Abstract
BACKGROUND:
Pregnant women with spinal cord injuries are often advised to continue oral baclofen during pregnancy to manage spasticity, though the potential for adverse events in neonates is not well understood.
OBJECTIVE:
Here, a case is described in which a male neonate with intrauterine baclofen exposure, born at 34 3/7 weeks via Cesarean section, demonstrated a two-minute episode of extensor posturing at fifteen minutes of life possibly concerning for baclofen withdrawal. His mother had taken baclofen 30 milligrams orally four times per day throughout pregnancy for management of spasticity associated with a remote cervical spinal cord injury. Due to concern for possible withdrawal, the neonate was started on a baclofen taper beginning within hours of birth while evaluation for alterative etiologies was underway. Symptoms were monitored using the Finnegan Neonatal Abstinence Scale. The neonate tolerated the baclofen taper well and was successfully tapered off by the fourteenth day of life with full resolution of symptoms and no apparent neurologic deficits.
CONCLUSION:
Further research is needed to assess the incidence of neonatal baclofen withdrawal with regard to maternal dosage and route of administration, and to determine the most appropriate monitoring and management protocols for the neonate.
Keywords
Introduction
Baclofen is a derivative of the neurotransmitter gamma-aminobutyric acid (GABA) that acts as an agonist on GABA-B sites to reduce muscle spasticity [1]. It is commonly used for the treatment of spasticity resulting from conditions including spinal cord injury [2]. There are approximately 291,000 individuals in the United States with Spinal Cord Injuries (SCI), and women with SCI aged 18–49 years report current pregnancy rates comparable to their able-bodied peers [3, 4]. Consequently, many women require ongoing treatment of spasticity throughout pregnancy. Unfortunately, limited data exist on baclofen use in human pregnancy. However, there have been animal studies that demonstrated evidence of potential harm to fetuses at doses above those recommended for humans. Given this information, baclofen should be used during pregnancy only if the potential maternal benefit justifies the potential risk to the fetus [5, 6].
The potential for baclofen withdrawal is well recognized in individuals treated with oral or intrathecal baclofen. Abrupt cessation of baclofen can be potentially life threatening and can lead to with-drawal symptoms including spasticity, rigidity, hallucinations, seizures, tachycardia, hyperthermia, and hypertension [5, 6]. However, the potential for neonatal baclofen withdrawal may be overlooked when maternal baclofen is continued throughout pregnancy. While intrathecal baclofen use during pregnancy has been described in multiple case reports without noted adverse events in neonates [7–12], there are a limited number of case reports that highlight the effects of intrauterine baclofen exposure and potential for neonatal withdrawal when maternal baclofen is administered orally [2, 13–16]. To the authors’ knowledge, there are five such cases reported in the literature which are summarized in Table 1. In these cases, there were concerns for neonatal baclofen withdrawal when maternal oral baclofen ranged from 10 milligrams two times daily to 40 milligrams four times daily throughout pregnancy. All five neonates were started on baclofen tapers lasting approximately one-and-a-half to three weeks in duration with subsequent improvement in symptoms. The case report here describes the assessment and management of an additional neonate who presented with an episode of extensor posturing at fifteen minutes of life possibly concerning for baclofen withdrawal in a pregnancy complicated by maternal oral baclofen use.
