Diazepam in Pregnancy and Breastfeeding
Fetal Risk Summary
Six studies on the reproductive effects of the benzodiazepine, diazepam, in rats and mice were reviewed by Shepard in 1989 (1). Cleft palates in mice and delayed neurobehavior development and postnatal malignancies in rats were the only adverse effects noted (1).
Diazepam and its metabolite, desmethyldiazepam, freely cross the placenta and accumulate in the fetal circulation with newborn levels about 1 to 3 times greater than maternal serum levels (2,3,4,5,6,7,8,9,10,11,12 and 13). Transfer across the placenta has been demonstrated as early as 6 weeks' gestation (12). Of interest, fetal drug levels were independent of maternal serum concentrations and time from drug administration to sampling. These data suggest that diazepam accumulates in the fetal circulation and tissues during organogenesis (12). At term, equilibrium between mother and fetus occurs in 510 minutes after IV administration (11). The maternal and fetal serum binding capacity for diazepam is reduced in pregnancy and is not correlated with albumin (14,15). The plasma half-life in newborns is significantly increased due to a decreased clearance of the drug. Because the transplacental passage is rapid at term, timing of the IV administration with uterine contractions will greatly reduce the amount of drug transferred to the fetus (7).
In a case of gross overdose, a mother who took 580 mg of diazepam as a single dose on about the 43rd day of gestation delivered an infant with cleft lip and palate, craniofacial asymmetry, ocular hypertelorism, and bilateral periauricular tags (16). The authors concluded that the drug ingestion was responsible for the defects. An association between diazepam and an increased risk of cleft lip or palate has been suggested by several studies (17,18,19 and 20). The findings indicated that 1st or 2nd trimester use of diazepam, and selected other drugs, is significantly greater among mothers of children born with oral clefts. However, a review of these studies, published in 1976, concluded that a causal relationship between diazepam and oral clefts had not yet been established, but even if it had, the actual risk was only 0.2% for cleft palate and only 0.4% for cleft lip with or without cleft palate (21). In addition, large retrospective studies showing no association between diazepam and cleft lip/palate have been published (22,23,24 and 25). The results of one of these studies has been criticized and defended (26,27). Although no association was found with cleft lip/palate, a statistically significant association was discovered between diazepam and inguinal hernia (27). This same association, along with others, was found in another investigation (28).
In 1,427 malformed newborns compared to 3,001 controls, 1st trimester use of tranquilizers (diazepam most common) was associated with inguinal hernia, cardiac defects, and pyloric stenosis (28). Second trimester exposure was associated with hemangiomas and cardiac and circulatory defects. The combination of cigarette smoking and tranquilizer use increased the risk of delivering a malformed infant by 3.7-fold as compared to those who smoked but did not use tranquilizers (28). A survey of 390 infants with congenital heart disease matched with 1,254 normal infants found a higher rate of exposure to several drugs, including diazepam, in the offspring with defects (29). Other congenital anomalies reported in infants exposed to diazepam include absence of both thumbs (two cases), spina bifida (one case), and absence of left forearm and syndactyly (one case) (30,31 and 32). Any relationship between diazepam and these defects is unknown.
A 1989 report described dysmorphic features, growth retardation, and central nervous system defects in eight infants exposed either to diazepam, 30 mg/day or more, or oxazepam, 75 mg/day or more throughout gestation (33). Three of the mothers denied use of drugs during pregnancy, but diazepam and its metabolite were demonstrated in their plasma in early pregnancy. The mothers did not use alcohol or street drugs, had regular prenatal care, and had no record of criminality or prostitution. The mean birth weight of the infants was 1.2 standard deviations below the Swedish average, only one having a weight above the mean, and one was small for gestational age. Six of the newborns had low Apgar scores primarily due to apnea, five needed resuscitation, all were hypotonic at birth, and all had neonatal drug withdrawal with episodes of opisthotonos and convulsions. Seven of the eight infants had feeding difficulties caused by a lack of rooting and sucking reflexes. Craniofacial defects observed in the infants (number of infants with defect shown in parenthesis) were short nose with low nasal bridge (six), uptilted nose (six), slanted eyes (eight), epicanthic folds (eight), telecanthus (two), long eyelashes (three), highly arched palate (four), cleft hard palate and bifid uvula (two), low-set/abnormal ears (four), webbed neck (three), flat upper lip (five), full lips (four), hypoplastic mandible (five), and microcephaly (two). Other defects present were small, wide-spaced nipples (two), renal defect (one), inguinal hernia (two), and cryptorchidism (two). An infant with severe psychomotor retardation died of possible sudden infant death syndrome at 11 weeks of age. Microscopic examination of the brain demonstrated slight cortical dysplasia and an increased number of single-cell neuronal heterotopias in the white matter. Six other children had varying degrees of mental retardation, some had severely disturbed visual perception, all had gross motor disability, and hyperactivity and attention deficits were common. Extensive special examinations were conducted to identify other possible etiologies, but the only common factor in the eight cases was maternal consumption of benzodiazepines (33). Based on the apparent lack of other causes, the investigators concluded that the clinical characteristics observed in the infants probably represented a teratogenic syndrome due to benzodiazepines.
