Muscle Relaxant
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
The human pregnancy experience with baclofen is limited to 10 cases, 7 of which involved intrathecal administration. This method results in plasma concentrations 100 times less than those achieved with oral administration (1). Late onset neonatal seizures were observed in one case in which the mother was taking 80 mg/day, the maximum recommended daily oral dose. No signs of toxicity were observed in the other two pregnancies in which the mothers were taking lower oral doses. This appears to be consistent with a dose–effect relationship, because the chemical and pharmacokinetic characteristics of baclofen suggest that it will cross the placenta. Although the human data are very limited, there is no evidence of developmental toxicity from other agents in the same pharmacologic class. The animal reproduction data have reduced relevance because, in one study, the teratogenic dose also caused maternal toxicity and, in another, a comparison with the human dose was not made. However, three other studies observed no teratogenicity in mice, rats, and rabbits, so the risk appears to be low. Taken in sum, more human data are required to assess the risk to the embryo and/or fetus adequately. However, the intrathecal route is probably low risk because of the expected very low systemic exposure. If a woman requires oral baclofen, it should not be withheld because of pregnancy, but the lowest dose possible should be used and offspring should be monitored for late-onset seizures.
FETAL RISK SUMMARY
Baclofen, an analog of γ-aminobutyric acid, is a centrally acting skeletal muscle relaxant. Although their specific mechanisms of action may differ, baclofen is in the same class of centrally acting skeletal muscle relaxants as carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, orphenadrine, and tizanidine. Plasma protein binding is only about 30%, and 70%–80% of the drug is excreted unchanged in the urine. The plasma elimination half-life is 3–4 hours, whereas the elimination half-life in the cerebrospinal fluid is 1–5 hours. The maximum recommended daily oral dose is 80 mg (1,2). Because of its specialized indication to control spasticity secondary to multiple sclerosis and other spinal cord diseases and injuries, its use in pregnancy is anticipated to be limited.
Reproduction studies have been conducted in pregnant rats, mice, and rabbits. In rats, a maternal toxic (decreased food intake and weight gain) dose approximately 3 times the maximum recommended human dose based on BSA was associated with an increased incidence of omphalocele (ventral hernias) in fetuses. This defect was not observed in mice and rabbits (1). Shepard reviewed three studies involving rats, mice, and rabbits in which the drug was administered during organogenesis and all reported negative teratogenic findings (3). In contrast, in a 1995 study of pregnant rats that administered 30- or 60-mg/kg doses, vertebral arch widening was observed on day 10 of gestation at the lower dose, similar to that produced by valproic acid in rats (4). The author concluded that baclofen could produce spina bifida or other neural tube defects in rats. Interestingly, the 60-mg/kg dose did not produce this effect, causing speculation that the dose caused a greater severity of neural tube defects, and thus a greater number of unrecorded early fetal deaths (4).
It is not known if baclofen crosses the human placenta. The molecular weight (about 214), low plasma protein binding and metabolism, and the plasma elimination half-life suggest that the drug will cross to the embryo and fetus.
Six reports involving seven pregnancies have been published in which a continuous intrathecal infusion of baclofen was administered via an implanted pump in six and intrathecal bolus dose in one (5–10). The first case involved a 29-year-old woman with quadriplegia who was treated with 1000 mcg/day for 15 months to control her intractable spasticity (5). Conception occurred after ovulation stimulation with clomiphene. The baclofen dose was gradually increased to 1200 mcg/day to maintain control of her spasticity as the pregnancy progressed. Because of severe symptoms of autonomic dysfunction and loss of spasticity control (even at 1400 mcg/day), a cesarean section was performed under epidural bupivacaine anesthesia during the 35th week of gestation. A 2.04-kg healthy female infant was delivered with Apgar scores of 9 and 10, presumably at 1 and 5 minutes, respectively (5).
The second and third cases, both involving the same woman, were published in 2000 (6). A 38-year-old woman became pregnant after approximately 3.5 years of continuous intrathecal baclofen infusion to control severe spasticity resulting from a complete 5th cervical vertebra (C5)–level medullar injury. Good control of her spasticity was obtained with 140 mcg/day throughout her pregnancy. A healthy, 2.155-kg male infant was delivered by cesarean section at 36 weeks’ gestation with Apgar scores of 9 and 10 at 1 and 5 minutes, respectively. The birth weight, length (47 cm), and head circumference (33 cm) were appropriate for gestational age. No major or minor malformations were noted on physical and ultrasonography examinations, and the child was developing normally at 24 months of age (6). Three months after delivery of her first infant, the woman became pregnant a second time while receiving 140 mcg/day throughout gestation. A cesarean section was performed at 34 weeks with delivery of a healthy, 2.24-kg male infant with Apgar scores of 8 and 10 at 1 and 5 minutes, respectively. The weight, length (46 cm), and head circumference (32 cm) were appropriate for gestational age. No abnormalities were noted in the infant, and he was developing normally at 12 months of age (6).
A 17-year-old woman, 27 weeks pregnant, presented with clinical symptoms and signs of severe tetanus (7). She was treated with intrathecal bolus doses of baclofen for 21 days to control her muscular contractures and paroxysms. The mean daily dose was 1350 mcg (range 250–1500 mcg).
She also received a continuous IV infusion of diazepam 20–200 mg/day. Diazepam was stopped at about 32 weeks’ gestation, 3 days before the onset of spontaneous labor. A healthy 1.50-kg male infant was delivered with an Apgar score of 10 at 5 minutes. The infant had no muscular weakness or evidence of respiratory or neurologic distress. The infant was discharged home with his mother at 9 days of age (7).
