https://orcid.org/0000-0002-0841-2216
ABSTRACT
The use of alprazolam in pregnancy can adversely affect maternal and neonatal health. This study examined neonatal outcomes following exposure to alprazolam in pregnancy. Women prescribed alprazolam during pregnancy (n = 48) between 2014 and 2018 were identified from routinely-collected state administrative prescribing records and perinatal data. Two comparison groups of women; 1) prescribed alprazolam outside of pregnancy (n = 96) and 2) women never prescribed alprazolam (n = 96) were also identified. The health of women and their children was examined using administrative hospital, mortality and perinatal data and compared to the comparison groups using generalized linear models. Prenatal alprazolam exposure was not associated with a reduction in average birth weight or gestational age. However, neonates prenatally exposed to alprazolam were more likely be classified as having low birth weight for gestational age compared with alprazolam comparison group (OR: 4.46, 95% CI: 1.54–12.95) and the non-alprazolam comparison group (OR: 3.27, 95% CI: 1.22–8.79). There were no cases of perinatal mortality or floppy baby syndrome in alprazolam-exposed neonates. While the use of alprazolam during pregnancy was not associated with an increased risk of severe adverse neonatal outcomes (e.g. perinatal mortality), it was associated with neonates being born with a low birth weight for gestational age.
Introduction
Benzodiazepines are commonly used to treat a variety of conditions, including anxiety and sleep disorders, in women of a reproductive age (Cunningham, Hanley, and Morgan Citation2010; Olfson, King, and Schoenbaum Citation2015). While the use of these medications is generally not recommended in pregnancy (MIMS Citation2023), unintentional exposure can occur, particularly as a result of unplanned pregnancy. Additionally, benzodiazepines can be helpful in the treatment of pregnancy-related conditions including eclampsia and hyperemesis gravidarum (Rajiv and Radhakrishnan Citation2019; Tasci et al. Citation2009). As such, exposure to benzodiazepines during pregnancy is not uncommon (Bais et al. Citation2020; Riska et al. Citation2014), with it estimated that 1.9% of pregnant women worldwide will use or be prescribed benzodiazepines (Bais et al. Citation2020).
The use of benzodiazepines during pregnancy has been associated with spontaneous abortion, reduced birth weight for length, poor respiratory effort, feeding difficulties, and neonatal withdrawal (Laegreid, Hagberg, and Lundberg Citation1992; Rementería and Bhatt Citation1977; Sheehy, Zhao, and Bérard Citation2019). However, the use of benzodiazepines in pregnancy does not appear to be associated with an increased risk of congenital abnormalities (Bellantuono et al. Citation2013; Grigoriadis et al. Citation2019). Much of the research on the use of benzodiazepines in pregnancy has grouped together different benzodiazepine drugs (Ban et al. Citation2014; Freeman et al. Citation2018; Huitfeldt et al. Citation2020; Sheehy, Zhao, and Bérard Citation2019). However, the effect of individual benzodiazepines in pregnancy may differ, given their varying pharmacological parameters. In particular, potent benzodiazepines and those with a long-half life may be associated with poorer neonatal health outcomes, due to a greater potential for dose accumulation. The examination of the safety of individual medications is thus important.
Alprazolam is a short-acting benzodiazepine (mean half-life of 11 hours), which is commonly used to treat anxiety and panic disorders (MIMS Citation2023). A small amount of literature currently exists surrounding the use of alprazolam in pregnancy. The use of alprazolam has also been associated with an increased risk of spontaneous abortion, low birth weight, and low Apgar score at 1 min (Lee et al. Citation2022). The association between alprazolam and congenital anomalies is unclear, with some studies reporting an increase in overall (Källén Citation2019) and a number of type specific anomalies (Tinker et al. Citation2019; Wikner et al. Citation2007) and others reporting no association (Lee et al. Citation2022). This study aimed to examine the maternal and neonatal safety associated with the use of alprazolam in pregnancy, using whole-population linked medicine dispensing, hospital, perinatal and mortality data.
Methods
Study design and setting
This study used a retrospective cohort of women dispensed alprazolam during pregnancy in Western Australia (WA) between 2014 and 2018. The study used administrative linked data from the WA Department of Health. In Australia, alprazolam has been classified as a Schedule 8 medicine (i.e. drug of dependence) since February 2014 (Review of PBS utilisation Citation2015). Alprazolam is available in 1 mg, 500 µg and 250 µg tablets (generally dispensed in quantities of 10). The defined daily dose for alprazolam is 1 mg (ATC and DDD Index Citation2022).
