Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child: Cochrane systematic review
Assessed as up to date: 2015/09/14
There is evidence that certain antiepileptic drugs (AEDs) are teratogenic and are associated with an increased risk of congenital malformation. The majority of women with epilepsy continue taking AEDs throughout pregnancy; therefore it is important that comprehensive information on the potential risks associated with AED treatment is available.Objectives
To assess the effects of prenatal exposure to AEDs on the prevalence of congenital malformations in the child.Search methods
We searched the Cochrane Epilepsy Group Specialized Register (September 2015), Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 11), MEDLINE (via Ovid) (1946 to September 2015), EMBASE (1974 to September 2015), Pharmline (1978 to September 2015), Reprotox (1983 to September 2015) and conference abstracts (2010-2015) without language restriction.Selection criteria
We included prospective cohort controlled studies, cohort studies set within pregnancy registries and randomised controlled trials. Participants were women with epilepsy taking AEDs; the two control groups were women without epilepsy and women with epilepsy who were not taking AEDs during pregnancy.Data collection and analysis
Three authors independently selected studies for inclusion. Five authors completed data extraction and risk of bias assessments. The primary outcome was the presence of a major congenital malformation. Secondary outcomes included specific types of major congenital malformations. Where meta-analysis was not possible, we reviewed included studies narratively.Main results
We included 50 studies, with 31 contributing to meta-analysis. Study quality varied, and given the observational design, all were at high risk of certain biases. However, biases were balanced across the AEDs investigated and we believe that the results are not explained by these biases.
Children exposed to carbamazepine (CBZ) were at a higher risk of malformation than children born to women without epilepsy (N = 1367 vs 2146, risk ratio (RR) 2.01, 95% confidence interval (CI) 1.20 to 3.36) and women with untreated epilepsy (N = 3058 vs 1287, RR 1.50, 95% CI 1.03 to 2.19). Children exposed to phenobarbital (PB) were at a higher risk of malformation than children born to women without epilepsy (N = 345 vs 1591, RR 2.84, 95% CI 1.57 to 5.13). Children exposed to phenytoin (PHT) were at an increased risk of malformation compared with children born to women without epilepsy (N = 477 vs 987, RR 2.38, 95% CI 1.12 to 5.03) and to women with untreated epilepsy (N = 640 vs 1256, RR 2.40, 95% CI 1.42 to 4.08). Children exposed to topiramate (TPM) were at an increased risk of malformation compared with children born to women without epilepsy (N = 359 vs 442, RR 3.69, 95% CI 1.36 to 10.07). The children exposed to valproate (VPA) were at a higher risk of malformation compared with children born to women without epilepsy (N = 467 vs 1936, RR 5.69, 95% CI 3.33 to 9.73) and to women with untreated epilepsy (N = 1923 vs 1259, RR 3.13, 95% CI 2.16 to 4.54). There was no increased risk for major malformation for lamotrigine (LTG). Gabapentin (GBP), levetiracetam (LEV), oxcarbazepine (OXC), primidone (PRM) or zonisamide (ZNS) were not associated with an increased risk, however, there were substantially fewer data for these medications.