A 23-year-old paraplegic woman at 30 weeks’ gestation was started on intrathecal baclofen for increasing spasticity and spasticity-related pain (8). An infusion pump was implanted under general anesthesia with an initial dose of 150 mcg/day. Over the following 6 weeks, the infusion dose required to control her spasms increased to 375 mcg/day. Labor was induced at 37 weeks’ gestation, and she gave birth to a healthy 2.81-kg female infant. The child was developing normally at 2 years of age (8).
A 2008 report described a 38-year-old woman with multiple sclerosis complicated by spasticity (9). The spasticity was treated with intrathecal baclofen 202.6 mcg/day throughout gestation. Because of spontaneous rupture of the membranes and a transverse lie at 36 5/7 weeks, a healthy 2.68-kg male infant was delivered by cesarean section. Apgar scores were 9 and 10, presumably at 1 and 5 minutes, respectively. No follow-up of the infant was reported (9). In a similar case, but in which intrathecal baclofen (dose not reported) was used throughout gestation to control spasticity secondary to cerebral palsy, a 28-year-old woman gave birth at 38 weeks to a healthy 3.30-kg infant (sex not specified) (10). Apgar scores were 9 and 10 at 1 and 5 minutes, respectively. At 1-year follow-up, the infant was doing well.
A 2001 case report described a paraplegic woman who had used baclofen 80 mg/day (the maximum recommended daily oral dose), oxybutynin 9 mg/day, and trimethoprim 100 mg/day throughout an uneventful pregnancy (11). The fetus developed tachycardia at an unspecified gestational age and an apparently healthy female infant was delivered (birth weight not given). Apgar scores were 10 at 1 and 5 minutes. At 7 days of age, the infant was admitted to the hospital for generalized seizures, but the mother had noted abnormal movements 2 days after birth. All diagnostic test results were negative and the seizures did not respond to phenytoin, phenobarbital, clonazepam, lidocaine, or pyridoxine. Because seizures had been reported in adults after abrupt withdrawal of baclofen, a dose of 1 mg/kg divided into four daily doses was started and the seizures stopped 30 minutes after the first dose. Baclofen was slowly tapered and then discontinued after 2 weeks. Magnetic resonance imaging of the infant’s brain on day 17 suggested a short hypoxic ischemic insult that was thought to have been secondary to the seizures (11).
A 41-year-old woman with stiff-limb syndrome was treated with oral baclofen and diazepam throughout an uncomplicated pregnancy (12). The dose of baclofen during the 1st trimester was 100 mg/day (i.e., >maximum recommended dose), whereas the diazepam dose was 60 mg/day. She was able to reduce the dose of the two drugs to 25 and 15 mg/day, respectively, from the 2nd trimester onward. Despite a birth complicated by fetal distress requiring assisted forceps delivery, the apparently healthy female infant had no evidence of sedation or withdrawal and remained well during breastfeeding. No other details regarding the infant were provided (12).
A 27-year-old woman was diagnosed about 2 months before pregnancy with stiff person syndrome (Moersche-Woltman syndrome) (13). She was treated with gabapentin (2700 mg/day), diazepam (30 mg/day), and a prednisone taper. When pregnancy was diagnosed, diazepam was discontinued but, without the drug, her muscle spasms increased and baclofen (30 mg/day) was started. The patient was able to wean down her medications in the 2nd and 3rd trimesters (specific details not provided). Labor commenced at about 40 weeks while still on gabapentin and baclofen. A cesarean section was conducted because of fetal repetitive late decelerations to deliver a 3230-g female infant with Apgar scores of 5 and 8 at 1 and 5 minutes, respectively. The infant, discharged home on day 4, was doing well (age assumed to be 6 weeks) (13).
A 2004 report described the pregnancy outcome of a 38-year-old woman with reflex sympathetic dystrophy who was treated throughout gestation with baclofen 20 mg/day, clonazepam 2 mg/day, and oxycodone 50 mg/day in divided doses (14). A 3.71-kg female infant was delivered by cesarean section at 39 2/7 weeks’ gestation because of breech presentation and maternal health considerations. The baclofen concentration in cord blood was below the level of quantitation (0.08 mcg/mL), but the interval between the last dose and birth was not specified. The infant developed transient respiratory distress shortly after birth that was attributed to retained lung fluid. Oral baclofen 0.5 mg/kg/day in four divided doses was started shortly after birth and tapered over 9 days. Although no seizure activity was observed, phenobarbital was started on day 2 because of narcotic withdrawal symptoms. On day 16 of life, the infant was discharged home on low-dose phenobarbital. Neurologic examination results were normal at discharge and at 6 weeks (14).
BREASTFEEDING SUMMARY
In an animal study, the γ-aminobutyric acid agonist, baclofen, was a potent inhibitor of suckling-induced prolactin release from the anterior pituitary (15). The drug had no effect on milk ejection. Because prolactin release is required to maintain lactation, the potential for decreased milk production with chronic use may exist. However, no human studies on this topic have been located.
Small amounts of baclofen are excreted into human milk after oral administration. A 20-year-old woman with spastic paraplegia, who was 14 days postpartum, was given a single 20-mg (94 microM) oral dose of baclofen (16). No mention was made as to whether her infant was nursing. Serum samples were drawn at 1, 3, 6, and 20 hours after the dose, and milk samples were obtained at 2, 4, 8, 14, 20, and 26 hours. The highest serum concentration measured, 1.419 microM/L, occurred at 3 hours, whereas the highest milk level, 0.608 microM/L, was obtained at 4 hours. The total amount of drug recovered from the milk during the 26-hour sampling period was 22 mcg (0.10 microM), or about 0.1% of the mother’s dose. The authors speculated that this amount would not lead to toxic levels in a nursing infant (16).
The American Academy of Pediatrics classifies baclofen as compatible with breastfeeding (17).
References
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