A 1992 study reported on heavy benzodiazepine exposure during pregnancy from Michigan Medicaid data collected during 1980 to 1983 (34). Of the 2,048 women, from a total sample of 104,339, who had received benzodiazepines, 80 had received 10 or more prescriptions for these agents. The records of these 80 women indicated frequent alcohol and substance abuse. Their pregnancy outcomes were three intrauterine deaths, two neonatal deaths in infants with congenital malformations, and 64 survivors. The outcome for 11 infants was unknown. Six of the 64 surviving infants had diagnoses consistent with congenital defects and neurological abnormalities. No cases of oral clefts were found in 1,354 1st trimester benzodiazepine exposures. The investigators concluded that the high rate of congenital anomalies was suggestive of multiple alcohol and substance abuse and may not have been related to benzodiazepine exposure. However, subtle defects, developmental abnormalities, and retardations may not have been included in the records (34).
A 1992 letter correspondence suggested that the Mbius syndrome observed in a 3-week-old infant was the result of in utero exposure to benzodiazepines (diazepam and oxazepam) (35). The mother had been treated for hypertension starting at 16 weeks' gestation with methyldopa. Diazepam (20 mg/day) was added at 25 weeks,' and shortly thereafter, hyoscine butylbromide, oxazepam (20 mg/day), and ritodrine were added. The infant had normal weight, length, and head circumference but was markedly hypotonic at birth. In addition to an expressionless face, malformations observed were epicanthal folds, short palpebral fissures, convergent strabismus, low nasal bridge, short upturned nose, hypertelorism, and high arched palate (35). An electromyogram confirmed bilateral cranial nerve VII palsy. The authors speculated that the Mbius syndrome and the strabismus were caused by the benzodiazepine therapy based on previous reports. At least one mechanism of Mbius syndrome (VI and VII nerve palsy), however, was thought to be a result of mechanical trauma induced by uterine contractions early in gestation that results in ischemia in the cranial nuclei VI and VII (see Shepard, 1995, in Misoprostol).
The pregnancy outcomes of five women who had attempted suicide with diazepam combined with other drugs early in gestation were described in a 1997 report (36). The gestational ages when the overdoses occurred were 34 weeks and the diazepam doses ranged from 90200 mg. All five of the infants were delivered at term and, except for an infant with bilateral undescended testis, were normal. The undescended testis were not thought to have been related to the self-poisoning (36).
A meta-analysis of cohort and case-control studies involving the association of 1st trimester exposure to benzodiazepines and major malformations was published in 1998 (37). Analysis of nine cohort studies (nonepileptic patients) showed no relationship to major malformations (odds ratio [OR] 0.90, 95% confidence interval [CI] 0.611.35) or to oral clefts (OR 1.19, 95% CI 0.344.15). Two cohort studies involving epileptic patients were also negative. In contrast, pooled data from nine case-control studies showed an association with major defects (OR 3.01, 95% CI 1.326.84) or to oral clefts alone (OR 1.79, 95% CI 1.132.82) (37). In correspondence concerning this study, objections were raised as to the exclusion of certain studies and to the statistical methods used (38,39 and 40).
