared. Multivariable logistic regression was performed to examine the association between alprazolam exposure and outcomes. The mean age was 32.9 (SD 4.0) years in the alprazolam-exposed group and 31.8 (SD 3.8) years in the unexposed group (p = 0.008). The alprazolam exposure group demonstrated a significantly higher likelihood of pregnancy and neonatal outcomes: spontaneous abortion (OR = 2.38; 95% CI 1.20-4.69), LBW (OR = 3.65; 95% CI 1.22-11.00), and Apgar score at 1 min ≤ 7 (OR = 2.19; 95% CI 1.02-4.67). There was no significant difference in congenital abnormalities between the exposure and non-exposure groups. Our findings confirmed that alprazolam exposure during pregnancy was significantly associated with adverse pregnancy and neonatal outcomes, including spontaneous abortion, low birth weight, and Apgar score at 1 min ≤ 7. Alprazolam during pregnancy should be appropriately regulated and monitored.

Keywords: alprazolam (Alp); anxiety disorders; low birth weight (LBW); pregnancy; spontaneous abortion (SA).

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Lee, Koh, Kim, Chun, Han, Hwang, Choi, Joo and Kwon.

Figures

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FIGURE 1
Selection of study participants.

References

    1. Ait-Daoud N., Hamby A. S., Sharma S., Blevins D. (2018). A Review of Alprazolam Use, Misuse, and Withdrawal. J. Addict. Med. 12 (1), 4–10. 10.1097/adm.0000000000000350
    1. Armstrong C. (2008). ACOG Guidelines on Psychiatric Medication Use during Pregnancy and Lactation. Am. Fam. Physician 78 (6), 772–778.
    1. Bais B., Molenaar N. M., Bijma H. H., Hoogendijk W. J. G., Mulder C. L., Luik A. I., et al. (2020). Prevalence of Benzodiazepines and Benzodiazepine-Related Drugs Exposure before, during and after Pregnancy: A Systematic Review and Meta-Analysis. J. Affect Disord. 269, 18–27. 10.1016/j.jad.2020.03.014
    1. Ban L., Tata L. J., West J., Fiaschi L., Gibson J. E. (2012). Live and Non-live Pregnancy Outcomes Among Women with Depression and Anxiety: A Population-Based Study. PLoS ONE 7 (8), e43462. 10.1371/journal.pone.0043462
    1. Bellantuono C., Tofani S., Di Sciascio G., Santone G. (2013). Benzodiazepine Exposure in Pregnancy and Risk of Major Malformations: a Critical Overview. Gen. Hosp. Psychiatry 35 (1), 3–8. 10.1016/j.genhosppsych.2012.09.003
    1. Creeley C. E., Denton L. K. (2019). Use of Prescribed Psychotropics during Pregnancy: a Systematic Review of Pregnancy, Neonatal, and Childhood Outcomes. Brain Sci. 9 (9), 235. 10.3390/brainsci9090235
    1. Czeizel A. E., Bod M., Halász P. (1992). Evaluation of Anticonvulsant Drugs during Pregnancy in a Population-Based Hungarian Study. Eur. J. Epidemiol. 8 (1), 122–127. 10.1007/BF03334986
    1. Enato E., Moretti M., Koren G. (2011). The Fetal Safety of Benzodiazepines: an Updated Meta-Analysis. J. Obstet. Gynaecol. Can. 33 (1), 46–48. 10.1016/S1701-2163(16)34772-7
    1. Eros E., Czeizel A. E., Rockenbauer M., Sorensen H. T., Olsen J. (2002). A Population-Based Case-Control Teratologic Study of Nitrazepam, Medazepam, Tofisopam, Alprazolum and Clonazepam Treatment during Pregnancy. Eur. J. Obstet. Gynecol. Reprod. Biol. 101 (2), 147–154. 10.1016/s0301-2115(01)00545-0
    1. Grigoriadis S., Graves L., Peer M., Mamisashvili L., Ruthirakuhan M., Chan P., et al. (2020). Pregnancy and Delivery Outcomes Following Benzodiazepine Exposure: A Systematic Review and Meta-Analysis. Can. J. Psychiatry 65 (12), 821–834. 10.1177/0706743720904860
