Pregnancy outcome following maternal exposure to pregabalin may call for concern

Winterfeld, Ursula; Merlob, Paul; Baud, David; Rousson, Valentin; Panchaud, Alice; Rothuizen, Laura E.; Bernard, Nathalie; Vial, Thierry; Yates, Laura; Pistelli, Alessandra; Ellfolk, Maria; Eleftheriou, Georgios; Vries, Loes C. de; Jonville‐Béra, Annie‐Pierre; Kadıoğlu, Mine; Biollaz, J.; Buclin, Thierry

doi:10.1212/wnl.0000000000002767

Cited by 77 publications

(59 citation statements)

References 20 publications

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“…Many of the same authors of the gabapentin study reported on pregnancy outcomes following in utero pregabalin exposure [18]. In this multicenter, prospective observational study across 8 participating Teratology Information Services in 7 countries, the prescribing indication for pregabalin was epilepsy in only 3.0 % of the women; the most common indications were pain (neuropathic pain and migraine; 74.3 %) and psychiatric disorders (45.1 %), with obvious overlaps.…”

Section: Pregabalinmentioning

confidence: 97%

Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

Pennell

2016

Neurotherapeutics

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Although prenatal exposure to antiepileptic drugs (AEDs) is known to impart relatively higher risks of major congenital malformations, prospective studies have provided refined data that allow us to differentiate the risks of different types and doses of AEDs. As the number of AED prescriptions has dramatically increased in reproductive-aged women with a variety of neuropsychiatric indications, the evolving concepts learned from studies in women with epilepsy can be applied to a much larger group of pregnant women to improve child outcomes while maintaining maternal disease control. In addition to careful selection of the type of medication, the amount of fetal exposure at conception and in the first trimester probably matters across all AEDs. Some AED polytherapy regimens are not associated with a higher risk of malformations, although other outcomes have not yet been formally studied. The individual woman's drug target concentration should be established preconception and maintained during pregnancy, to prevent seizure worsening. Substantial pharmacokinetic changes occur with many of the medications during pregnancy and postpartum, and interindividual variability supports the use of therapeutic drug monitoring for most AEDs. During pregnancy, vigilance and close monitoring should also include intrauterine fetal growth, obstetric complications, and neonatal complications. Breastfeeding can provide additional neurodevelopmental benefit and should be an option for women on AEDs. Knowledge of these key principles enhances our ability to make treatment recommendations with resultant improved maternal and child outcomes. Additional prospective studies are needed to further define the risk-benefit ratio across a variety of medications, dosing strategies, and neuropsychiatric disorders.

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Section: Pregabalinmentioning

confidence: 97%

Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

Pennell

2016

Neurotherapeutics

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“…1 Of 116 infants exposed during the first trimester, 7 (6%) had structural malformations compared to 12 of 580 (2.1%) in the reference group. The imbalance was largely explained by 4 cases of cerebral ventricle enlargement (3.2%) in the exposed group compared to 3 (0.5%) in the control group.…”

mentioning

confidence: 92%

“…The structure and composition of these data are very similar to those of MAX, and the methods we used to create the linked cohort and to analyze the data followed the same protocol. Finally, we added the adjusted estimates from the MAX and the MarketScan populations to the crude estimates of the recent multicenter study 1 and estimated a pooled RR using the DerSimonian and Laird random-effects model. We considered the crude estimates provided by the multicenter study to be adjusted because the authors reported that adjustment did not change the point estimates.…”