Participants
The study included all women who had been dispensed alprazolam during pregnancy and who gave birth between June 2014 and December 2018 in WA. Women were considered exposed to alprazolam if they were dispensed two or more scripts during pregnancy, with a combined minimum of 40 tablets.
Outcomes in the alprazolam exposure in pregnancy group were compared with two comparison groups. The first comprised women who had been dispensed alprazolam prior to conception or following birth (but not during pregnancy) and had given birth during the study period. The second included women who had no record of alprazolam dispensing at any time. Comparison groups were matched 2:1 to the alprazolam during pregnancy group on smoking status during pregnancy and having previously been pregnant (yes/no). The second comparison group was also matched on maternal age (categories: <25, 20–24, 25–29, 30–34, 35–39, 40+ years). Matching was performed using the ccmatch command in Stata. The study groups were limited to singleton pregnancies. Where the mother had multiple pregnancies during the study period, a single pregnancy was randomly selected and included in the study.
The two comparison groups were included to provide different perspectives. The groups who were dispensed alprazolam prior to or following pregnancy were likely quite similar to the alprazolam group in terms of their health, including the prevalence of mental health conditions such as anxiety, which can impact both maternal and neonatal health outcomes. Additionally, women who use alprazolam before or after pregnancy were potentially more likely to have been prescribed a different benzodiazepine during pregnancy, which may have influenced neonatal outcomes. The non-alprazolam comparison group was less likely to have been prescribed a benzodiazepine during pregnancy but was likely more different to the alprazolam group in terms of demographics and health characteristics.
Data sources
Women included in the study were identified using a combination of the WA Monitoring of Drugs of Dependence System (MODDS) and the Midwives Notification System. The MODDS contains records of all Schedule 8 medications dispensed in WA. Schedule 8 medications are those with a recognized therapeutic need but a higher risk of misuse, abuse and dependence (Scheduling handbook Citation2019) and are therefore subject to restrictions in terms of prescribing and dispensing in Australia. Two benzodiazepine medications are considered schedule 8 medications, alprazolam and flunitrazepam. The Midwives Notification System contains information on all neonates born within WA. This includes all live and stillborn neonates with a gestation age greater than 20 weeks or a birth weight of more than 400 g where gestational age is unknown. Within the Midwives Notification System, the neonate’s date of birth and the estimated length of gestation were used to estimate the date of conception. The estimate length of gestation is estimated by midwife at time of birth with reference to the last menstrual period, the estimated date of delivery and appearance of the neonate.
For the neonate, the Midwives Notification System, Hospital Morbidity Data Collection, and the WA Death Register were used to ascertain information on neonatal health outcomes as detailed below. For women in the study, the Hospital Morbidity Data Collection was used to examine hospital admissions for mental health disorders in the 5 years leading up to conception, during pregnancy, and the postpartum period (0–42 days following birth). Characteristics of labor and delivery were taken from the Midwives Notification System.
Data availability
Data used in this study are not publically available. This is a condition of data access, and acts to preserve participant confidentiality. Code used in the study is available from the corresponding author upon reasonable request.
Maternal and neonatal health outcomes
Maternal outcomes of interest focused on the maternal health, pregnancy complications, and characteristics of labor/delivery. Given that alprazolam is commonly used to treat anxiety, hospitalizations for mental illness were examined for the pre-conception period (5 years prior to conception), pregnancy, and the postpartum period (0–42 days following birth). Hospitalizations with a mental illness were identified using primary and co-diagnoses assigned to each admission using Statistical Classification of Diseases and Related Health Problems 10th Revision, Australian Modification (ICD-10-AM) codes. For mental illness, the ICD-10-AM codes F00-F99 were used. Other maternal outcomes including diabetes and pre-and eclampsia were examined using data from the Midwives Notification System. Complications of pregnancy, including threatened pre-term labor, threatened abortion and ante- and post-partum hemorrhage, were also examined using data from the Midwives Notification System, as were characteristics of labor and delivery (e.g. onset of labor and cesarean section).
Neonatal outcomes of interest included birth size, length of gestation, perinatal mortality, diagnoses with neonatal abstinence syndrome, floppy baby syndrome, or infant respiratory distress syndrome, and length of hospital stay following birth. Birth size was examined in terms of average birth weight, length, and head circumference, which was ascertained from data within the Midwives Notification System. Birth weight, length and head circumference were also expressed as the percentage of optimal birth weight, length, and head circumference, taking into account the neonate’s gestational age as derived per (Blair et al. Citation2005, Citation2005). Additionally, the percentage of neonates classified as being small for gestational age (<10th decile) and neonates born weighing less than 2500 g was calculated.
