G
GABAPENTIN
Anticonvulsant
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
A 2005 report of gabapentin monotherapy raises concerns of drug-induced developmental toxicity (1). Although limited, other studies involving monotherapy have not confirmed these findings. Moreover, a 2012 review concluded that the available data were not sufficient to determine whether or not exposure to gabapentin was harmful to the fetus (2). Because the agent is often combined with other anticonvulsants, the actual cause of a defect may be obscured. If a woman’s condition requires gabapentin, the benefits of therapy to her appear to outweigh the potential risks to her embryo and/or fetus. A 2009 review on the treatment of cluster headache in pregnancy and lactation concluded that, if indicated, gabapentin was the drug of choice (3).
FETAL RISK SUMMARY
Gabapentin (Neurontin) is an anticonvulsant used as adjunctive therapy for the treatment of partial seizures in patients with epilepsy (4,5). The drug also is indicated for the management of postherpetic neuralgia in adults (5). Gabapentin enacarbil (Horizant) is a prodrug that is undergoes extensive first-pass hydrolysis by enterocytes and to a lesser extent in the liver to form gabapentin so that blood levels are low and transient (≤2% of gabapentin plasma levels) (6). The prodrug is indicated for the treatment of moderate-to-severe restless legs syndrome (6). Gabapentin has been used off-label for multiple other conditions, including migraine and chronic headache, bipolar disorder, peripheral neuropathy, diabetic neuropathy, complex regional pain syndrome, attention deficit disorder, trigeminal neuralgia, periodic limb movement disorder of sleep, and alcohol withdrawal syndrome (7).
Fetotoxicity in mice exposed during organogenesis to maternal oral doses of about 1–4 times the maximum recommended human dose based on BSA (MRHD) was characterized by delayed ossification of bones in the skull, vertebrae, forelimbs, and hindlimbs. The no-effect dose in mice was about half of the MRHD. Delayed ossification was also observed in rats exposed in utero to 1–5 times the MRHD. Hydroureter or hydronephrosis was observed in rat pups exposed in utero during organogenesis and during the perinatal and postnatal periods after similar doses. The causes of the urinary tract anomalies were unclear. The no-effect dose in rats during organogenesis was approximately equal to the MRHD in the teratogenicity study. When compared with controls, exposure to gabapentin during organogenesis did not increase congenital malformations, other than hydroureter or hydronephrosis in rats, in mice, rats, and rabbits at 4, 5, or 8 times, respectively, the MRHD. In rabbits, doses less than about ¼ to 8 times the MRHD caused an increased incidence of postimplantation fetal loss (5).
Animal reproduction studies have been conducted with gabapentin enacarbil (6). In rats and rabbits given the drug throughout organogenesis, increased embryo–fetal mortality and decreased fetal body weights were observed. The no-effect dose in rats and rabbits was about 3 and 16 times, respectively, the recommended human dose of 600 mg/day based on BSA (RHD). When rats were dosed throughout pregnancy and lactation, decreased growth and survival were noted. The no-effect dose was about three times the RHD (6).
Both gabapentin and gabapentin enacarbil were carcinogenic (pancreatic acinar cell adenomas and carcinomas) in rats, but assays for mutagenicity were negative. No adverse effects on fertility were observed with either agent (5,6).
Consistent with its low molecular weight (about 171), absence of metabolism and plasma protein binding, gabapentin crosses the placenta. In a 2005 study involving six women, the mean cord:maternal plasma concentration ratio was 1.7 (range 1.3–2.1) (8). The drug declined in the neonates with an estimated half-life of 14 hours.
No cases of fetal or newborn adverse outcomes were reported to the FDA through 1996 (F. Rosa, personal communication, FDA, 1996).
A 2005 abstract reported 62 pregnancy outcomes after exposure to gabapentin, lamotrigine, or topiramate (1). The study included a blinded dysmorphology examination. Thirty women used gabapentin, one of whom delivered an infant with a major malformation: pyloric stenosis with bilateral fifth finger clinodactyly and prominent epicanthal folds (mother treated for seizures with monotherapy). Two of the 13 infants that were examined by a dysmorphologist had anticonvulsant facies (one monotherapy and the other combined with carbamazepine). In addition, two had neurologic abnormalities: failure to gaze up (sunsetting), opisthotonus, frontal bossing, medial flare of the eyebrows, and small for gestational age (mother treated for depression with gabapentin, doxepin, clonazepam, nefazodone, and zolpidem); sunsetting and metopic ridge (mother treated for chronic fatigue and fibromyalgia with gabapentin, lorazepam, and fluoxetine). Although they were not conclusive, the findings suggested reason for concern with gabapentin, as well as the same phenotype that has been observed with older anticonvulsants (1).
In a brief 1995 communication, a newborn exposed to gabapentin and carbamazepine during pregnancy had a cyclops holoprosencephaly (no nose and one eye) (9). Of the seven suspected cases of holoprosencephaly described in this report, five involved the use of carbamazepine (two cases of monotherapy and three of combined therapy). Because of the lack of family histories, an association with familial holoprosencephaly or maternal neurologic problems could not be excluded (9).
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
