Exposure to Pregabalin During the First Trimester Leads to Increased Incidence of Major Birth Defects

Exposure during the first trimester of pregnancy to pregabalin (also known as Lyrica), a drug commonly prescribed to manage neuropathic pain, pain resulting from shingles, spinal cord injury or fibromyalgia, and which is also administered in combination with other medications to treat certain types of seizures in epileptic patients, has recently been implicated in a study published in Neurology¹, with an increased occurrence of birth defects.

Although a structural derivative of the neurotransmitter GABA, pregabalin does not bind to GABA or benzodiazepine receptors, but its prolonged application to rat neurons in culture results in increased density of the GABA transporter protein, GAT1 and in increased rate of GABA transport². Pregabalin does not bind to opiate, serotonin or dopamine receptors, nor does it affect cyclooxygenase acitivity. It is thought that its anti-nociceptive and anti-convulsant properties are conferred by and mediated through its specific binding to the α2δ subunit of voltage-gated calcium (Ca²⁺) channels in the CNS³. Binding of gabapentin to Ca²⁺ channels reduces influx of Ca²⁺ into neurons, resulting in a reduction of glutamate release from synaptic terminals and reduced activation of substance P-mediated activation of AMPA receptors on noradrenergic synapses, leading to decreased neuronal activity⁴.

Several animal studies reported developmental toxicity of pregabalin, with occurrence of teratogenic effects⁵, skeletal malformations, growth retardation, neural tube defects, lethality, reproductive system impairments, and behavioral abnormalities⁶. The authors therefore sought to address pregabalin toxicity during pregnancy.

For this study, data was collected from 8 Teratology Information Services in 7 European countries between 2004 and 2013. Pregnancy outcomes were recorded from 164 women treated with pregabalin during pregnancy for pain (n=115, mostly neuropathic pain), psychiatric disorders (n=39) and epilepsy (n=5), and 656 controls not exposed to anti-epileptic drugs or known teratogenic drugs during pregnancy.

77% of patients in the pregabalin group started treatment before pregnancy, discontinuing it at a median of 6 weeks of gestation; 61% of patients continued beyond 6 weeks, and 33% beyond 7 weeks of gestation. Exposure to pregabalin during the first trimester of pregnancy was observed for 96% of patients within this group, with a median duration of exposure of 6 weeks, and a median daily dose of 150 mg.

Major birth defects (MBD) were more frequent in pregabalin-exposed pregnancies than in controls (9.6 vs 2.8, p<.001), and so were pregnancy terminations (9,8 vs 5.0%, p=.02 for elective terminations; 5.5 vs 1.8%, p=.008 for medical terminations), resulting in a lower rate of live births in pregabalin pregnancies (71.9 vs 85.2%, p<.001).

This observational prospective cohort study indicates an increased risk of MBDs resulting from exposure to pregabalin during the first trimester of pregnancy. The authors caution that additional studies will be warranted to establish a clear link between MBDs and pregabalin exposure during that period, as the sample size in the present study was relatively small, and as some of the subjects were concomitantly exposed to other medications. 

References

1. Winterfeld U, Merlob P, Baud D, et al. Pregnancy outcome following maternal exposure to pregabalin may call for concern. Neurology. 2016;

2.Whitworth TL, Quick MW. Upregulation of gamma-aminobutyric acid transporter expression: role of alkylated gamma-aminobutyric acid derivatives. Biochem Soc Trans. 2001;29(Pt 6):736-41.

3. Stahl SM, Porreca F, Taylor CP, Cheung R, Thorpe AJ, Clair A. The diverse therapeutic actions of pregabalin: is a single mechanism responsible for several pharmacological activities?. Trends Pharmacol Sci. 2013;34(6):332-9.

4. Wedekind D, Bandelow B. [The alpha2delta subunit of the voltage-dependent calcium channel. A new pharmaceutical target for psychiatry and neurology]. Nervenarzt. 2005;76(7):888-91.

5. Etemad L, Mohammad A, Mohammadpour AH, Vahdati mashhadi N, Moallem SA. Teratogenic effects of pregabalin in mice. Iran J Basic Med Sci. 2013;16(10):1065-70.

6.FDA highlights of prescribing information for Lyrica: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021446s028lbl.pdf