Current Issue : Article / Volume 3, Issue 2

Safety Profile of Benzodiazepines During Pregnancy

Mohammad M Iqbal*,1Esha Aneja2

1California Department, Correction and Rehabilitation

2College of Medicine, California Northstate University

Correspondng Author:

Mohammad M Iqbal*,

Citation:

Mohammad M Iqbal, Esha Aneja. (2024). Safety Profile of Benzodiazepines During Pregnancy. Psychiatry and Psychological Disorders. 3(2); DOI: 10.58489/2836-3558/024

Copyright:

© 2024 Mohammad M Iqbal, this is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • Received Date: 15-08-2024   
  • Accepted Date: 20-08-2024   
  • Published Date: 24-08-2024
Abstract Keywords:

Benzodiazepines, Pregnancy, Congenital defects, Malformations

Abstract

Objective: 

Benzodiazepines are commonly and frequently prescribed during pregnancy for various psychiatric disorders. Their use has continued to be debated due to possible congenital effects though evidence about possible teratogenicity is equivocal. We aim to evaluate the association between the benzodiazepine use during pregnancy and their risk of causing major congenital malformations.

Methods: 

In order to understand the effects of benzodiazepine use during pregnancy, A MEDLINE search of the literature between 1966 and 2023 was conducted with the terms “pregnancy,” “benzodiazepines,” “diazepam,” “clonazepam, alprazolam,” “chlordiazepoxide,”,” “lorazepam,” “fetus,” and “neonates.” 

Results: 

The most commonly prescribed benzodiazepines during pregnancy are alprazolam, lorazepam and diazepam. Although benzodiazepine use during pregnancy was associated with a small increased risk of overall congenital malformations and heart defects in some studies, it was at doses higher than the usual daily dose. Our findings suggest that therapeutic benefits of benzodiazepines must be considered despite the potential risks. The recent studies suggest safety of using Diazepam, chlordiazepoxide with similar data for Lorazepam at low doses. It is still prudent for physicians to carefully monitor response on lowest possible dosages of benzodiazepines while dividing its daily use with longest safety data for pregnancy females. Consideration should also be given for monotherapy for the shortest possible duration while continuously recommending alternative modalities.

Conclusions: 

In spite of benzodiazepine use during pregnancy being shown to have congenital malformation in a few studies, this data is still insufficient to be conclusive. Therefore, it is necessary to consider safety profile, low dosages, shortest possible benzodiazepine usage as a monotherapy while alternative therapies besides medications should also be actively recommended.

Introduction

Benzodiazepines are one of the most commonly used classes of anti-anxiety medications in the United States. They are commonly prescribed to women of childbearing age and pregnant women [1] to reduce anxiety and manage preeclampsia or third-trimester eclampsia. These agents are also used in the treatment of generalized anxiety disorder, panic disorder with or without agoraphobia, sedation, light anesthesia and anterograde amnesia of postoperative events, seizure control, and skeletal muscle relaxation

Benzodiazepine compounds are divided into three main categories: long-acting compounds - diazepam, chlordiazepoxide, flurazepam clorazepate, prazepam and galazepam; intermediate-acting compounds - clonazepam, lorazepam, estazolam and quazepam; and short-acting compounds - alprazolam, oxazepam, temazepam, triazolam and midazolam. The most commonly prescribed benzodiazepines in the United States are diazepam, chlordiazepoxide, clonazepam, lorazepam, and alprazolam.

Although the physiological effects of benzodiazepines are still not fully known, their effects of have been mediated by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). The drug appears to act on the limbic, thalamic and hypothalamic levels of the central nervous system, producing sedative and hypnotic effects, anxiety reduction, anticonvulsant effects and skeletal muscle relaxation. While high-affinity binding sites for benzodiazepines have been identified in the central nervous system, both GABA and chloride increase the affinity of these sites for the drug.

There are many potential risks to the fetus when anti-anxiety medications are prescribed to pregnant women. Teratogenic effects have been immediate or sometimes delayed. Potential reported effects include abortion, malformations, intrauterine growth retardation, functional defects, carcinogenesis, and mutagenesis. There is highest risk of defects in the fetus when it is exposed to these drugs between 2 and 8 weeks after conception. If the drug is administered at or near term, fetal dependence and withdrawal symptoms may occur. This paper discusses the risks of benzodiazepines commonly used during pregnancy and the possible long-term effects on the development of exposed children.

Methods

We used the terms or a combination of terms 'benzodiazepines', 'diazepam', 'chlordiazepoxide', 'alprazolam', 'lorazepam', 'clonazepam', “neonates”, "Fetus" and “pregnancy” from 1966 to December 2023 in our MEDLINE search for the literature. A total of 105 papers were included in the literature search. These articles are classified by drug and evaluated based on the scientific information on risks to the fetus during pregnancy (Table 1).

Table 1: Classification, dosages, and effects of benzodiazepines during pregnancy

Drug NamesFDA CategoryApproved daily dosage rangeEffects on fetus on Pregnancy

Diazepam

D

4-40 mg

Pregnancy: Oral clefts, central nervous system anomalies, ocular hypertelorism, absence of both fingers, dislocation of head of right radius, polycystic kidney, periauricular tags, cardiovascular anomalies, polydactyly, hemangioma, neonatal withdrawal syn- drome, floppy infant syndrome, low birth weight and head circumference, mental retardation, decreased fetal movement, temporary loss of beat-to- beat variability on fetal heart tracings, jaundice, kernicterus.

Chlordiazepoxide

D

5-300 mg

Spastic diplegia, microcephaly, duodenal atresia, fetal death, mental deficiency, neonatal withdrawal,

Clonazepam

D

1-6 mg

Congenital heart disease, ventral septal defect, hip dislocation,

uteropelvic junction obstruction, bi-lateral inguinal hernia, undescended testicle, paralytic ileus of the small bowel, cyanosis, lethargy, hypotonia, apnea

Lorazepam

D

5-10 mg

Anal atresia and neonatal withdrawal

symptoms, such as low Apgar scores, depressed respiration, hypothermia, poor suckling, jaundice, sleep disturbances associated with intravenous use

Alprazolam

D

0.75mg-4 mg (anxiety)

1.5-10mg (panic)

Cleft lip, inguinal hernia, hypospadias, cryptorchidism, tracheo-esophageal fistula, patent ductus (panic), arteriosus, microcephaly, strabismus, congenital hip dislocation, fused lacrimal duct, Down’s syndrome, cat’s eye with Pierre Robin syndrome, pyloric stenosis, umbilical hernia, ankle inversion, lipomeningocele, neonatal withdrawal syndrome

Pregnancy categories: FDA classifies various drugs used in pregnancy into five categories, categories A, B, C, D and X. Category A is considered the safest category and category X is absolutely contraindicated in pregnancy. This provides therapeutic guidance for the clinician.

