Favorable pregnancy outcomes following continual intramuscular lorazepam use in late pregnancy

Benzodiazepines are widely prescribed to women of childbearing age most commonly for anxiety and sleep disorders. Overall it is estimated that three percent of women receive benzodiazepines during pregnancy.¹ Use of benzodiazepines during pregnancy is often controversial due to conflicting studies in the literature. Early case-control studies with diazepam suggested an increased risk of cleft lips and palates with maternal benzodiazepine exposure during the first trimester.²³ Although later case-controlled studies refuted these findings.⁴ Moreover, a meta-analysis which reviewed all cohort and case-control studies looking at first trimester expose to benzodiazepines found no overall risks of congenital malformations; however pooled data from case-control studies suggested a twofold increase risk of oral clefts.⁵ Thus the potential teratogenicity of benzodiazepines expose in the first-trimester remains controversial.

In contrast, two major complications, “floppy infant syndrome” and neonatal withdrawal, have been widely reported in the literature to occur in infants exposed to benzodiazepines prior to delivery.^6–8 Features of “floppy infant syndrome” include lethargy, respiratory depression and decreased muscle tone.⁶ Infants who experience this effect usually have no difficulties recovering and have no long-term side effects. Symptoms of neonatal withdrawal include hypertonia, hyperreflexia, irritability, inconsolable crying, tremors, cyanosis, apnea, and difficulty feeding. Neonatal withdrawal has been reported to occur within a few days to three weeks after birth, depending on the benzodiazepine the infant was exposed to. Symptoms of withdrawal have been reported to last up to three months postpartum. It is therefore typically recommended that clinicians taper the mother off the benzodiazepine prior to delivery to minimize neonatal withdrawal syndrome.⁶⁹

Despite the increasing amount of literature available evaluating the risks of benzodiazepines during pregnancy, there are little published reports on continual use of parental benzodiazepines during the third trimester of pregnancy. We report a unique case in which a pregnant woman received high-dose intramuscular lorazepam during the last three weeks of pregnancy.

BRIEF PATIENT HISTORY

A 35-week pregnant female in her 20s presented to our hospital exhibiting catatonic symptoms (non-verbal, non-responsive with waxing and waning periods of agitation and inability to eat or drink) and required an involuntary admission. The patient's family reported that the patient started acting avoidant the day prior and today become non-verbal and stood in a “trance-like state” for hours. The patient had no prior psychiatric history and admission labs were unremarkable. She was only taking prenatal vitamins prior to admission and was started on lorazepam 0.5 mg orally every 6 hours in the emergency room for treatment of her catatonia. Within four hours of receiving her first dose of lorazepam 0.5 mg orally, she started to speak and requested food. However, four hours later the patient was non-responsiveness and refused medications and labs. During the next 24 hours, the patient's symptoms fluctuated between periods where the patient would speak, eat and take oral medications followed by episodes of staring, mutism, and standing for hours in one spot. On hospital day 2 the patient become agitated and was combative with staff resulting in her lorazepam being increased to 2 mg orally or intramuscularly (IM) three times a day. On hospital day 3, electroconvulsive therapy (ECT) was discussed with the patient and her family; however, at that time the patient refused ECT treatments due to concerns about her pregnancy. Risperidone 0.25 mg orally twice a day was started on hospital day 4 for suspected psychosis and her lorazepam dosage was increased to 2 mg four times a day (either orally or IM). Over the next 2 weeks (15 days) the patient's symptoms would wax and wane with gradual improvement to episodes where the patient would be non-responsive and refuse meals and medications. On hospital day 19 (three weeks prior to delivery), the patient started to refuse all medications, and thus required daily IM injections of lorazepam interchanged with oral lorazepam when the patient was cooperative with medications. Daily IM dosages ranged from 2–8 mg/day with total daily dosages of 8 mg. On hospital day 34, she was induced at term and delivered a healthy baby vaginally with no complications and with Apgar scores of 9 and 9 at 1 and 5 minutes, respectively. The infant was subsequently discharged 2 days later and no withdrawal symptoms were noted.

The patient was transferred back to the psychiatry unit the day following delivery and was started on haloperidol 5 mg orally twice daily and lorazepam 2 mg orally three times a day. After her delivery, she started to take oral medications and began talking and participating in activities. The treatment team felt the patient's final diagnosis was bipolar mood disorder, currently depressed with catatonic features and was discharged 8 days later on the following medications: divalproex extended release 1000 mg at bedtime, haloperidol 5 mg twice daily and citalopram 20 mg daily.

DISCUSSION

Management of psychiatric disorders during pregnancy is a complex clinical issue. Clinicians have to evaluate the potential fetal risk posed by medications while balancing the risk to the mother. Benzodiazepines or ECT are typically considered first-line treatment for catatonia.¹⁰ However, treatment of catatonia in pregnancy is not well-defined. EspÍnola-Nadurille et al. described a case of malignant catatonia during a second-trimester pregnancy that was successfully treated with ECT and oral lorazepam.¹¹ Symptoms of catatonia immediately improved within one hour of the patient receiving lorazepam. The patient received ten ECT treatments and maintenance lorazepam treatment. Our patient did not receive ECT since she expressed concerns about ECT treatment during pregnancy.

Although reports of neonatal withdrawal and fetal complications at time of delivery have been well- documented in the literature for benzodiazepines, there are limited data available for continual use of IM lorazepam prior to delivery. Much of the literature for parental lorazepam use during the third trimester of pregnancy derives from use for cesarian sections, labor pains, eclampsia or as a sedative.

Placental transfer of lorazepam and its inactive glucuronide metabolite has been established via umbilical cord measurements.¹² However, the extent of placental transfer appears to occur at a much slower rate and with no accumulation compared to diazepam and other benzodiazepines. Unfortunately, lorazepam's short half-life (around 12 hours) may increase the risk of neonatal withdrawal compared to other benzodiazepines.⁶

Whitelaw et al. studied the effects of parenteral lorazepam compared to oral lorazepam in neonates born to mothers who received lorazepam during labor for mild to severe hypertension.⁸ Fifty-three neonates were followed up to 5 days postpartum. No complications were observed in full-term neonates whose mothers received oral lorazepam for mild hypertension except for delays in establishing feeding. Mothers who received orally an average of 5.5 mg daily prior to delivery had the most trouble establishing feeding. In contrast, intravenous administration of lorazepam for severe hypertension produced neonatal withdrawal, low Apgar scores, hypothermia, intubation and delays in establishing feedings. However, most of the infants exposed to intravenous lorazepam were also preterm which may have contributed to some of the above symptoms. Dosages of intervenous lorazepam ranged from 1.5 mg – 4 mg/hour. Furthermore the authors found that lorazepam was slowly excreted from the newborns, with measurable lorazepam concentrations up to eight days after birth.

For our patient, we had to weigh the risks of untreated catatonia not only on the mother but also for the fetus. We also had to consider both the fetal and neonatal risks of exposure to the benzodiazepine. Since our patient responded well to lorazepam, we decided to continue its use throughout the remainder of her pregnancy. This case illustrates favorable outcomes after prenatal use of IM lorazepam. It should be noted, however, that no neonatal withdrawal scale was recorded for our infant. It is possible that our infant may have experienced minor withdrawal symptoms, which were not recorded in the chart. Even though this case illustrated no complications, use of benzodiazepines in the last trimester of pregnancy needs to be used cautiously, and furthermore use of parenteral benzodiazepines in late pregnancy should be restricted to hospitals with neonatal intensive care units.