The estimated length of gestation was also taken from the Midwives Notification System and expressed as an average and the percentage of neonates born before 37 weeks (pre-term). Perinatal mortality included stillborn neonates (of at least 20 weeks gestation or 400 g birth weight where gestation was unknown) and neonates who died during the first 28 days following birth. This was ascertained from a combination of the Midwives Notification System and the WA Death Register. Diagnosis of neonatal abstinence syndrome, floppy baby syndrome, and infant respiratory depress syndrome within 28 days of birth were identified using the Hospital Morbidity Data Collection. The Hospital Morbidity Data Collection was also used to determine the neonate’s length of stay following birth.
Statistical analysis
Descriptive statistics were performed comparing maternal characteristics at birth. Comparisons between the alprazolam during pregnancy group and the two comparison groups were made using univariable generalized linear models. Univariable analysis was used as the study sample was small and the two groups were similar in terms of maternal characteristics as a result of matching. For neonatal outcomes, analysis was also performed adjusting for hospitalization for a mental health condition during pregnancy. Analysis was carried out using StataMP version 17.
Ethics approval was granted by the Department of Health Human Research Ethics Committee (RGS0000003029) and the University of Western Australia Human Research Ethics Committee (RA/4/20/5530). A waiver of consent was obtained for this study, as it met the criteria set out in the National Statement on Ethical Conduct in Human Research.
Results
In the alprazolam during pregnancy group, exposure was most common early in pregnancy, with 83.3% (n = 40) of women dispensed alprazolam during the first trimester, compared with 70.8% (n = 34) in the second trimester and 58.3% (n = 28) during the third trimester. Women in this group were dispensed a median of four prescriptions during pregnancy (IQR: 2–6), with a median of 200 tablets (IQR: 100–357) dispensed during pregnancy. Women treated with alprazolam during pregnancy were not significantly different to either comparison group in terms of maternal age, smoking status, remoteness and socio-economic area of residence ().
Table 1. Characteristics of women treated with alprazolam during pregnancy compared with pregnant women who had used alprazolam prior to pregnancy and pregnant women who had never used alprazolam.
Maternal health
For women treated with alprazolam during pregnancy, the odd of being hospitalized with a diagnosis of a mental health disorder in the 5 years prior to pregnancy were 3.6-times higher than for women who had never been treated with alprazolam (OR: 3.60, 95% CI: 1.75, 11.01). However, there was no significant difference between women treated with alprazolam during pregnancy and those treated with alprazolam before or after pregnancy (OR: 1.62, CI: 0.75, 3.54) (). During pregnancy, women treated with alprazolam were considerably more likely to be hospitalized with a diagnosis of a mental health disorder compared with both the alprazolam (OR: 3.05, CI: 1.39, 6.64) and non-alprazolam (OR: 7.20, CI: 2.85, 18.21) comparison groups. There were 34 hospitalizations that occurred in women treated with alprazolam (19 women) and of these only 6 (17.7%) involved a primary diagnosis of mental illness with the others typically relating to pregnancy care. No difference in the percentage of women hospitalized for a mental health disorder in the postpartum period between study groups was observed.
Table 2. Maternal, labor, and delivery outcomes in women treated with alprazolam during pregnancy compared with pregnant women who had used alprazolam prior to pregnancy and pregnant women who had never used alprazolam.
There was no significant difference between women dispensed alprazolam during pregnancy and the two comparison groups in terms of onset of labor, threatened abortion or threatened pre-term labor. There were five women (10.4%) treated with alprazolam who were diagnosed with antepartum hemorrhage, compared with less than five in the two comparison groups, respectively. The majority of cases of antepartum hemorrhage in women treated with alprazolam were classified as “other” (i.e. not placenta praevia or placental abruption), although no women dispensed alprazolam during pregnancy experience a postpartum hemorrhage.
Neonatal health
Outcomes in neonates exposed to alprazolam in pregnancy were not significantly different to those within the alprazolam comparison group, with the exception of an increased risk of the neonate being born within the lowest decile for gestational age (OR: 4.46, CI: 1.54, 12.95) and percentage of birth weight (coeff: −6.30, 95% CI: −11.86, 0.75) (). Compared with the non-alprazolam comparison group, women dispensed alprazolam during pregnancy were also more likely to be born within the lowest decile for gestation age (OR: 3.27, CI: 1.22, 8.79). Differences between the alprazolam group and the two comparison groups remained consistent following adjustment for maternal admission to hospital during pregnancy.