Diazepam

Diazepam has been used in substance use withdrawal primarily alcohol, benzodiazepine and barbiturate withdrawal, seizures, hallucinations, and as skeletal muscle relaxant. Diazepam was the most frequently prescribed benzodiazepine across the world till the early 1980’s [2]. 

Diazepam and its major metabolite, N-desmethyldiazepam, are both highly lipid soluble and pharmacological active facilitating they’re freely crossing the human placenta during pregnancy [3-10]. After 6 months of pregnancy, the placenta loses cytotrophoblasts (Langerhans cells), further facilitating the transplacental transfer of diazepam [11]. Diazepam and N-desmethyldiazepam also bind more strongly to fetal plasma proteins than to maternal plasma proteins. Maternal protein binding is found to be lower in pregnant than in nonpregnant women [12-14].

Diazepam rapidly crosses the placenta in early pregnancy, reaching significantly higher concentrations in cord plasma than in maternal plasma after intravenous or intramuscular administration, with a maternal-fetal ratio of 1.2 to 2 [15,16]. And in the long run [4.17–19]. Diazepam can accumulate significantly in adipose tissue. Elevated levels of it are also found in the brain, heart and lungs [4]

Since diazepam has the characteristics of easy penetration across the blood brain barrier, lipophiliic nature [10], long retention in neural tissues as seen in monkeys, [21] and high absorption in animal fat tissue [20], it is indicative of human tissue acting as a depot for it.  Although majority of diazepam and its metabolites continue in active concentration in newborns for at least a week after being administered in high doses to the mother, a small concentration of it has been found to be metabolized in neonates [4] with its mean plasma half life of about 31 hours.

Most of the epidemiological studies have been equivocal in determining the risk of congenital malformation among neonates born to pregnant mothers taking diazepam.

Bellantuono and colleagues found Benzodiazepine exposure in first trimester to not be associated with an increasing risk of congenital malformations in their review of twelve studies [22].  Diazepam and Chlordiazepoxide should be considered drugs of first choice according to them when a BZD needs to be prescribed in early pregnancy. 

No consistent data in favor of congenital malformation or other adverse events due to diazepam exposure during early pregnancy was also found by Czeizel and colleagues [23]. They also suggested that association between diazepam exposure and congenital malformation could be due to a recall bias in mother of nonmalformed children. 

Whereas studies have shown higher use of diazepam during first trimester of pregnancy among mothers whose children were born with oral cleft palate found in 6.3 percent of 30 children after diazepam exposure in first trimester which is significantly higher than 1.1 percent found in control children. [24]. Similar exposure rate of 6.2% for cleft palate was reported by Saxen [25] which was consistent with their other review of 599 cases of oral clefts showing a significant association with first trimester use of primarily diazepam among anti-anxiety agents [26].

Although some epidemiological studies have shown association between oral cleft with use of diazepam during pregnancy [25, 27-30] whereas several other prospective and retrospective studies did not find a higher risk of congenital malformations [27, 31-35]. Interestingly the higher use of diazepam in the last few decades has not shown a consistent association with the higher incidence of cleft lip or cleft palate cases.

While there was a case of spina bifida occulta in a newborn whose mother was administered diazepam and protriptyline during the first few months of pregnancy [36] and another case of congenital absence of bilateral thumbs including metacarpal bones and dislocation of the right radius head in a newborn whose mother received 6 mg of daily diazepam for three weeks with hydroxyprogesterone during pregnancy [37], there is no clear cut evidence of diazepam causing these birth defects as there was simultaneous use of other concomitant medications.

While no permanent damage was reported by Cerqueira and colleagues in children of five pregnant women who received toxic doses of benzodiazepines during mid or late pregnancy, however they found a single high dose of 580 mg of diazepam to be associated with cleft lip and palate, ocular hypertelorism, bilateral periauricular tags and craniofacial asymmetry around 43rd gestational day [38].

In a study of 17 infants born to women who took diazepam or other benzodiazepines during pregnancy, both low birth weight and small head circumference were reported [39]. Although their weight returned to normal by ten months however their head circumference continued to be smaller than expected at 18 months of age [40]

Studies pertaining to association between use of diazepam during first trimester of pregnancy and congenital malformations were found to be inconsistent. While two studies with 383 and 390 children suggested an association between diazepam use and congenital heart disease and other anomalies— polydactyly and hemangioma [1, 41]. Whereas Bracken and team did not find such association of congenital heart defects with diazepam use in their reanalysis of such data [1]. Moreover three other studies with 298, 150, 90 children also were consistent in not showing any association between diazepam use in pregnancy and congenital heart defects [42-44].

There are two major neonatal complications that need to be specially discussed for infants with prolonged exposure to maternal diazepam with daily dosages exceeding 30 to 40 mg primarily through intravenous or intramuscular route during pregnancy and labor [6,7, 9, 45-49]. These include primarily neonatal syndrome and floppy infant syndrome. 

Neonatal withdrawal symptoms include hyperreflexia, hypertonia, irritability, restlessness, tremors, bradycardia, cyanosis, suckling difficulties, abnormal sleep pattern, apnea, diarrhea, vomiting, risk of aspiration during feeding, and growth retardation. Neonatal syndrome has been associated with higher incidence of low Apgar scores when dosages of diazepam exceeded 30 mg [50].

While floppy infant syndrome is another complication described with acute use of diazepam via intramuscular or intravenous route during labor [6,46,47,49,51,52]. Its features include withdrawal symptoms, lethargy, feeding, respiratory difficulties, hypothermia where they recovered without long lasting sequelaeThis coincides with the known physiological changes in the newborn with increased free fatty acid concentrations during the first days after delivery. This increase leads to a greater concentration of free diazepam and N-desmethyl- diazepam and hence likely severe effects on the infant.

