Abstract
Purpose
Methods
Results
Conclusions
Keywords
1. Introduction
1.1 Historical context
1.2 Rise of the registries
Registry | UK and Ireland Epilepsy and Pregnancy Register [12] | North American Epilepsy and Pregnancy Registry [13] | EURAP [14] |
---|---|---|---|
Methodology | National, prospective based in the United Kingdom. Ascertainment is approximately 33% of the population of WWE in pregnancy | National prospective based in United states of America, and Canada. | International (>40 countries) prospective/retrospective (includes Australian data) |
Participation | 50% self-enrollment WWE, and rest through physicians, nurses, midwives. | Self-enrollment by WWE | Through a network of physicians who report cases. No self-enrollment. |
Inclusion criteria | Women with epilepsy, treated on AEDs or untreated in 1st trimester | Women taking AED for any reason in pregnancy | Pregnancies with AED exposure at conception. |
Exclusion criteria | Pre-enrollment knowledge of malformation, or change in 1st trimester AED, or commencing the AED after conception. | If AEDs are switched in first trimester | Change in 1st trimester AED, or outcome not classifiable. |
Data collection methods, and follow up | At enrollment and at 3 months after birth, the patient’s general practitioner provides follow up on the case. | Telephone interview with patient at 7 months gestation, and then 8–12 weeks after pregnancy further interview, and in 60% of cases data extracted from patient/infants medical records. | Within 12 months of birth, and also followed up during pregnancy at end of each trimester. |
Type and level of exposure | Drug and dose (including dose changes recorded). Highest dose recorded taken as dose exposure. | Drug dose and brand | Drug regime and dose |
Drug levels | Not systematically recorded | Not systematically recorded | Not systematically recorded |
Diagnosis of epilepsy | Physician reported diagnosis of epilepsy, and clinical geneticist reviews medical record to determine if malformation present | Self reported diagnosis. Medical teratologist blinded review of medical record. | Made by patient’s physician. Central classification of outcomes based on teratologists assessment of medical reports. |
Eurocat. European surveillance of congenital anomalies. Available on: www.eurocat-network.eu [last accessed 27.08.16].
1.3 Results from the registries (Table 2)
Registry | MCM rate following antiepileptic drug exposure | ||||
---|---|---|---|---|---|
Valproate | Carbamazepine | Lamotrigine | Levetiracetam | Topiramate | |
UK and Ireland Registry [12] | 82/1220 (6.7% CI 5.5–8.3%) | 43/1657 (2.6% CI 1.9–3.5%) | 49/2098 (2.3% CI 1.8–3.1%) | 2/304 (0.7% CI 0.2–2.5%) | 3/70 (4.3% CI 1.7–13.3%) |
EURAP [14] | Dose <700 mg | Dose <400 mg | Dose <300 mg | N/A | N/A |
24/431 (5.6% CI 3.6–8.2%) | 5/148 (3.4% CI 1.1–7.7%) | 17/836 (2.0% CI 1.2–3.2%) | |||
Dose ≥700–<1500 mg | Dose ≥400–<1000 mg | Dose ≥300 mg | |||
50/480 (10.4% CI 7.8–13.5%) | 56/1047 (5.3% CI 4.1–6.9%) | 20/444 (4.5% CI 2.8–6.9%) | |||
Dose ≥1500 mg | Dose ≥1000 mg | ||||
24/99 (24.2% CI 16.2–33.9%) | 18/207 (8.7% CI 5.2–13.4%) | ||||
Australian registry of AEDs in pregnancy [20] | 35/253 (13.8% CI 1.7–10.6%) | 19/346 (5.5% CI 0.6–4.4%) | 14/307 (4.6% CI 0.5–3.8%) | 2/82 (2.4% CI 0.2–3.8%) | 1/42 (2.4% CI 0.1–6.1%) |
International Lamotrigine Pregnancy Registry [15] | N/A | N/A | 35/1558 (2.2% CI 1.6–3.1%) | N/A | N/A |
North American Antiepileptic Drug Pregnancy Registry [13] | 30/323 (9.3% CI 6.4–13.0%) | 31/1033 (3.0% CI 2.1–4.2%) | 31/1562 (2.0% CI 1.4–2.8%) | 11/450 (2.4% CI 1.2–4.3%) | 15/359 (4.2% CI 2.4–6.8%) |
1.4 Extension of the registries
Anti-epileptic drug prenatal exposure | Neuro-developmental data available |
---|---|
Sodium valproate | Valproate is the most consistent AED, across the studies, with an increased risk of adverse cognitive outcomes. The NEAD study has shown that after controlling for confounders the mean IQ at 6 years of age was 8–11 points lower in children exposed to prenatal valproate, compared to carbamazepine, lamotrigine or phenytoin. The adverse cognitive profile appears to be dose related. Less than 1000 mg/day had a similar outcome to other AED exposed children. Even in children exposed to <800 mg/day despite similar IQ scores, they had reduced verbal abilities, and required more educational interventions. A Cochrane review has determined that the reduction in IQ is enough to influence later life educational achievements and occupational potential. |
Carbamazepine | Carbamazepine is one of the most well studied of the AEDs in pregnancy from a neurocognitive perspective. IQ appears to be comparable in school aged children to controls, as well as children exposed to lamotrigine. With regards to specific skills the NEAD study raised possibility of dose relationship with poorer verbal and motor skills. |