    1. Grigoriadis S., VonderPorten E. H., Mamisashvili L., Tomlinson G., Dennis C. L., Koren G., et al. (2013). The Impact of Maternal Depression during Pregnancy on Perinatal Outcomes: a Systematic Review and Meta-Analysis. J. Clin. Psychiatry 74 (4), e321–41. 10.1177/070674372090486010.4088/JCP.12r07968
    1. Jaiswal A. K. (2002). Effect of Prenatal Alprazolam Exposure on Anxiety Patterns in Rat Offspring. Indian J. Exp. Biol. 40, 35–39.
    1. Källén B., Borg N., Reis M. (2013). The Use of central Nervous System Active Drugs during Pregnancy. Pharmaceuticals (Basel) 6 (10), 1221–1286. 10.3390/ph6101221
    1. Ks S. (2019). A Quarter of Koreans Take Prescription Drugs. Korea JoongAng Daily. Retrieved November 5 from Available at: .
    1. Larsen E. C., Christiansen O. B., Kolte A. M., Nick Macklon N. (2013). New Insights into Mechanisms behind Miscarriage. BMC Med. 11, 154. 10.1186/1741-7015-11-154
    1. Lee J. Y., Kang W. S., Kim J. W., Kim Y. J. (2015). Prescription Patterns of Benzodiazepine for Outpatients in a Psychiatric Department in Korea. Anxiety and mood 11 (2), 143–148.
    1. Lee M. H., Choi J. W., Lee J., Shin A., Oh S. M., Jung S. J., et al. (2019). Trends in Prescriptions for Sedative-Hypnotics Among Korean Adults: a Nationwide Prescription Database Study for 2011-2015. Soc. Psychiatry Psychiatr. Epidemiol. 54 (4), 477–484. 10.1007/s00127-018-1615-x
    1. Ministry of Drug and Food Safety (2021).List of Drugs Contraindicated for Use in Pregnant Women. Available at: (Accessed November 24, 2021).
    1. Moosavi S., Pimentel M., Wong M. S., Rezaie A. (2021). Irritable Bowel Syndrome in Pregnancy. Am. J. Gastroenterol. 116 (3), 480–490. 10.14309/ajg.0000000000001124
    1. Ornoy A., Arnon J., Shechtman S., Moerman L., Lukashova I. (1998). Is Benzodiazepine Use during Pregnancy Really Teratogenic? Reprod. Toxicol. 12 (5), 511–515. 10.1016/s0890-6238(98)00035-5
    1. Palagini L., Gemignani A., Banti S., Manconi M., Mauri M., Riemann D. (2014). Chronic Sleep Loss during Pregnancy as a Determinant of Stress: Impact on Pregnancy Outcome. Sleep Med. 15 (8), 853–859. 10.1016/j.sleep.2014.02.013
    1. Rayburn W. F., Christensen H. D., Gold K. M., Gonzalez C. L. (2002). Neurobehavior Effects in Four Strains of Mice Offspring Exposed Prenatally to Alprazolam. Am. J. Obstet. Gynecol. 187 (4), 968–972. 10.1067/mob.2002.127133
    1. Sheehy O., Zhao J. P., Bérard A. (2019). Association between Incident Exposure to Benzodiazepines in Early Pregnancy and Risk of Spontaneous Abortion. JAMA psychiatry 76 (9), 948–957. 10.1001/jamapsychiatry.2019.0963
    1. St Clair S. M., Schirmer R. G. (1992). First-trimester Exposure to Alprazolam. Obstet. Gynecol. 80 (5), 843–846.
    1. Takzare N., Bakhtiarian A., Saeedi E., Nekoui V. (2011). The Teratogenic Effects of Alprazolam Intake on Rat Fetus. Tehran Univ. Med. J. 68 (10).
    1. Tinker S. C., Reefhuis J., Bitsko R. H., Gilboa S. M., Mitchell A. A., Tran E. L., et al. (20191997–2011). Use of Benzodiazepine Medications during Pregnancy and Potential Risk for Birth Defects, National Birth Defects Prevention Study, 1997-2011. Birth Defects Res. 111 (10), 613–620. 10.1002/bdr2.1497
    1. WHO Expert Consultation (2004). Appropriate Body-Mass index for Asian Populations and its Implications for Policy and Intervention Strategies. Lancet 363 (9403), 157–163. 10.1016/S0140-6736(03)15268-3
    1. World Health Organization (2021). WHO Collaborating Centre for Drug Statistics Methodology. Available at: (Accessed November 24, 2021).

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