A large United Kingdom primary care database based study of children born to women aged 15–45 years between 1990 and 2010 calculated absolute risks of major congenital anomaly (MCAs) for children with first trimester exposures of different anxiolytic and hypnotic drugs [53]  Their findings indicated an overall MCA prevalence of 2.7% in 1,159 children of mothers prescribed diazepam, 2.9% in 379 children with temazepam, 2.5% in 406 children with zopiclone, and 2.7% in 19,193 children whose mothers had diagnosed depression and/or anxiety but no first trimester drug exposures. This first UK population-based study showed no evidence of increased risks of MCAs associated with antenatal drug exposure to diazepam, temazepam, zopiclone or other anxiolytic/hypnotic drugs and concluded that prescription of these drugs during early pregnancy may be safe in terms of MCA risk, but findings from other studies would help before safety can be confirmed.

Based on these numerous studies, there is no conclusive evidence which proves that diazepam causes teratogenicity. Although congenital malformations have been found to be associated with diazepam use in pregnancy in some studies; however congenital malformations have not been found to be conclusive in majority of these studies.  Therefore, diazepam can be used for the shortest and lowest dosage during pregnancy and tapered prior to delivery especially to avoid neonatal withdrawal and floppy infant syndrome. 

Chlordiazepoxide

Chlordiazepoxide hydrochloride is a long acting benzodiazepine which has been used for treatment of anxiety disorders, preoperative anxiety and withdrawal effects of chronic alcoholism. It is also used for its weak analgesic and appetite stimulating effects. It also has low toxicity and safety for pre anesthetic use during labor including intravenous route [54]. It has similar concentration in fetal blood as in maternal circulation possibly due to its ready transmission across the placenta [55].

Several congenital anomalies including microcephaly, cognitive deficiency, duodenal atresia and spastic diplegia as well as higher fetal death rates were found frequently in infants whose mothers took Chlordiazepoxide during the first 42 days of pregnancy compared to those whose mothers took other medications or none (11.4 per 100 compared with 4.6 per 100 and 2.6 per 100, respectively) by Milkovich and Van den Berg during their study of 19,044 live births [56].

Whereas frequency of congenital anomalies was no greater than expected among infants of mothers who took chlordiazepoxide during their first trimester in several studies [1,41,57-59].  During a follow up study of 50, 282 pregnancies, Hartz and team compared 1870 children within utero exposure to chlordiazepoxide to 48, 412 non exposed children [59]. Congenital defects were found to be at a similar rate as well as no difference in rates was found comparing exposure in first trimester to other times of pregnancy. In addition, incidence of mental and motor abnormalities at eight months or in IQ scores at 4 years of age were not found to be different in children after in utero exposure to chlordiazepoxide.

Similarly, chlordiazepoxide use during pregnancy was not associated with congenital defects in other studies such as a study with 1427 infants exposed to chlordiazepoxide in the first trimester [1] and no causal association found with chlordiazepoxide exposure in a study of 390 infants with congenital heart disease [41] or in 1201 children with cleft palate, lip or both [60].

Czeizel and colleagues observed a higher risk of cardiovascular malformation even though no specific pattern was reported with Chlordiazepoxide use in pregnancy which went against any hypothesis of a specific teratogenic effects of Chlordiazepoxide per their findings [61].

When Chlordiazepoxide at 100 mg dose was compared to placebo use intramuscularly during the first stage of labor during a random double blind study of 200 pregnant women, no CNS depressant effects were noted in infants [62]. Therefore, chlordiazepoxide was suggested to be safe to be administered to pregnant women in labor at doses up to 100 mg without adverse effects on the neonate.

On the other hand, chronic Chlordiazepoxide exposure in utero or to small dosages during labor was found to be associated with neonatal withdrawal syndrome in some case reports (63.64). One case of severe emotional disorder after treatment with 30 mg daily dose of chlordiazepoxide for five years when her dose was lowered to 20 mg daily in the 12th week of pregnancy [64] and in another case it was after mother was given 500 mg of chlordiazepoxide intravenously over four hours prior to her cesarian section [65]. While another case was given 25 mg of chlordiazepoxide four times a day during pregnancy to lower mental stress [63] and all these cases showed neonatal withdrawal symptoms within a few days of birth. 

It has been noted that symptoms of neonatal withdrawal appear within a few days to three weeks after birth and can last up to a few months with most children having full recovery. Whereas delayed withdrawal syndrome is more likely after receiving benzodiazepine such as diazepam, chlordiazepoxide, alprazolam and triazolam during pregnancy. Most infants have recovered without sequelae. Some infants develop signs of these much later and their concentrations of drug in neonatal blood and umbilical cord serum should be correlated with clinical observations.

In summary, majority of evidence for chlordiazepoxide use during pregnancy shows lack of association with adverse effects on themselves or their infants though there have been a few reports of adverse effects during pregnancy. In situations where its use cannot be avoided, it certainly should be minimized by lowering its daily dosage and duration as clinically necessary.  The risks to the mother and fetus with using chlordiazepoxide should continue to be weighed against the potential benefits to the pregnant mother.

Clonazepam

Clonazepam is a benzodiazepine which has been used as an anticonvulsant since 1973. It is metabolized mainly by hydroxylation though this metabolic pathway is impaired in the neonates. Although the half life in neonates is not known, benzodiazepine derivatives typically have half lives that are two to four times greater in neonates than adults [66].  While adults have half lives of 20 to 60 hours for clonazepam. 

Some case reports have documented congenital malformations in infants of mothers with epilepsy who took clonazepam alone or with other medications during pregnancy [66-71]. One of these studies found that 12 of 104 children had congenital malformations after being exposed to antiepileptic drugs (AED) in utero, 3 of these 12 children had taken clonazepam in combination with AED’s [71]. In addition, combination of clonazepam with phenobarbital at 1 to 6 mg daily dose showed higher risk of congenital heart disease and hip dislocation which was possibly due to multidrug interaction and combination therapy [65] or increased AED in maternal plasma concentration [72].

