oursto several months depending on the degree of dependence and the pharmacokinetic profile ofthe benzodiazepine.
Symptoms may be mild and transient or severe. Standard managementfor neonatal withdrawal syndrome has not yet been defined. Observe newborns who are
exposed to NAYZILAM in utero during the later stages of pregnancy for symptoms of
withdrawal and manage accordingly.
Labor and Delivery
Administration of benzodiazepines immediately prior to or during childbirth can result in afloppy infant syndrome, which is characterized by lethargy, hypothermia, hypotonia,respiratory depression, and difficulty feeding. Floppy infant syndrome occurs mainly withinthe first hours after birth and may last up to 14 days. Observe exposed newborns for thesesymptoms and manage accordingly.
Data
Human Data
Congenital Anomalies
Although there are no adequate and well-controlled studies of NAYZILAM in pregnantwomen, there is information about benzodiazepines as a class. Dolovich et al. published ameta-analysis of 23 studies that examined the effects of benzodiazepine exposure during thefirst trimester of pregnancy. Eleven of the 23 studies included in the meta-analysis consideredthe use of chlordiazepoxide and diazepam and not other benzodiazepines.
The authorsconsidered case-control and cohort studies separately. The data from the cohort studies didnot suggest an increased risk for major malformations (OR 0.90; 95% CI 0.61—1.35) or fororal cleft (OR 1.19; 95% CI 0.34—4.15). The data from the case-control studies suggested anassociation between benzodiazepines and major malformations (OR 3.01, 95% CI 1.32—6.84) and oral cleft (OR 1.79; 95% CI 1.13—2.82). The limitations of this meta-analysisincluded the small number of reports included in the analysis, and that most cases foranalyses of both oral cleft and major malformations came from only three studies. A followup to that meta-analysis included 3 new cohort studies that examined risk for majormalformations and one study that considered cardiac malformations. The authors found nonew studies with an outcome of oral clefts. After the addition of the new studies, the oddsratio for major malformations with first trimester exposure to benzodiazepines was 1.07
(95% CI 0.91—1.25).
Neonatal Withdrawal and Floppy Infant SyndromeNeonatal withdrawal syndrome and symptoms suggestive of floppy infant syndromeassociated with administration of benzodiazepines during the later stages of pregnancy andperipartum period have been reported. Findings in published scientific literature suggest thatthe major neonatal side effects of benzodiazepines include sedation and dependence withwithdrawal signs. Data from observational studies suggest that fetal exposure tobenzodiazepines is associated with the neonatal adverse events of hypotonia, respiratoryproblems, hypoventilation, low Apgar score, and neonatal withdrawal syndrome.
Animal DataWhen midazolam (0, 0.2, 1, or 4 mg/kg/day) was administered intravenously to pregnant ratsduring the period of organogenesis, no adverse effects on embryofetal development wereobserved. The highest dose tested, which was associated with minimal evidence of maternaltoxicity, is approximately 4 times the maximum recommended human dose (MRHD) of 10mg based on body surface area (mg/m2).
When midazolam (0, 0.2, 0.6, and 2 mg/kg/day) was administered intravenously to rabbitsduring the period of organogenesis, no |
