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).
The Lamotrigine Pregnancy Registry, an ongoing project conducted by the manufacturer, was first published in January 1997 (10). The final report was published in July 2010. The Registry is now closed. Among 32 prospectively enrolled pregnancies exposed to gabapentin and lamotrigine, with or without other anticonvulsants, 27 were exposed in the 1st trimester, resulting in 25 live births without defects, 1 spontaneous abortion (SAB), and 1 birth defect. There were five exposures in the 2nd/3rd trimester resulting in live births without defects (10).
A 1998 noninterventional observational cohort study described the outcomes of pregnancies in women who had been prescribed ≥1 of 34 newly marketed drugs by general practitioners in England (11). Data were obtained by questionnaires sent to the prescribing physicians 1 month after the expected or possible date of delivery. In 831 (78%) of the pregnancies, a newly marketed drug was thought to have been taken during the 1st trimester with birth defects noted in 14 (2.5%) singleton births of the 557 newborns (10 sets of twins). In addition, two birth defects were observed in aborted fetuses. However, few of the aborted fetuses were examined. Gabapentin was taken during the 1st trimester in 17 pregnancies. The outcomes of these pregnancies included 2 SABs, 4 elective abortions (EABs), and 11 normal newborns (1 premature) (11). Although no congenital malformations were observed, the study lacked the sensitivity to identify minor anomalies. Late-appearing major defects may also have been missed due to the timing of the questionnaires.
A 1996 review reported 16 pregnancies exposed to gabapentin from preclinical trials and postmarketing surveillance (12). The outcomes of these pregnancies included five EABs, one ongoing pregnancy, seven normal infants, and three infants with birth defects. No specific information was provided on the defects other than that there was no pattern of malformation and all had been exposed to polytherapy for epilepsy (12).
A 2002 review concluded that gabapentin could be used for chronic headache during early pregnancy but not later because of concerns about delaying fetal bony growth plate development (13). The reason for this concern was not stated, but the animal data above may have influenced the conclusion. In a 2002 report of a postmarketing surveillance study in England, there were no congenital anomalies in the 11 infants of women who used gabapentin in the 1st trimester (14).
Results from the Neurontin Pregnancy Registry were reported in 2003 (15). There were 51 fetuses, including 3 sets of twins, from 39 women with epilepsy and other disorders. At conception, 17 were taking gabapentin alone, 30 were taking it with other antiepileptic drugs, and 4 were not receiving gabapentin. At delivery, the numbers were 19, 21, and 4, respectively. There were six SABs and one EAB. Among the 44 live births, there were 2 (4.5%) major anomalies: hypospadia (gabapentin plus valproate) and single kidney (gabapentin alone, changed to phenobarbital at 16 weeks’). There also was one (2.3%) minor defect (defect of left external ear canal and two small skin tags on the jaw). The outcomes were comparable to the risk of major (4%–8%) defects in infants of epileptic mothers and the risk of minor (3%–10%) defects in the general population (15).
The United Kingdom Epilepsy and Pregnancy Register prospective study reported the malformation risks of antiepileptic drugs (AEDs) (16). Among the 3607 cases, there were 31 pregnancies (excludes an unspecified number of pregnancy losses with no major defects) exposed to gabapentin monotherapy. There was one major anomaly (type not specified). Compared to no exposure to AED, the adjusted odds ratio was 1.76, 95% confidence interval 0.22–14.49 (p = 0.596) (16).
A brief report described the use of gabapentin in seven women with hyperemesis gravidarum (17). Therapy was started at a mean gestational age of 8 weeks and discontinued at a median gestational age of 21 weeks (range 10–25 weeks). The mean dose was 1843 mg (range 1200–3000 mg). Two birth defects were observed: hydronephrosis and tethered spinal cord. The latter defect occurred in an infant conceived by in vitro fertilization, a process known to increase the risk of congenital defects (17).
A study published in 2009 examined the effect of AEDs on the head circumference in newborns (18). Significant reductions in mean birth-weight-adjusted mean head circumference (bw-adj-HC) was noted for monotherapy with carbamazepine and valproic acid. No effect on bw-adj-HC was observed with gabapentin, phenytoin, clonazepam, and lamotrigine. A significant increase in the occurrence of microcephaly (bw-adj-HC smaller than 2 standard deviations below the mean) was noted after any AED polytherapy but not after any monotherapy, including carbamazepine and valproic acid. The potential effects of these findings on child development warrant study (18).
A 2013 prospective cohort study compared the outcomes of 223 pregnancies exposed to gabapentin (average dose 1000 mg/day, range 100–4800 mg/day combined with other drugs) with 223 pregnancies not exposed to gabapentin or known teratogens (19). Indications for use of gabapentin were known in 207 cases: epilepsy (34%), pain (90%), and psychiatric conditions (22%). In the two groups, there was no statistical difference in the number of major malformations 7 (4.1%) vs. 5 (2.5%), SABs 22 (9.8%) vs. 17 (7.6%), stillbirths 2 (1.1%) vs. 0, or IUGR 6 (3.5%) vs. 4 (1.9%). Statistically significant outcomes were found for live births (76.2% vs. 90%), EABs (13% vs. 2.2%), preterm birth (10.5% vs. 3.9%), and low (<2500 g) birth weight (10.5% vs. 4.4%). The seven infants with major malformations were exposed to gabapentin and other drugs in the 1st trimester. The defects were ventricular septal defect (2 infants); anencephaly; macrocephaly, microtrognathism, and cutis marmorata; pyloric stenosis; bilateral varus clubfoot; and cryptorchidism. Although the authors noted the small size of their study, and the absence of a comparative group with other antiepileptic drugs, they concluded that gabapentin did not appear to increase the risk for major malformations (19).
A 27-year-old woman was diagnosed about 2 months before pregnancy with stiff person syndrome (Moersche-Woltman syndrome) (20). 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) (20).
BREASTFEEDING SUMMARY
Consistent with its low molecular weight (about 171) and lack of plasma protein binding, gabapentin is excreted breast milk. A 2005 study described the use of gabapentin during pregnancy in five women, three of whom breastfed their infants (7). One infant was born at 33 weeks’, but all five had normal Apgar scores. No congenital defects were noted in the five infants. In the three women who breastfed, their doses were 600, 1800, and 2100 mg/day, respectively. Milk and plasma sampling occurred on postpartum days 21, 16, and 97, respectively. Infant plasma levels of gabapentin after completion of nursing were 1.3, 1.5, and 1.9 µM, respectively, and the milk:plasma ratios were 1.0, 1.3, and 0.8, respectively. The estimated infant dose as a percentage of the mother’s weight-adjusted dose was 1.3%–3.8% (not specified by infant) (7).
In a 2006 case report, a 34-year-old mother had been taking gabapentin 600 mg three times daily (36.7 mg/kg/day) and amitriptyline 2.5 mg/day for 6 weeks while nursing her male infant (21). On the date the milk samples were obtained, her infant was 1.6 months old and weighed 3.1 kg. The milk:plasma ratio was 0.86 and the relative infant was 2.34% of the mother’s weight-adjusted dose. The plasma concentration in the infant (0.4 mg/L) was about 6% of the mother’s plasma concentration. No adverse effects were noted in the infant, who was doing well (21).
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