On the other hand, Weinstock’s team studied 38 women with histories of panic disorder who used clonazepam during pregnancy [73]. Obstetrical records describing pregnancy, labor and delivery and infant Apgar scores were obtained for all subjects along with Neonatal nursery records were obtained for 27 subjects. Maternal outcome assessed by obstetrical records and acute neonatal outcome assessed by Apgar scores did not reveal that Clonazepam use during pregnancy appeared to be directly related to any obstetric complications during pregnancy, labor, or delivery. There was no evidence of neonatal toxicity or withdrawal syndromes in babies born to mothers who took clonazepam during pregnancy. Absence of serious maternal or neonatal compromise following clonazepam use during pregnancy in these mothers and infants is somewhat reassuring.

Whereas five infants who had congenital malformations with clonazepam use showed ureteropelvic junction obstruction, one with an undescended testicle, other with ventricular septal defect, two had bilateral inguinal hernias in a study by Johnson and colleagues [74,75].

A 40 year old multiparous mother who took clonazepam throughout pregnancy with myoclonic sleep disorder delivered an infant of 6 pounds at 36 weeks with cyanosis, apnea, lethargy and hypotonia [66]. However no congenital malformation was found at birth or at five months of age. The mother’s serum clonazepam concentration was found to be 32 ng/mL, and the infant’s cord blood clonazepam concentration was 19 ng/mL at delivery with therapeutic range is 5 to 70 ng/mL. The concentration in breast milk was constant between 11 and 13 ng/mL and the ratio of breast milk concentration to maternal serum concentration was about 1 to 3 with no evidence of drug accumulation found after breast- feeding.

On similar lines, respiratory depression was found in neonates of pregnant mothers receiving Clonazepam of 5.5 mg daily throughout till delivery in another study [69].

 Bases on these studies, it is recommended that infants of mothers who received clonazepam during pregnancy have their serum drug concentrations monitored and closely observed for any signs of central nervous system depression or apnea. It is therefore recommended that clonazepam be used during pregnancy only when its therapeutic benefit justifies the risks to the fetus. 

Lorazepam

Lorazepam is a benzodiazepine that belongs to a group of 1, 4 benzodiazepine derivatives that have much higher potency than others that belong to the closely related chlordiazepoxide group of derivatives. It is used as a tranquilizer for anxiety in a relatively smaller dosage range of 1 to 4mg as well as an anticonvulsant during surgical anesthesia and for insomnia associated with anxiety [76].

Lorazepam and its inactive metabolite do not cross the placenta as easily as benzodiazepines like diazepam and thus do not cause long lasting adverse effects to the neonates [8].  Such finding of lower cord plasma concentration of lorazepam compared to its maternal concentration has been reflected in several studies [77,78]. Lorazepam is mostly metabolized to its inactive compound glucuronide that does not accumulate in the tissues.  Its relatively shorter half life of 12 hours in adults also makes it a good option for anxiety treatment as well as sedation during and after delivery [79].

One study found that congenital anal atresia approximates a rate of 3 cases every 10,000 unexposed newborns in Italy [80]. Considering a six fold increase in anal atresia after in utero exposure to Lorazepam, it relates to less than 20 cases every 10, 000 newborns, which means less than 0.2% of newborns per another study [81]. During first trimester exposure to lorazepam, Godet and team found 187 cases of congenital malformations among 100.000 live births showing a significant anal atresia association in five of these cases after lorazepam use [82].

Lorazepam use was also found to be associated with higher odds (OR odds ratio) of right ventricular outflow obstruction defects (cOR: 3.2; 95% CI: 0.9, 10.9), specifically pulmonary valve stenosis (cOR: 4.1; 95% CI: 1.2, 14.2). elevated odds ratio for lorazepam exposure and its risk for gastroschisis (cOR: 3.5; 95% CI: 0.9, 13.7) in another study. [83]. 

During their study on Lorazepam risks in pregnancy, Noh and colleagues conducted a nationwide retrospective cohort study using healthcare data retrieved from the Health Insurance Review and Assessment Service (HIRA) database, which covered 50 million people (approximately 99% of the South Korean population), from 1 July 2009 to 31 December 2019.   [84]Their data comprised individual-level demographics and all records of diagnosis and healthcare utilization. Based on mean daily lorazepam-equivalent doses, the adjusted RRs (relative risk) for overall malformations and heart defects were 1.05 (0.99 to 1.12, p = 0.077) and 1.12 (1.04 to 1.21, p = 0.004) for <1>2.5 mg/day doses, respectively, suggesting a dose–response relationship. 

Furthermore, a small but significantly increased risk of congenital malformations in the high-dose group (the mean daily lorazepam-equivalent dose >2.5 mg/day, which is higher than the daily dose defined by the World Health Organization was found due to this dose response curve) [36, 85].  

Preterm infants showed greater incidence of low Apgar scores, hypothermia and poor suckling whose mothers had received Lorazepam via oral or intravenous route. For severe hypertension, intravenous use of lorazepam was associated with neonatal withdrawal, low Apgar scores, hypothermia, respiratory depression and poor suckling. Due to these serious effects on neonates after lorazepam use via oral route prior to 37 weeks or during any month of pregnancy via intravenous route, such Lorazepam administration should be only considered in facilities with neonatal intensive care. 

There are concerns of neonatal withdrawal due to lorazepam’s short half life suggesting that tapering its dose gradually before expected delivery date would prevent such withdrawal. At the same time, benzodiazepine antagonist, Flumazenil can be useful to minimize fetal or neonatal toxicity [86]. 

Lorazepam as an oral dose should only be used in severe cases or life threatening situations for which safer drugs are either not available or are not efficacious. Also, since safety of injectable use of lorazepam has not been established, its use is not recommended at all during labor and delivery or cesarian surgeries.  Pregnant mothers should be advised about the risks and potential harm to the fetus if Lorazepam use is continued after patient becomes pregnant while receiving this benzodiazepine. 

Alprazolam

Alprazolam is one of the most widely prescribed benzodiazepine for treatment of anxiety disorders including generalized anxiety disorder, panic disorder with or without agoraphobia since its introduction in 1980 [87,88].  It has a relatively shorter half life of 10 to 24 hours compared to other benzodiazepines resulting in less cumulative drowsiness after administering multiple doses [89,90]. Alprazolam with its two hydroxylated metabolites is known to cross the placenta [90,91].