For AED comparisons, children exposed to VPA had the greatest risk of malformation (10.93%, 95% CI 8.91 to 13.13). Children exposed to VPA were at an increased risk of malformation compared with children exposed to CBZ (N = 2529 vs 4549, RR 2.44, 95% CI 2.00 to 2.94), GBP (N = 1814 vs 190, RR 6.21, 95% CI 1.91 to 20.23), LEV (N = 1814 vs 817, RR 5.82, 95% CI 3.13 to 10.81), LTG (N = 2021 vs 4164, RR 3.56, 95% CI 2.77 to 4.58), TPM (N = 1814 vs 473, RR 2.35, 95% CI 1.40 to 3.95), OXC (N = 676 vs 238, RR 3.71, 95% CI 1.65 to 8.33), PB (N = 1137 vs 626, RR 1.59, 95% CI 1.11 to 2.29, PHT (N = 2319 vs 1137, RR 2.00, 95% CI 1.48 to 2.71) or ZNS (N = 323 vs 90, RR 17.13, 95% CI 1.06 to 277.48). Children exposed to CBZ were at a higher risk of malformation than those exposed to LEV (N = 3051 vs 817, RR 1.84, 95% CI 1.03 to 3.29) and children exposed to LTG (N = 3385 vs 4164, RR 1.34, 95% CI 1.01 to 1.76). Children exposed to PB were at a higher risk of malformation compared with children exposed to GBP (N = 204 vs 159, RR 8.33, 95% CI 1.04 to 50.00), LEV (N = 204 vs 513, RR 2.33, 95% CI 1.04 to 5.00) or LTG (N = 282 vs 1959, RR 3.13, 95% CI 1.64 to 5.88). Children exposed to PHT had a higher risk of malformation than children exposed to LTG (N = 624 vs 4082, RR 1.89, 95% CI 1.19 to 2.94) or to LEV (N = 566 vs 817, RR 2.04, 95% CI 1.09 to 3.85); however, the comparison to LEV was not significant in the random-effects model. Children exposed to TPM were at a higher risk of malformation than children exposed to LEV (N = 473 vs 817, RR 2.00, 95% CI 1.03 to 3.85) or LTG (N = 473 vs 3975, RR 1.79, 95% CI 1.06 to 2.94). There were no other significant differences, or comparisons were limited to a single study.
We found significantly higher rates of specific malformations associating PB exposure with cardiac malformations and VPA exposure with neural tube, cardiac, oro-facial/craniofacial, and skeletal and limb malformations in comparison to other AEDs. Dose of exposure mediated the risk of malformation following VPA exposure; a potential dose-response association for the other AEDs remained less clear.Authors' conclusions
Exposure in the womb to certain AEDs carried an increased risk of malformation in the foetus and may be associated with specific patterns of malformation. Based on current evidence, LEV and LTG exposure carried the lowest risk of overall malformation; however, data pertaining to specific malformations are lacking. Physicians should discuss both the risks and treatment efficacy with the patient prior to commencing treatment.
Weston Jennifer, Bromley Rebecca, Jackson Cerian F, Adab Naghme, Clayton-Smith Jill, Greenhalgh Janette, Hounsome Juliet, McKay Andrew J, Tudur Smith Catrin, Marson Anthony G
Treatment for epilepsy in pregnant women and the physical health of the child
For most women who have epilepsy, continuing their medication during pregnancy is important for their health. Over the last 25 years, research has shown that children exposed to these medications in the womb can be at a higher risk of having a malformation or birth defect.
This review aimed to understand whether exposure to antiepileptic drugs (AEDs) during pregnancy is linked to an increased risk of having a child with a malformation.
Characteristics of the studies
The review included 50 published studies. We compared the children of women with epilepsy who were taking a single AED to the children of women without epilepsy or women who had epilepsy but who were not treating it with AEDs. We also made comparisons between children exposed to different AEDs in the womb. The evidence presented in this review was up to date in September 2015.
The amount of data available from the studies reviewed varied greatly by the AED under investigation, and this could account for some of the findings.
- Children exposed to valproate compared to other AEDs had the highest level of risk of a malformation at 10.93%. The children exposed to valproate had a higher level of risk than both groups of control children and than children exposed to carbamazepine, gabapentin, levetiracetam, lamotrigine, oxcarbazepine, phenobarbital, phenytoin, topiramate and zonisamide. The level of risk of having a malformation was linked to the amount or dose of valproate the child was exposed to in the womb.
- Children exposed to carbamazepine were at a higher risk of malformations than both groups of control children and children exposed to levetiracetam and lamotrigine.
- Children exposed to phenobarbital were at a higher risk of malformations than children born to women without epilepsy but not those born to women with untreated epilepsy. They were also at a higher risk of malformation than children exposed to gabapentin, levetiracetam or lamotrigine.
- Children exposed to phenytoin were at an increased risk of malformation compared with both groups of control children and children exposed to levetiracetam and lamotrigine.; although the result of the comparison to levetriacetam is less clear.
- Children exposed to topiramate were at a higher risk of malformation than children born to women without epilepsy but not those born to women with untreated epilepsy. They were at a higher risk of malformation in comparison to the children exposed to levetiracetam or lamotrigine.
- There were no other significant differences between AEDs, or comparisons were limited to a single study.
- We also found higher rates of specific types of malformations, particularly associating phenobarbital exposure with heart malformations and valproate exposure with a range of specific types of malformation affecting a number of different areas of the body.