Summary of the five case reports in the literature of neonatal baclofen withdrawal following pregnancies complicated by maternal oral baclofen administration
Summary of the five case reports in the literature of neonatal baclofen withdrawal following pregnancies complicated by maternal oral baclofen administration
A 2.4 kg male neonate was born to a 30-year-old gravida two para zero female at 34 3/7 weeks via Cesarean section due to maternal hypertension and muscle spasms in the setting of autonomic dysreflexia along with breech presentation. Given the concern that ongoing maternal uterine contractions would result in recurrent episodes of autonomic dysreflexia, the decision was made to deliver the neonate despite his prematurity. Apgar scores were 3, 5, and 8 at 1, 5, and 10 minutes respectively. The neonate had a weak cry at delivery, and after one minute of delayed cord clamping he was noted to be apneic with poor tone, but with heart rate greater than 100 beats per minute. Arterial cord blood gas indicated a pH of 7.02, pCO2 of 51.90, pO2 of 10.9, and HCO3 of 12.6. During initial resuscitation efforts, his heart rate temporarily dropped below 100 beats per minute and decreased oxygen saturations were noted. Following initiation of positive pressure ventilation, mask repositioning, and performance of deep suctioning, his respiratory status improved. By six minutes of life, the neonate was breathing on his own, though he remained on continuous positive airway pressure due to ongoing retractions and nasal flaring. At fifteen minutes of life, the neonate had a two-minute episode of posturing with extended arms and legs. In reviewing his medical history, the pregnancy had been notable for maternal oral baclofen (30 milligrams four times daily; last dose had been in the evening on the day prior to delivery) and oral diazepam (2.5 milligrams daily as needed) for spasticity associated with a remote cervical spinal cord injury. Other maternal medications included oxybutynin 5 milligrams daily, bupropion 300 milligrams daily, escitalopram 10 milligrams daily, and midodrine 5 milligrams daily. Given the concern for possible neonatal baclofen withdrawal, the pediatric neurology and pediatric physical medicine and rehabilitation teams were consulted for recommendations shortly after his birth. He underwent long term electroencephalogram monitoring without any identified seizures. Cranial ultrasound did not indicate any evidence of intraventricular or intraparenchymal hemorrhage, or evidence of ventricular dilatation. Ultrasound of the spinal cord was also unremarkable. A workup to evaluate for an infectious etiology was also unremarkable. Given that no other potential etiologies were identified, the neonate’s presentation was presumed to be consistent with baclofen withdrawal pending ongoing further medical workup.
After discussion between the pediatric physical medicine and rehabilitation and pharmacy teams, the decision was made to empirically start the neonate on a baclofen taper while the workup for alternative etiologies was underway. Within nine hours of his birth, the neonate was started on oral baclofen 0.125 milligrams/kilogram/dose every six hours with the goal of tapering this medication gradually over approximately two weeks. During this time, he was monitored for ongoing withdrawal signs and symptoms using the Finnegan Neonatal Abstinence Scale [17]. Scores ranged from zero to six due to mild tremors, regurgitation, poor feeding, sneezing, impaired sleep, fever, and a hyperactive Moro Reflex. Notably, the Finnegan Neonatal Abstinence Scale scores remained below clinically relevant thresholds for the entire duration of the taper. The dose of baclofen was weaned every three to four days by increasing the dosing interval, with the specific taper plan outlined in Table 2. The neonate’s withdrawal signs and symptoms gradually improved during this time and were consistently zero by day of life (DOL) nine. He remained admitted for monitoring until DOL fourteen due to concern for possible baclofen withdrawal and prematurity. During this time, no alterative explanations for his two-minute episode of posturing were identified. His baclofen was successfully discontinued on DOL fourteen with full resolution of symptoms. Although he had a General Movements Assessment that revealed poor repertoire of movement prior to discharge, this was attributed to his prematurity. There were no apparent neurologic deficits upon discharge. When he was seen in follow-up by physical medicine and rehabilitation five months following his birth, he was noted to have torticollis and plagiocephaly but he was otherwise doing well developmentally, and his neurologic exam was otherwise unremarkable. Repeat cranial ultrasound six months after his birth was unremarkable. His torticollis and plagiocephaly improved following physical therapy and helmet therapy. Subsequently, he continued to reach developmental milestones appropriately.
Summary of the empiric baclofen taper used for the management of this neonate’s withdrawal concerns
Summary of the empiric baclofen taper used for the management of this neonate’s withdrawal concerns
The management of spasticity in pregnancy is a challenging clinical dilemma, as limited data exist regarding the safety of anti-spasticity medications for the developing fetus. As with many clinical decisions in pregnancy, the potential maternal benefit must be weighed against the potential for fetal harm. For mothers with SCI, baclofen use during pregnancy is often necessary for adequate treatment of severe spasticity [7, 8]. Baclofen may be administered either orally or intrathecally, and the route of administration may have implications on neonatal withdrawal risk following delivery. While orally dosed baclofen generates plasma concentrations that may result in clinically significant intrauterine exposure to neonates, intrathecal baclofen therapy leads to plasma concentrations 100 times less than those occurring with oral administration [18]. The lack of adverse events noted in neonates born to mothers treated with intrathecal baclofen provides some support for this method of administration in pregnancy [7–12].