St Clair and Schirmer found no defects or congenital malformation in their study with 411 infants who were exposed to alprazolam during first trimester of pregnancy [90]. Whereas another study found congenital malformations in five infants exposed to Alprazolam during pregnancy including one case of congenital hip dysplasia, hypospadias, one inguinal hernia, one cleft lip and one fused lacrimal duct [92]. Similarly, Johnson and associates found major malformations in 10 infants exposed to alprazolam [74,75]. 

In a Korean study, Lee’s team evaluated 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. Their 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.  [93] Alprazolam use during pregnancy thus should be appropriately regulated and monitored.

There were 3 cases of congenital malformations in neonates exposed in utero to alprazolam either as single drug or in combination in another study including down’s syndrome, cat’s eye with Pierre Robin syndrome, pyloric stenosis, umbilical hernia, moderate tongue tie, club foot and ankle inversion. However no clear cut association was found between the use of alprazolam and congenital malformation [94].

Tinker and colleagues found that exposure to alprazolam appeared to drive the observed associations with malformations of anophthalmia or microphthalmia (cOR: 4.0; 95% CI: 1.2, 13.1), esophageal atresia or stenosis (aOR: 2.7; 95% CI: 1.2, 5.9), and hypospadias (aOR: 0.3; 95% CI: 0.1, 0.9). Alprazolam use was also associated with higher odds of atrioventricular septal defect (AVSD; cOR: 2.5; 95% CI: 0.8, 8.1) [95]

Furthermore, data from the Swedish Medical Birth Register from 1996 to 2011 showed an association between alprazolam use and the broad category of all types of cardiac defects (OR: 2.4; 95% CI: 1.4, 4.2). [96]

Two isolated cases of neonatal withdrawal syndrome in infants whose mothers took alprazolam throughout their pregnancy have been reported [94]. In one case the mother took 3 mg a day, and a mild neonatal withdrawal syndrome developed when the infant was two days old. In the second case, the mother took 7 to 8 mg a day. By contrast, Shader [97] described a case in which no perinatal adverse effects were observed after the mother had been treated with alprazolam throughout her pregnancy at an average dosage of 1.5 mg a day.

These studies show that Alprazolam use can possibly increase the risk of congenital malformation when used during first trimester of pregnancy and therefore it is best to avoid its use during the first trimester. Furthermore, discontinuation of such alprazolam use after becoming pregnant or intending to become pregnant is recommended.

Discussion and conclusions

Currently, there is insufficient information with Benzodiazepine use in pregnancy to determine whether the potential benefits to the mother outweigh the potential risks to the fetus, so therapeutic value of any benzodiazepine must be evaluated against its theoretical side effects on the fetus before and after birth. This is primarily because Benzodiazepines have not been tested directly in pregnant women to assess the effects of benzodiazepines on the fetus, newborn, or infant.

Based on the available literature, both Diazepam and Chlordiazepoxide appear to be relatively safe for use during pregnancy There is data showing central nervous depression and apnea with Clonazepam use during pregnancy suggesting that its use should only be considered where benefits to the mother outweigh the risks to the fetus. Whereas Lorazepam should only be used in severe or life threatening cases of anxiety related conditions for which safer drugs are not available or efficacious. However Alprazolam use should be avoided in pregnancy.

To avoid the potential risk of birth defects, physicians should use benzodiazepines with a long safety record and prescribe benzodiazepine monotherapy at the lowest effective dose and for the shortest duration. In addition, the daily dose should be divided into at least two doses to avoid peak drug concentrations. As a general rule of thumb, exposure to any form of benzodiazepines should be avoided during the first three months of pregnancy. This is because the fetus is most vulnerable to drug toxicity during this period of active organogenesis. However, drug use during pregnancy is certainly not contraindicated. Finally, the best way to monitor the safety and efficacy of treatment with benzodiazepine use during pregnancy must be determined.

Nonpharmacological treatments for many anxiety disorders (behavioral techniques, relaxation techniques, relaxation exercises, psychotherapy, caffeine avoidance) can also be effective during pregnancy. These non-pharmacological approaches would be beneficial to be considered prior to any medication treatment for anxiety disorders during pregnancy.