Table 3. Characteristics and outcomes of neonates prenatally exposed to alprazolam compared with non-exposed neonates, whose mothers had been dispensed alprazolam prior to pregnancy or had never been dispensed alprazolam.
Discussion
The use of alprazolam during pregnancy did not appear to be associated with an increased risk of serious adverse neonatal health outcomes. Additionally, there were low levels of both neonatal abstinence syndrome and no neonates diagnosed with floppy baby syndrome. Exposure to alprazolam during pregnancy was not associated with an increased risk of low Apgar score, a longer hospital stay following birth, or an increase in the odds of being admitted to the special care unit. Similarly, alprazolam exposure was not associated with a reduction in length of gestation or an increased risk of pre-term birth. Neonates exposed to alprazolam in utero were three- to four-times more likely to be born within the lowest 10% birth weight for gestational age compared with both the comparison groups, which is consistent with previous research (Lee et al. Citation2022). On average, alprazolam neonates were almost 170 g lighter than neonates born to the alprazolam not during pregnancy comparison group and 32 g lighter than the non-alprazolam comparison group; however, neither difference was statistically significant.
Mothers treated with alprazolam during pregnancy were between three- and seven-times more likely to be admitted to hospital during pregnancy with a mental health diagnosis, compared with comparison groups. The timing of these admissions in relation to the use of alprazolam is important. The admissions may be precursors for the commencement of alprazolam, the result of cessation of alprazolam treatment, or occur while stable on or off treatment, with each scenario having different implications. For the majority of mental health admissions in women treated with alprazolam in pregnancy, the primary reason for hospitalization was related to pregnancy care rather than the mental health condition.
There was no difference between the two groups in terms of onset of labor or complications including threatened abortion, threatened pre-term labor and pre-eclampsia. There was, however, some evidence to suggest and increased risk of antepartum hemorrhage in women treated with alprazolam compared with non-alprazolam women, which warrants further investigation. Alprazolam and other benzodiazepines have not previously been associated with an increased risk of antepartum hemorrhage, although, cigarette smoking and the use of illicit drugs during pregnancy have been associated with an increased risk of antepartum hemorrhage (Abdel-Latif et al. Citation2007; Altvorst et al. Citation2012; Hulse et al. Citation1998; Kennare, Heard, and Chan Citation2005). However, no women treated with alprazolam had a postpartum hemorrhage.
A substantial limitation of this study was the study sample size. Despite using whole-population data, only 48 women and neonate pairs were exposed to alprazolam in pregnancy in WA over the 5-year observation period. As such, statistical power to robustly examine rare events such as perinatal mortality was lacking and some imprecision around estimates for other outcomes was evident, although associations still reached statistical significance. Additionally, the small sample size did not allow for outcomes to be examined by trimester of exposure.
The selected comparison group included women who had been prescribed alprazolam prior to pregnancy. While this group was likely more comparable to the alprazolam during pregnancy group in terms of a number of characteristics, these women may have also been prescribed other benzodiazepines during pregnancy. However, it was not possible to determine if women in this group were prescribed other benzodiazepines during pregnancy, as only alprazolam and flunitrazepam are classified as Schedule 8 drugs and are these included in the MODDS data. While matching and adjustments were performed to account for confounding between the groups, differences between the groups may have contributed to the outcomes.
A number of outcomes could not be examined with the available data, including congenital anomalies and pregnancy loss prior to 20 weeks. Similarly, outcomes were limited to the perinatal period, although in utero exposure to alprazolam may be associated with poor health outcomes beyond this time.
The use of alprazolam during pregnancy was not associated with an increased risk of serious adverse neonatal outcomes, including perinatal mortality. However, an association was seen with low birth weight and use of alprazolam during pregnancy. The study sample size was relatively small, limiting the ability to draw strong conclusions about such rarer outcomes and further research in larger populations is warranted.
Acknowledgments
The research team would like to acknowledge the support of the Western Australian Data Linkage Branch, the Western Australian Department of Health, and the data custodians of the Western Australian Registry of Births, Deaths and Marriages, Midwives Notification System, Hospital Morbidity Data Collection, the Victorian Department of Justice, and the National Coronial Investigation System for their assistance with the study.
Disclosure statement
EK & DP have received funding from MundiPharma International for an unrelated research project. KC has no interests to declare.
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References
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