mentioning

confidence: 99%

Pregabalin use early in pregnancy and the risk of major congenital malformations

et al. 2017

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Objective: To assess whether first-trimester exposure to pregabalin is associated with an increased risk of major congenital malformations, as recently suggested in a pregnancy registry study.Methods: We performed a cohort study nested in the US Medicaid Analytic eXtract (MAX). The study population included 1,323,432 pregnancies resulting in a live-born infant between 2000 and 2010. We examined the risk of major congenital malformations among infants born to women exposed to pregabalin during the first trimester compared with women unexposed to anticonvulsants. We used propensity score fine stratification to control for .50 potential confounders, and we estimated relative risks (RRs) and 95% confidence intervals (CIs) in generalized linear models. The analyses were replicated in the Truven Health MarketScan Commercial Database (MarketScan). Pooled estimates based on the adjusted RR produced in MAX, MarketScan, and the previous registry study were calculated.Results: Of 477 infants exposed to pregabalin during the first trimester in MAX, 28 (5.9%) had malformations compared to 3.3% in nonexposed infants. The crude RR of major congenital malformations for pregabalin was 1.80 (95% CI 1.26-2.58). After propensity score adjustment, the RR moved to 1.16 (95% CI 0.81-1.67). Restriction to pregabalin monotherapy and sensitivity analyses produced similar results. The adjusted RR for major congenital malformations for the 174 infants exposed in MarketScan was 1.03 (95% CI 0.56-1.90). The pooled RR was 1.33 (95% CI 0.83-2.15) for pregabalin any use and 1.02 (95% CI 0.69-1.51) for pregabalin monotherapy. A recent multicenter study from the European Teratology Information Services network reported an association between pregabalin use in pregnancy and the risk of major congenital malformations in the fetus, among other adverse outcomes, including elective and medically indicated terminations. Conclusions:1 Of 116 infants exposed during the first trimester, 7 (6%) had structural malformations compared to 12 of 580 (2.1%) in the reference group. The imbalance was largely explained by 4 cases of cerebral ventricle enlargement (3.2%) in the exposed group compared to 3 (0.5%) in the control group. Both the authors and the editors called for concern but also for the need of confirmation with independent studies. 2 We tested the association between first-trimester exposure to pregabalin and the risk of major congenital malformations in a large cohort of pregnant women nested in the US Medicaid Analytic eXtract (MAX) and replicated the study in the Truven Health MarketScan Commercial Claims and Encounters Database (MarketScan).

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“…Discussions should include careful risk-benefi t assessment of reasonable treatment options for the patient's seizure or epilepsy type; 3) for seizure (or epilepsy) types where valproate is the most eff ective treatment, the risks and benefi ts of valproate and other treatment alternatives should be discussed; 4) valproate should not be prescribed as a fi rst-line treatment for focal epilepsy; 5) valproate may be offered as a fi rst-line treatment for epilepsy syndromes where it is the most eff ective treatment, including idiopathic (genetic) generalized syndromes associated with tonic-clonic seizures; 6) valproate may be off ered as a fi rst-line treatment in situations where pregnancy is highly unlikely (e.g., signifi cant intellectual or physical disability); and 7) women and girls taking valproate require regular follow-up for ongoing consideration of the most appropriate treatment regimen 41 . For newer AEDs, one multicenter, observational prospective cohort study conducted by our ENTIS colleagues in 2016 demonstrated a signal for an increased risk of major birth defects after fi rst trimester exposure to pregabalin, but these results need confi rmation through independent studies 42 . Newer data also suggest that lamotrigine and levetiracetam are associated with a relatively low risk for both anatomic and developmental adverse eff ects, although further studies are needed for these and other AEDs 43 .…”

Section: Congenital Malformations Pervasive and Behavioral Aspects mentioning

confidence: 99%

The Croatian Model of Integrative Prospective Management of Epilepsy and Pregnancy

Miškov¹,

Juraški

Mikula³

et al. 2016

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SUMMARY -Epilepsy is the most common neurological complication in pregnancy. Women with epilepsy have a higher risk of complications in pregnancy. In Croatia, women with epilepsy are treated by neurologists at tertiary centers according to the place of residence. We prospectively followed-up pregnancies in women with epilepsy and healthy controls, and analyzed the factors responsible for their delivery outcomes and development of their babies. Healthy pregnant women had a higher level of education and economic status, but pregnant women with epilepsy took folic acid in a higher proportion than controls, possibly due to timely preconception counseling. Complications during pregnancy depended on the number of antiepileptic drugs and epilepsy control. We noticed some behavioral and cognitive aspects in children exposed in utero to valproic acid, which required follow up. Th e rate of congenital malformations was not increased. In conclusion, women with epilepsy should receive preconception counseling about the risk for pregnancy, but also about the possibilities to minimize that risk. We have introduced a model of integrative management of pregnancy and epilepsy based on close collaboration among diff erent clinical experts in Croatia, in order to provide prompt counseling and timely intervention.

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Pregnancy outcome following maternal exposure to pregabalin may call for concern

Cited by 77 publications

References 20 publications

Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

Pregabalin use early in pregnancy and the risk of major congenital malformations

The Croatian Model of Integrative Prospective Management of Epilepsy and Pregnancy

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