References

  1. Bracken, M. B., & Holford, T. R. (1981). Exposure to prescribed drugs in pregnancy and association with congenital malformations. Obstetrics & Gynecology, 58(3), 336-344.
  2. Shader, R. I., & Greenblatt, D. J. (1993). Use of benzodiazepines in anxiety disorders. New England Journal of Medicine, 328(19), 1398-1405.
  3. Kuhnz, W., & Nau, H. (1983). Differences in in vitro binding of diazepam and N‐desmethyldiazepam to maternal and fetal plasma proteins at birth: Relation to free fatty acid concentration and other parameters. Clinical Pharmacology & Therapeutics, 34(2), 220-226.
  4. Mandelli, M., Morselli, P. L., Nordio, S., Pardi, G., Principi, N., Sereni, F., & Tognoni, G. (1975). Placental transfer of diazepam and its disposition in the newborn. Clinical Pharmacology & Therapeutics, 17(5), 564-572.
  5. Bakke, O. M., Haram, K., Lygre, T., & Wallem, G. (1981). Comparison of the placental transfer of thiopental and diazepam in caesarean section. European Journal of Clinical Pharmacology, 21, 221-227.
  6. Gillberg, C. (1977).
  7. Mazzi, E. (1977). Possible neonatal diazepam withdrawal: a case report. American journal of obstetrics and gynecology, 129(5), 586-587.
  8. Cree, J. E., Meyer, J., & Hailey, D. M. (1973). Diazepam in labour: its metabolism and effect on the clinical condition and thermogenesis of the newborn. Br Med J, 4(5887), 251-255.
  9. Shannon, R. W., Fraser, G. P., Aitken, R. G., & Harper, J. R. (1972). Diazepam in preeclamptic toxaemia with special reference to its effect on the newborn infant. International Journal of Clinical Practice, 26(6), 271-275.
  10. Van der Kleijn, E. (1969). Protein binding and lipophilic nature of ataractics of the meprobamate-and diazepine-group. Archives internationales de pharmacodynamie et de therapie, 179(1), 225-250.
  11. Anderson WAD: Pathology, 3rd ed. St Louis, Mosby, 1957
  12. ALLEN, M. D., & GREENBLATT, D. J. (1981). Comparative protein binding of diazepam and desmethyldiazepam. The Journal of Clinical Pharmacology, 21(5‐6), 219-223.
  13. Colburn, W. A., & Gibaldi, M. (1978). Plasma protein binding of diazepam after a single dose of sodium oleate. Journal of Pharmaceutical Sciences, 67(6), 891-892.
  14. Krasner J, Yaffe SJ: Drug-protein binding in the neonate, in Basic and Therapeutic Aspects of Perinatal Pharmacology. Edited by Morselli PL, Garattini S, Sereni F. New York, Raven, 1975
  15. Erkkola, R., Kanto, J., & Sellman, R. (1974). Diazepam in early human pregnancy. Acta obstetricia et gynecologica Scandinavica, 53(2), 135-138.
  16. Kanto, J., & Erkkola, R. (1974). The feto-maternal distribution of diazepam in early human pregnancy. In Annales chirurgiae et gynaecologiae Fenniae (Vol. 63, No. 6, pp. 489-491).
  17. Erkkola, R., Kangas, L., & Pekkarinen, A. (1973). The transfer of diazepam across the placenta during labour. Acta obstetricia et gynecologica Scandinavica, 52(2), 167-170.
  18. Gamble, J. A. S., Moore, J., Lamki, H., & Howard, P. J. (1977). A study of plasma diazepam levels in mother and infant. BJOG: An International Journal of Obstetrics & Gynaecology, 84(8), 588-591.
  19. Kanto, J., Erkkola, R., & Sellman, R. (1973). Accumulation of diazepam and N-demethyldiazepam in the fetal blood during the labour. Annals of clinical research, 5(6), 375-379.
  20. IDÄNPÄÄN-HEIKKILÄ, J. E., TASKA, R. J., Allen, H. A., & SCHOOLAR, J. C. (1971). Placental transfer of diazepam-14C in mice, hamsters and monkeys. Journal of Pharmacology and Experimental Therapeutics, 17 6(3), 752-757.
  21. Marcucci, F., Fanelli, R., Frova, M., & Morselli, P. L. (1968). Levels of diazepam in adipose tissue of rats, mice and man. European Journal of Pharmacology, 4(4), 464-466.
  22. Bellantuono, C., Tofani, S., Di Sciascio, G., & Santone, G. (2013). Benzodiazepine exposure in pregnancy and risk of major malformations: a critical overview. General hospital psychiatry, 35 (1), 3-8.
  23. Czeizel, A. E., Erös, E., Rockenbauer, M., Sørensen, H. T., & Olsen, J. (2003). Short-term oral diazepam treatment during pregnancy: a population-based teratological case-control study. Clinical drug investigation, 23, 451-462.
  24. Aarskog, D. (1975). Association between maternal intake of diazepam and oral clefts. The Lancet, 306(7941), 921.
  25. SAXÉN, I. (1975). Associations between oral clefts and drugs taken during pregnancy. International journal of epidemiology, 4 (1), 37-44.
  26. Saxén, I., & Saxén, L. (1975). Association between maternal intake of diazepam and oral clefts. The Lancet, 306(7933), 498.
  27. Rosenberg, L., Mitchell, A. A., Parsells, J. L., Pashayan, H., Louik, C., & Shapiro, S. (1983). Lack of relation of oral clefts to diazepam use during pregnancy. New England Journal of Medicine, 309(21), 1282-1285.
  28. Entman, S. S., & Vaughn, W. K. (1984). Lack of relation of oral clefts to diazepam use in pregnancy. The New England journal of medicine, 310(17), 1121-1122.
  29. Czeizel, A. (1976). Diazepam, phenytoin, and aetiology of cleft lip and/or cleft palate. The Lancet, 307(7963), 810.
  30. Saxén, I. (1975). Epidemiology of cleft lip and palate. An attempt to rule out chance correlations. Journal of Epidemiology & Community Health, 29(2), 103-110.
  31. Czeizel A, Lendvay A: In utero exposure to benzodiazepines [letter]. Lancet 1:628, 1987
  32. Shiono, P. H., & Mills, J. L. (1984). Oral clefts and diazepam use during pregnancy. The New England Journal of Medicine, 311(14), 919-920.
  33. Czeizel, A. E. (1986). Endpoints of reproductive dysfunction in an experimental epidemiological model: self-poisoned pregnant women. Developments in toxicology and environmental science, 12, 49-61.
  34. Czeizel, A., Pazsy, A., Pusztai, J., & Nagy, M. (1983). Aetiological monitor of congenital abnormalities: a case-control surveillance system. Acta Paediatrica Hungarica, 24(1), 91-99.
  35. Gelenberg AJ (ed): Diazepam: not a terato- gen? Massachusetts General Hospital Newsletter 7(2), 1984