Quality of the studies
The quality of how studies were designed varied, but we do not consider that this accounts for the results of the review.
This review found that children exposed to valproate in the womb were at an increased risk of having a malformation at birth and that the level of risk is determined by the dose of valproate the child is exposed to. Based on current evidence, levetiracetam and lamotrigine appear to be the AEDs associated with the lowest level of risk, but more data are needed, particularly concerning individual types of malformation.
Implications for practice
There is consistent evidence that prenatal exposure to VPA increases the risk of having a child with a major congenital malformation with the increase in risk covering neural tube, cardiac, skeletal and limb and oro-facial cleft and craniofacial malformations.
Exposure to CBZ is associated with an increased risk of malformations but to a lesser extent than VPA. The risk with PB appears to be related specifically to cardiac malformations in comparison to other AEDs. Finally, no increase risk of malformation is found for LTG or LEV compared with controls and more favourable outcomes are found for the child compared with VPA and other AEDs. Whilst the RDs for comparisons not including VPA may appear relatively small at around1-2%, the importance of a cardiac or neural tube defect on the individual child and family should be considered. Also, at a societal level a 1% increase in malformation rate will result in significantly more affected children born each year which represents a significant cost to health and educational services.
Given the variance in outcome data pertaining to the malformation risk associated with a individual treatment the primary implication for practice is that counselling should be tailored to the individual treatment and its dose. Although traditional counselling has been that 90% of children born to women with epilepsy have healthy children, this simplifies a complex set of data. The dose of AED and considerations regarding specific malformation types should also be central to counselling. It is also important to highlight that whilst major malformations are likely to represent the more severe end of a continuum of effect, minor malformations can still result in health problems and impact on quality of life. Finally, the limited data about the newer AEDs should be discussed with women planning a pregnancy or who are in the childbearing years. Absence of risk data should not imply lack of risk.
Implications for research
The role of the clinician and women with epilepsy working together to improve the evidence base should be considered and the collection of data should be embedded in routine practice enabling pregnancy registers and other study designs.
Whilst research methodologies have become more refined over the years there are still a number of limitations in the data which could be addressed in future research. Firstly, the reporting of an overall malformation figure is, as demonstrated above for PB, unlikely to be the most reliable measure of risk and where data is large enough to allow, prevalences pertaining to specific malformation types should be investigated and reported. To facilitate this, all studies however large or small should provide information on specific malformation types to aid future meta-analyses and generation of risk estimates. Secondly, registries and reporting clinicians should be encouraged to use the standardised phenotypic terms which are now used in recognised phenotype ontologies such as the Human Phenotype Ontology (HPO) (http://human-phenotype-ontology.github.io/about.html). This will not only allow more accurate comparison across studies but analysis of the computational codes attached to HPO terms can also indicate similarities in underlying genomic pathways involved in aetiology and direct further investigation. Thirdly, treatment dose should also be considered a central aspect of reporting given its key feature of human teratogens (Brent 2004) and as highlighted by the dose mediated risk documented for VPA. The advice which may be given to an individual female on VPA would likely be very different depending on her dose. The studies which did investigate the relationship between dose and outcome used varying cut offs and therefore comparisons across studies was difficult. In the future research groups should look to standardise dose categories to enable uniform reporting. Fourthly, all data should be reported for the control groups, even if just in tabular format to aid future meta-analysis.
The fifth recommendation would be that observations have shown that some women who take AEDs, even at a very low dose, appear to be at higher risk of having a child with an AED-associated malformation. Further research focusing on identification of genomic variants which might modify how different women metabolise AEDs is crucial so that those who may be at higher risk of having a child with a malformation, even taking a lower dose of a specific AED, can be identified. Whilst this has proven difficult in the past, whole exome/genome sequencing, with careful selection of individuals for testing is likely to make this more achievable (Ku 2011).
Finally, there is a clear trend that data for newer drugs is coming from the large national registers. This is not surprising given the time it can take for cases in individual hospitals to accumulate. The continued existence of these registers are of central importance to the generation of information to inform preconceptual counselling and efforts to increase reporting to such registers should be undertaken at a clinician and regulatory level.Get full text at The Cochrane Library
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