The neonate in this case had a presentation concerning for baclofen withdrawal following a pregnancy complicated by maternal oral baclofen use. However, the episode of extensor posturing beginning at fifteen minutes of life was much sooner than the timing of symptoms reported in the five other cases described in Table 1 [2, 13–16]. The subsequent signs of possible withdrawal as noted using the Finnegan Neonatal Abstinence Scale were consistent with findings reported in the five other case reports, though to a lesser degree given the maximum score of six. Notably, the neonate’s scores remained below clinically relevant thresholds while he was being treated with a baclofen taper. This suggests that his symptoms were either well managed with this taper or were not actually secondary to baclofen withdrawal. Despite an extensive workup for alternative etiologies, no other definitive cause of this neonate’s presentation was identified. Even so, several considerations challenge whether this episode was truly reflective of withdrawal. First, the extensor posturing that began at fifteen minutes of life was much sooner than withdrawal symptoms would be expected to manifest. Second, the pregnancy had been complicated by multiple maternal medications that may have contributed, including a small dose of diazepam. Third, and perhaps most importantly, the neonate’s significant distress as noted by low initial Apgar scores, umbilical cord blood gas results, and need for resuscitation efforts may have contributed to the posturing episode noted just minutes later.
When further evaluating the concern for potential baclofen withdrawal in the five cases outlined in Table 1, two of the cases provide convincing reports of withdrawal based upon maternal oral baclofen dosing, timing of neonatal symptoms, extent of neonatal symptoms as measured by Finnegan Neonatal Abstinence Scale scoring, and response to baclofen tapers [13, 14]. One case report was convincing for withdrawal based upon these parameters, but was confounded by multiple maternal medications including lorazepam and pregabalin along with the initiation of phenobarbital and clonidine to manage withdrawal symptoms prior to the initiation of baclofen [16]. Another case report with the relatively low maternal oral dose of baclofen of 10 milligrams two times per day was confounded by other maternal medications including clonazepam and OxyContin, and was further complicated by the need for phenobarbital therapy to manage Finnegan Neonatal Abstinence Scale symptoms [15]. Furthermore, although the neonate in the fifth case presented with symptoms in a plausible time frame for withdrawal and had confirmed epileptic findings on electroencephalography, this case was confounded by magnetic resonance imaging findings consistent with hypoxic ischemic encephalopathy [2]. Despite these questions about the true etiologies of their presentations, all five neonates could have been at risk for baclofen withdrawal symptoms. Furthermore, all five tolerated their short baclofen tapers well and were noted to have significant improvements in their symptoms. Much like the five other cases, the neonate discussed here also responded well to a short baclofen taper with full resolution of symptoms. The neonatologist’s high index of suspicion for possible neonatal baclofen withdrawal following his posturing event at fifteen minutes of life enabled early involvement of the pediatric physical medicine and rehabilitation team. This ultimately led to the prompt initiation of a baclofen taper and successful management and/or prevention of the possible withdrawal concerns.
Although maternal oral baclofen use during pregnancy may raise concerns for neonatal baclofen withdrawal, some of these concerns might be mitigated if the maternal dosing can be tapered prior to delivery. One case report of a 41-year-old female with stiff limb syndrome causing spasms managed with oral baclofen 100 milligrams per day and diazepam 60 milligrams per day described success with this strategy [19]. Beginning in the second trimester, the patient’s baclofen dose was reduced to 25 milligrams per day and her diazepam to 15 milligrams per day. Her spasms remained manageable despite these reductions. Although the birth was complicated by initial fetal distress that necessitated forceps delivery, the neonate otherwise did well after birth. The report explicitly noted that no symptoms of sedation or withdrawal were observed, and the neonate did not require any therapy with benzodiazepines. The utility of this approach in reducing oral maternal baclofen during pregnancy should be further explored.
These cases highlight the need for obstetricians, neonatologists, and physiatrists to recognize the potential for neonatal withdrawal when mothers continue baclofen throughout pregnancy, especially when the oral route of administration is used. Once identified, health care providers can determine a plan prior to delivery for monitoring signs and symptoms of withdrawal and consideration of an empiric baclofen taper before these signs and symptoms emerge. Ultimately, it is evident that further research is needed to assess for the incidence of neonatal baclofen withdrawal associated with maternal dosage and route of administration, and to determine the most appropriate monitoring and management protocols.
Footnotes
Acknowledgments
The authors have no acknowledgements.
Conflict of interest
The authors have no conflicts of interest to report.
Ethical considerations
The parent of the patient provided verbal informed consent over the telephone to publish this case.