  36. New Zealand Committee on Drug Reactions: Fourth annual report. New Zealand Medical Journal 70:118–122, 1969
  37. Istavan EJ: Drug-associated congenital abnormalities? [letter] Canadian Medical As- sociation Journal 103:1394, 1970
  38. Cerqueira, M. J., Olle, C., Bellart, J., Baro, F., Cabero, L., Queralto, J. M., & Espinosa, J. R. (1988). Intoxication by benzodiazepines during pregnancy. The Lancet, 331(8598), 1341.
  39. Laegreid, L., Hagberg, G., & Lundberg, A. (1992). The effect of benzodiazepines on the fetus and the newborn. Neuropediatrics, 23(01), 18-23.
  40. Laegreid, L., Hagberg, G., & Lundberg, A. (1992). Neurodevelopment in late infancy after prenatal exposure to benzodiazepines-a prospective study. Neuropediatrics, 23(02), 60-67.
  41. Rothman, K. J., Fyler, D. C., Goldblatt, A., & Kreidberg, M. B. (1979). Exogenous hormones and other drug exposures of children with congenital heart disease. American journal of epidemiology, 109(4), 433-439.
  42. Zierler, S., & Rothman, K. J. (1985). Congenital heart disease in relation to maternal use of Bendectin and other drugs in early pregnancy. New England Journal of Medicine, 313(6), 347-352.
  43. Tikkanen, J., & Heinonen, O. P. (1992). Risk factors for conal malformations of the heart. European journal of epidemiology, 8, 48-57.
  44. Tikkanen, J., & Heinonen, O. P. (1991). Risk factors for ventricular septal defect in Finland. Public health, 105(2), 99-112
  45. Scanlon, J. W. (1975). Effect of benzodiazepines in neonates. The New England journal of medicine, 292(12), 649-650.
  46. Haram, K. (1977).
  47. Rementería, J. L., & Bhatt, K. (1977). Withdrawal symptoms in neonates from intrauterine exposure to diazepam. The Journal of pediatrics, 90(1), 123-126.
  48. Backes, C. R., & Cordero, L. (1980). Withdrawal symptoms in the neonate from presumptive intrauterine exposure to diazepam: report of case. Journal of the American Osteopathic Association, 79(9), 584-585.
  49. Speight, A. N. P. (1977). Floppy-infant syndrome and maternal diazepam and/or nitrazepam. The Lancet, 310(8043), 878.
  50. FLOWERS, C. E., RUDOLPH, A. J., & DESMOND, M. M. (1969). Diazepam (Valium) as an AdjuNC. t in Obstetric Analgesia. Obstetrics & Gynecology, 34(1), 68-81.
  51. Speight, A. N. (1978). Diazepam in pre-eclamptic toxaemia. British Medical Journal, 1(6124), 1420.
  52. Woods, D. L., & Malan, A. F. (1978). Side-effects of maternal diazepam on the newborn infant. South African medical journal= Suid-Afrikaanse tydskrif vir geneeskunde, 54(16), 636.
  53. Ban, L., West, J., Gibson, J. E., Fiaschi, L., Sokal, R., Doyle, P., ... & Tata, L. J. (2014). First trimester exposure to anxiolytic and hypnotic drugs and the risks of major congenital anomalies: a United Kingdom population-based cohort study. PLoS One, 9(6), e100996.
  54. MARK, P. M., & HAMEL, J. (1968). Librium for patients in labor. Obstetrics & Gynecology, 32(2), 188-194.
  55. Pankaj, V., & Brain, P. F. (1991). Effects of prenatal exposure to benzodiazepine-related drugs on early development and adult social behaviour in Swiss mice--I. Agonists. General pharmacology, 22(1), 33-41.
  56. Milkovich, L., & van den Berg, B. J. (1974). Effects of prenatal meprobamate and chlordiazepoxide hydrochloride on human embryonic and fetal development. New England Journal of Medicine, 291(24), 1268-1271.
  57. Crombie, D. L., Pinsent, R. J., Fleming, D. M., Rumeau-Rouquette, C., Goujard, J., & Huel, G. (1975). Fetal effects of tranquilizers in pregnancy. The New England Journal of Medicine, 293(4), 198-199.
  58. Kullander, S., & Källén, B. (1976). A prospective study of drugs and pregnancy. Acta Obstetricia et Gynecologica Scandinavica, 55(4), 287-295.
  59. Hartz, S. C., Heinonen, O. P., Shapiro, S., Siskind, V., & Slone, D. (1975). Antenatal exposure to meprobamate and chlordiazepoxide in relation to malformations, mental development, and childhood mortality. New England Journal of Medicine, 292(14), 726-728.
  60. Czeizel, A. (1987). Lack of evidence of teratogenicity of benzodiazepine drugs in Hungary. Reproductive Toxicology, 1(3), 183-188.
  61. Czeizel, A. E., Rockenbauer, M., Sørensen, H. T., & Olsen, J. (2004). A population-based case–control study of oral chlordiazepoxide use during pregnancy and risk of congenital abnormalities. Neurotoxicology and teratology, 26 (4), 593-598.
  62. Decancq Jr, H. G., Bosco, J. R., & Townsend Jr, E. H. (1965). Chlordiazepoxide in labor: its effect on the newborn infant. The Journal of pediatrics, 67(5), 836-840.
  63. Bitnun, S. (1969). Possible effect of chlordiazepoxide on the fetus. Canadian Medical Association Journal, 100(7), 351.
  64. Athinarayanan, P. (1976). Chlordiazepoxide withdrawal in the neonate. American journal of obstetrics and gynecology, 124, 212-213.
  65. Kaneko, S., Otani, K., Fukushima, Y., Ogawa, Y., Nomura, Y., Ono, T., ... & Goto, M. (1988). Teratogenicity of antiepileptic drugs: analysis of possible risk factors. Epilepsia, 29(4), 459-467.
  66. Fisher, J. B., Edgren, B. E., Mammel, M. C., & Coleman, J. M. (1985). Neonatal apnea associated with maternal. clonazepam therapy: A case report. Obstetrics & Gynecology, 66(3), 36S.
  67. Czeizel, A. E., Bod, M., & Halasz, P. (1992). Evaluation of anticonvulsant drugs during pregnancy in a population-based Hungarian study. European journal of epidemiology, 8(1), 122-127.
  68. Haeusler, M. C., Hoellwarth, M. E., & Holzer, P. (1995). Paralytic ileus in a fetus–neonate after maternal intake of benzodiazepine. Prenatal diagnosis, 15(12), 1165-1167.
  69. Kriel, R. L., & Cloyd, J. (1982). Clonazepam and pregnancy. Annals of neurology, 11(5), 544-544.
  70. Calabrese, J. R., & Gulledge, A. D. (1986). Carbamazepine, clonazepam use during pregnancy. Psychosomatics, 27(6), 464.
  71. Eşkazan, E., & Aslan, S. (1992). Antiepileptic therapy and teratogenicity in Turkey. International Journal of Clinical Pharmacology, Therapy, and Toxicology, 30 (8), 261-264.
