Pregnancy Registry   
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as clobazam, during pregnancy. Physicians are advised to recommend that pregnant patients taking clobazam enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. 

Risk Summary   
There are no adequate and well-controlled studies of clobazam in pregnant women. Available data suggest that the class of benzodiazepines is not associated with marked increases in risk for congenital anomalies. Although some early epidemiological studies suggested a relationship between benzodiazepine drug use in pregnancy and congenital anomalies such as cleft lip and/or palate, these studies had considerable limitations. More recently completed studies of benzodiazepine use in pregnancy have not consistently documented elevated risks for specific congenital anomalies. There is insufficient evidence to assess the effect of benzodiazepine pregnancy exposure on neurodevelopment.   
  
There are clinical considerations regarding exposure to benzodiazepines during the second and third trimester of pregnancy or immediately prior to or during childbirth. These risks include decreased fetal movement and/or fetal heart rate variability, “floppy infant syndrome,” dependence, and withdrawal [ see Clinical Considerations and Human Data].   
  
Administration of clobazam to pregnant rats and rabbits during the period of organogenesis or to rats throughout pregnancy and lactation resulted in developmental toxicity, including increased incidences of fetal malformations and mortality, at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those expected at therapeutic doses in patients [ see Animal Data]. Data for other benzodiazepines suggest the possibility of long-term effects on neurobehavioral and immunological function in animals following prenatal exposure to benzodiazepines at clinically relevant doses. Clobazam should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Advise a pregnant woman and women of childbearing age of the potential risk to a fetus.   
  
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. 

Clinical Considerations   
Fetal/Neonatal Adverse Reactions   
Infants born to mothers who have taken benzodiazepines during the later stages of pregnancy can develop dependence, and subsequently withdrawal, during the postnatal period. Clinical manifestations of withdrawal or neonatal abstinence syndrome may include hypertonia, hyperreflexia, hypoventilation, irritability, tremors, diarrhea, and vomiting. These complications can appear shortly after delivery to 3 weeks after birth and persist from hours to several months depending on the degree of dependence and the pharmacokinetic profile of the benzodiazepine. Symptoms may be mild and transient or severe. Standard management for neonatal withdrawal syndrome has not yet been defined. Observe newborns who are exposed to clobazam 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 a floppy infant syndrome, which is characterized by lethargy, hypothermia, hypotonia, respiratory depression, and difficulty feeding. Floppy infant syndrome occurs mainly within the first hours after birth and may last up to 14 days. Observe exposed newborns for these symptoms and manage accordingly. 

Data   
Human Data    
Congenital Anomalies    
Although there are no adequate and well controlled studies of clobazam in pregnant women, there is information about benzodiazepines as a class. Dolovich et al. published a meta-analysis of 23 studies that examined the effects of benzodiazepine exposure during the first trimester of pregnancy. Eleven of the 23 studies included in the meta-analysis considered the use of chlordiazepoxide and diazepam and not other benzodiazepines. The authors considered case-control and cohort studies separately. The data from the cohort studies did not suggest an increased risk for major malformations (OR 0.90; 95% CI 0.61 to 1.35) or for oral cleft (OR 1.19; 95% CI 0.34 to 4.15). The data from the case-control studies suggested an association between benzodiazepines and major malformations (OR 3.01; 95% CI 1.32 to 6.84) and oral cleft (OR 1.79; 95% CI 1.13 to 2.82). The limitations of this meta-analysis included the small number of reports included in the analysis, and that most cases for analyses of both oral cleft and major malformations came from only three studies. A follow up to that meta-analysis included 3 new cohort studies that examined risk for major malformations and one study that considered cardiac malformations. The authors found no new studies with an outcome of oral clefts. After the addition of the new studies, the odds ratio for major malformations with first trimester exposure to benzodiazepines was 1.07 (95% CI 0.91 to 1.25). 

Neonatal Withdrawal and Floppy Infant Syndrome   
Neonatal withdrawal syndrome and symptoms suggestive of floppy infant syndrome associated with administration of clobazam during the later stages of pregnancy and peripartum period have been reported in the postmarketing experience. Findings in published scientific literature suggest that the major neonatal side effects of benzodiazepines include sedation and dependence with withdrawal signs. Data from observational studies suggest that fetal exposure to benzodiazepines is associated with the neonatal adverse events of hypotonia, respiratory problems, hypoventilation, low Apgar score, and neonatal withdrawal syndrome. 

Animal Data   
In a study in which clobazam (0, 150, 450, or 750 mg/kg/day) was orally administered to pregnant rats throughout the period of organogenesis, embryofetal mortality and incidences of fetal skeletal variations were increased at all doses. The low-effect dose for embryofetal developmental toxicity in rats (150 mg/kg/day) was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, lower than those in humans at the maximum recommended human dose (MRHD) of 40 mg/day. 

Oral administration of clobazam (0, 10, 30, or 75 mg/kg/day) to pregnant rabbits throughout the period of organogenesis resulted in decreased fetal body weights, and increased incidences of fetal malformations (visceral and skeletal) at the mid and high doses, and an increase in embryofetal mortality at the high dose. Incidences of fetal variations were increased at all doses. The highest dose tested was associated with maternal toxicity (ataxia and decreased activity). The low-effect dose for embryofetal developmental toxicity in rabbits (10 mg/kg/day) was associated with plasma exposures for clobazam and N-desmethylclobazam lower than those in humans at the MRHD.

Oral administration of clobazam (0, 50, 350, or 750 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased embryofetal mortality at the high dose, decreased pup survival at the mid and high doses and alterations in offspring behavior (locomotor activity) at all doses. The low-effect dose for adverse effects on pre- and postnatal development in rats (50 mg/kg/day) was associated with plasma exposures for clobazam and N-desmethylclobazam lower than those in humans at the MRHD.