Lamotrigine | Studies of global neurodevelopment carried out to date are relatively limited, but all 4 studies show that lamotrigine exposed childred are comparable to controls in terms of global neurodevelopment and adaptive behaviour. It is still not clear if there is any specific effects on fine motor skills, and language. With regards language there are conflicting results from small studies, with a questionaire study suggesting some increased difficulty with sentence structure at 36 months. There are no published comparisons with levetiracetam. No dose effect on cognition has been demonstrated. |
Levetiracetam | Limited provisional data exist. The longest data is from a series of 53 children having been followed up until 3–4 years of age. Levetiracetam was found to be similar to controls in terms of development and language, and other cognitive functions. No dose effect has been identified at this stage. |
Topiramate | One study detailing 9 children is available, and clearly is not sufficient to base any firm recommendations on. Further studies are required. |
1.5 Changing focus
Maternal, Newborn and Infant Clinical Outcome Review Programme. MBRRACE. Saving lives, improving mothers’ care lessons learned to inform future maternity care from the UK and Ireland confidential enquiries into maternal deaths and morbidity 2009–2012. Available at: https://www.npeu.ox.ac.uk/downloads/files/mbrrace-uk/reports/Saving%20Lives%20Improving%20Mothers%20Care%20report%202014%20Full.pdf [last accessed 23.11.15].
1.6 Improving services
Maternal, Newborn and Infant Clinical Outcome Review Programme. MBRRACE. Saving lives, improving mothers’ care lessons learned to inform future maternity care from the UK and Ireland confidential enquiries into maternal deaths and morbidity 2009–2012. Available at: https://www.npeu.ox.ac.uk/downloads/files/mbrrace-uk/reports/Saving%20Lives%20Improving%20Mothers%20Care%20report%202014%20Full.pdf [last accessed 23.11.15].
National Society for Epilepsy. Pregnancy and parenting. Available at: https://www.epilepsysociety.org.uk/pregnancy-and-parenting#.V8HgZSMrLLY [last accessed 27.08.16].
1.7 Guidelines/directives
National Institute for Health and Clinical Excellence. Epilepsies: diagnosis and management (clinical guideline 137). Available at: www.nice.org.uk/guidance/cg137; 2012 [last accessed 26.10.16].
- Harden C.L.
- Meador K.J.
- Pennell P.B.
- Hauser W.A.
- Gronseth G.S.
- French J.A.
- et al.
- Harden C.L.
- Pennell P.B.
- Koppel B.S.
- Hovinga C.A.
- Gidal B.
- Meador K.J.
- et al.
- Harden C.L.
- Hopp J.
- Ting T.Y.
- Pennell P.B.
- French J.A.
- Hauser W.A.
- et al.
European Medicines Agency. Assessment report. Procedure under article 31 of directive 2001/83/EC resulting from pharmacovigilance data. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Valproate_and_related_substances_31/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500177352. pdf [last accessed 26.08.16].
Medicines and Healthcare Products Regulatory Agency. Medicines related to valproate: risk of abnormal pregnancy outcomes. Available at: https://www.cas.dh.gov.uk/ViewandAcknowledgment/ViewAlert.aspx?AlertID=102287 [last accessed 26.08.16].
Medicines and Healthcare Products Regulatory Agency. Medicines related to valproate: risk of abnormal pregnancy outcomes. Available at: https://www.cas.dh.gov.uk/ViewandAcknowledgment/ViewAlert.aspx?AlertID=102287 [last accessed 26.08.16].
Green-top guideline no. 68. Epilepsy in pregnancy. Available at: https://www.rcog.org.uk/globalassets/documents/guidelines/green-top-guidelines/gtg68_epilepsy.pdf; 2016 [last accessed 26.08.16].
Clinical practice guidelines with emphasis on women with epilepsy |
---|
Crawford et al. [10] |
NICE [49] National Institute for Health and Clinical Excellence. Epilepsies: diagnosis and management (clinical guideline 137). Available at: www.nice.org.uk/guidance/cg137; 2012 [last accessed 26.10.16]. |
AES/AAN 50 ,
Management issues for women with epilepsy-focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia. 2009; 50: 1237-1246 51 ,
Management issues for women with epilepsy-focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia. 2009; 50: 1247-1255 52
Practice parameter update: management issues for women with epilepsy—focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009; 73: 2126-2132 |
SIGN [53] |
Greentop guidelines [56] Green-top guideline no. 68. Epilepsy in pregnancy. Available at: https://www.rcog.org.uk/globalassets/documents/guidelines/green-top-guidelines/gtg68_epilepsy.pdf; 2016 [last accessed 26.08.16]. |
1.8 Future directions
2. Conclusions
Conflict of interest statement
Author’s contributions
References
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