  72. Dansky, L. V. (1980). Maternal epilepsy and congenital malformations: a prospective study with monitoring of plasma anticonvulsant levels during pregnancy. Neurology, 3, 15.
  73. Weinstock, L., Cohen, L. S., Bailey, J. W., Blatman, R., & Rosenbaum, J. F. (2001). Obstetrical and neonatal outcome following clonazepam use during pregnancy: a case series. Psychotherapy and psychosomatics, 70 (3), 158-162.
  74. Johnson, K. A., Jones, K. L., Chambers, C. D., Dick, L., & Felix, R. (1995). Pregnancy outcome in women exposed to non-Valium benzodiazepines. Reproductive Toxicology, 6(9), 585.
  75. Johnson, K. A., Jones, K. L., Chambers, C. D., Dick, L., & Felix, R. (1995). Pregnancy outcome in women exposed to non-Valium benzodiazepines. Reproductive Toxicology, 6(9), 585.
  76. Gilles D, Lader M: Guide to the Use of Psychotropic Drugs. New York, Churchill Livingstone, 1986
  77. McBride, R. J., Dundee, J. W., Moore, J., Toner, W., & Howard, P. J. (1979). A study of the plasma concentrations of lorazepam in mother and neonate. British journal of anaesthesia, 51(10), 971-978.
  78. Kanto, J., Aaltonen, L., Liukko, P., & Mäenpää, K. (1980). Transfer of lorazepam and its conjugate across the human placenta. Acta pharmacologica et toxicologica, 47(2), 130-134.
  79. Whitelaw, A. G., Cummings, A. J., & McFadyen, I. R. (1981). Effect of maternal lorazepam on the neonate. Br Med J (Clin Res Ed), 282(6270), 1106-1108.
  80. Centre for International Clearinghouse for Birth Defects Surveillance and Research: Annual report 2010 with data for 2008.2010. Centre for International Clearinghouse for Birth Defects Surveillance and Research Rome, Italy).
  81. Bonnot, O., Vollset, S. E., Godet, P. F., D’Amato, T., & Robert, E. (2001). Maternal exposure to lorazepam and anal atresia in newborns: results from a hypothesis-generating study of benzodiazepines and malformations. Journal of Clinical Psychopharmacology, 21(4), 456-458.
  82. Godet, P. F., Damato, T., Dalery, J., & Robert, E. (1995). Benzodiazepines in pregnancy: analysis of 187 exposed infants drawn from a population-based birth defects registry. Reproductive Toxicology, 6(9), 585.
  83. Tinker, S. C., Reefhuis, J., Bitsko, R. H., Gilboa, S. M., Mitchell, A. A., Tran, E. L., ... & National Birth Defects Prevention Study. (2019). Use of benzodiazepine medications during pregnancy and potential risk for birth defects, National Birth Defects Prevention Study, 1997–2011. Birth defects research, 111(10), 613-620.
  84. Noh, Y., Lee, H., Choi, A., Kwon, J. S., Choe, S. A., Chae, J., ... & Shin, J. Y. (2022). First-trimester exposure to benzodiazepines and risk of congenital malformations in offspring: A population-based cohort study in South Korea. PLoS medicine, 19(3), e1003945.
  85. World Health Organization (WHO) Collaborating Centre for Drug Statistics Methodology. The anatomical therapeutic chemical (ATC) classification system and defined daily dose (DDD) index 2021. Available from: https://www.whocc.no/atc_ddd_index/.)
  86. Herd, B., & Clarke, F. (1991). Complete heart block after flumazenil. Human & experimental toxicology, 10(4), 289-289.
  87. Christensen HD, Gonzalez CL, Rayburn WF: Impact of prenatal alprazolam (Xanax N) on social play in inbred mice. Teratology 51:181–182, 1995
  88. Gonzalez C, Smith R, Christensen HD, et al: Prenatal alprazolam induces subtle impairments in hind limb balance and dexterity in C57BL/6 mice [abstract]. Teratology 49:39, 1994
  89. Garzone, P. D., & Kroboth, P. D. (1989). Pharmacokinetics of the newer benzodiazepines. Clinical pharmacokinetics, 16, 337-364.
  90. St CLAIR, S. M., & SCHIRMER, R. G. (1992). First-trimester exposure to alprazolam. Obstetrics & Gynecology, 80 (5), 843-846.
  91. Ornoy, A., Arnon, J., Shechtman, S., Moerman, L., & Lukashova, I. (1998). Is benzodiazepine use during pregnancy really teratogenic? Reproductive Toxicology, 12 (5), 511-515.
  92. Schick-Boschetto B, Zuber C: Alprazolam exposure during early human pregnancy [abstract]. Teratology 45:460, 1992
  93. Lee, H., Koh, J. W., Kim, Y. A., Chun, K. C., Han, J. Y., Hwang, J. H., ... & Kwon, H. Y. (2022). Corrigendum: Pregnancy and neonatal outcomes after exposure to Alprazolam in pregnancy. Frontiers in Pharmacology, 13, 934265.
  94. Barry, W., & Sheri, M. (1987). Exposure to benzodiazepines in utero. The Lancet, 329 (8547), 1436-1437.
  95. Tinker, S. C., Reefhuis, J., Bitsko, R. H., Gilboa, S. M., Mitchell, A. A., Tran, E. L., ... & National Birth Defects Prevention Study. (2019). Use of benzodiazepine medications during pregnancy and potential risk for birth defects, National Birth Defects Prevention Study, 1997–2011. Birth defects research, 111(10), 613-620.
  96. Reis, M., & Källén, B. (2013). Combined use of selective serotonin reuptake inhibitors and sedatives/hypnotics during pregnancy: risk of relatively severe congenital malformations or cardiac defects. A register study. BMJ open, 3(2), e002166.
  97. SHADER, R. I. (1994). Is there anything new on the use of psychotropic drugs during pregnancy?. Journal of clinical psychopharmacology, 14(6), 438.

Become an Editorial Board Member

Become a Reviewer

What our clients say

MEDIRES PUBLISHING

At our organization, we prioritize excellence in supporting the endeavors of researchers and practitioners alike. With a commitment to inclusivity and diversity, our journals eagerly accept various article types, including but not limited to Research Papers, Review Articles, Short Communications, Case Reports, Mini-Reviews, Opinions, and Letters to the Editor.

This approach ensures a rich tapestry of scholarly contributions, fostering an environment ripe for intellectual exchange and advancement."

Contact Info

MEDIRES PUBLISHING LLC,
447 Broadway, 2nd Floor, Suite #1734,
New York, 10013, United States.
Phone: +1-(302)-231-2656
Email: info@mediresonline.org