Another 1998 study described the outcomes of 460 pregnancies (subjects) exposed to benzodiazepines, 98% during the 1st trimester, compared to 424 control pregnancies (41). Subjects and controls had called the Israeli Teratogen Information Service concerning either exposure to benzodiazepines (subjects) or various other nonteratogenic exposures (controls). Diazepam was used by 89 women, but several subjects in the total group used more than one type of benzodiazepine. Subjects were older (31.7 vs. 29.4 years, p=0.001) and called earlier in pregnancy (10.3 vs. 12.9 weeks', p=0.001) than controls. There were also more spontaneous and induced abortions in subjects, 8.7% vs. 5.2% p=0.047 and 14.1% vs. 4.7% p=0.001, respectively. None of the induced abortions involved major congenital defects. The higher rates of spontaneous and induced abortions were thought to be related to the lower gestational ages at calling and to the counseling of the callers, respectively (41). The gestational ages and birth weights of the two groups were similar. Major malformations were observed in 11 of the 355 subject live births (3.1%) and in 10 of 382 control live births (2.6%) (ns). The birth defects in infants of subjects were four cases of congenital heart disease (ventricular septal defect, pulmonic stenosis, and two unspecified with one neonatal death; carbamazepine used in two cases), two cases of polydactyly, two cases of hydronephrosis, and one each of esophageal atresia, cerebral palsy, and Down's syndrome (41).
Several investigators have observed that the use of diazepam during labor is not harmful to the mother or her infant (42,43,44,45,46,47,48 and 49). A dose response is likely as the frequency of newborn complications rises when doses exceed 3040 mg or when diazepam is taken for extended periods, allowing accumulation to occur (50,51,52,53,54,55 and 56). Two major syndromes of neonatal complications have been observed:
\tFloppy infant syndrome:
- Hypotonia \t
- Lethargy \t
- Sucking difficulties
- Intrauterine growth retardation \t
- Tremors \t
- Irritability \t
- Hypertonicity \t
- Diarrhea/vomiting \t
- Vigorous sucking
Under miscellaneous effects, diazepam may alter thermogenesis, cause loss of beat-to-beat variability in the fetal heart rate, and decrease fetal movements (33,57,58,59,60,61 and 62).
In summary, the effects of benzodiazepines, including diazepam, on the human embryo and fetus are controversial. Although a number of studies have reported an association with various types of congenital defects, other studies have not found such associations. Maternal denial of exposure, as reported in one study, and the concurrent exposure to other toxic drugs and substances (e.g., alcohol and smoking) may be confounding factors. However, the risk appears to be low, if indeed diazepam and the other agents do cause birth defects. Continuous use during gestation has resulted in neonatal withdrawal and a dose-related syndrome is apparent if diazepam is used close to delivery. Consequently, if the maternal condition requires the use of diazepam during pregnancy, the lowest possible dose should be taken. Moreover, abrupt discontinuance of benzodiazepines should be avoided. Severe withdrawal symptoms (physical and psychological) may occur in the mother and, in some cases, result in the substitution of other substances (e.g., alcohol) to treat the symptoms (63). Fetal withdrawal, such as that observed with narcotics, has not been reported, but should be considered.
Breast Feeding Summary
Diazepam and its metabolite, n-demethyldiazepam, enter breast milk (61,62,64,65,66,67,68 and 69). Lethargy and loss of weight have been reported (67,69). Milk:plasma ratios varied between 0.2 and 2.7 (66).
A mother who took 610 mg daily throughout pregnancy delivered a full-term, normally developed male infant (69). The infant was breast-fed and the mother continued to take her diazepam. Sedation was noted in the infant if nursing occurred less than 8 hours after taking a dose. Paired samples of maternal serum and breast milk were obtained on five occasions between 1 and 4 months after delivery. Milk concentrations of diazepam and desmethyldiazepam varied between 7.5 and 87 ng/mL and 19.2 and 77 ng/mL, respectively. The milk:serum ratios for diazepam varied between 0.14 and 0.21 in four samples but was 1.0 in one sample. The ratio for desmethyldiazepam varied from 0.10 to 0.18 in four samples and was 0.53 in the sample with the high diazepam ratio. A serum level was drawn from the infant on one occasion, revealing levels of diazepam and the metabolite of 0.7 and 46 ng/mL, respectively (69).
Diazepam may accumulate in breast-fed infants, and its use in lactating women is not recommended. The American Academy of Pediatrics considers the effects of diazepam on the nursing infant to be unknown, but they may be of concern (70).
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