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Meta-Analysis
. 2014 Oct 30;2014(10):CD010236.
doi: 10.1002/14651858.CD010236.pub2.

Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child

Rebecca Bromley  1 , Jennifer Weston, Naghme Adab, Janette Greenhalgh, Anna Sanniti, Andrew J McKay, Catrin Tudur Smith, Anthony G Marson
Affiliations
Meta-Analysis

Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child

Rebecca Bromley et al. Cochrane Database Syst Rev. .

Abstract

Background: Accumulating evidence suggests an association between prenatal exposure to antiepileptic drugs (AEDs) and increased risk of both physical anomalies and neurodevelopmental impairment. Neurodevelopmental impairment is characterised by either a specific deficit or a constellation of deficits across cognitive, motor and social skills and can be transient or continuous into adulthood. It is of paramount importance that these potential risks are identified, minimised and communicated clearly to women with epilepsy.

Objectives: To assess the effects of prenatal exposure to commonly prescribed AEDs on neurodevelopmental outcomes in the child and to assess the methodological quality of the evidence.

Search methods: We searched the Cochrane Epilepsy Group Specialized Register (May 2014), Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2014, Issue 4), MEDLINE (via Ovid) (1946 to May 2014), EMBASE (May 2014), Pharmline (May 2014) and Reprotox (May 2014). No language restrictions were imposed. Conference abstracts from the last five years were reviewed along with reference lists from the included studies.

Selection criteria: Prospective cohort controlled studies, cohort studies set within pregnancy registers and randomised controlled trials were selected for inclusion. Participants were women with epilepsy taking AED treatment; 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 (RB, JW and JG) independently selected studies for inclusion. Data extraction and risk of bias assessments were completed by five authors (RB, JW, AS, NA, AJM). The primary outcome was global cognitive functioning. Secondary outcomes included deficits in specific cognitive domains or prevalence of neurodevelopmental disorders. Due to substantial variation in study design and outcome reporting only limited data synthesis was possible.

Main results: Twenty-two prospective cohort studies were included and six registry based studies. Study quality varied. More recent studies tended to be larger and to report individual AED outcomes from blinded assessments, which indicate improved methodological quality.The developmental quotient (DQ) was lower in children exposed to carbamazepine (CBZ) (n = 50) than in children born to women without epilepsy (n = 79); mean difference (MD) of -5.58 (95% confidence interval (CI) -10.83 to -0.34, P = 0.04). The DQ of children exposed to CBZ (n = 163) was also lower compared to children of women with untreated epilepsy (n = 58) (MD -7.22, 95% CI -12.76 to - 1.67, P = 0.01). Further analysis using a random-effects model indicated that these results were due to variability within the studies and that there was no significant association with CBZ. The intelligence quotient (IQ) of older children exposed to CBZ (n = 150) was not lower than that of children born to women without epilepsy (n = 552) (MD -0.03, 95% CI -3.08 to 3.01, P = 0.98). Similarly, children exposed to CBZ (n = 163) were not poorer in terms of IQ in comparison to the children of women with untreated epilepsy (n = 87) (MD 1.84, 95% CI -2.13 to 5.80, P = 0.36). The DQ in children exposed to sodium valproate (VPA) (n = 123) was lower than the DQ in children of women with untreated epilepsy (n = 58) (MD -8.72, 95% -14.31 to -3.14, P = 0.002). The IQ of children exposed to VPA (n = 76) was lower than for children born to women without epilepsy (n = 552) (MD -8.94, 95% CI -11.96 to -5.92, P < 0.00001). Children exposed to VPA (n = 89) also had lower IQ than children born to women with untreated epilepsy (n = 87) (MD -8.17, 95% CI -12.80 to -3.55, P = 0.0005).In terms of drug comparisons, in younger children there was no significant difference in the DQ of children exposed to CBZ (n = 210) versus VPA (n=160) (MD 4.16, 95% CI -0.21 to 8.54, P = 0.06). However, the IQ of children exposed to VPA (n = 112) was significantly lower than for those exposed to CBZ (n = 191) (MD 8.69, 95% CI 5.51 to 11.87, P < 0.00001). The IQ of children exposed to CBZ (n = 78) versus lamotrigine (LTG) (n = 84) was not significantly different (MD -1.62, 95% CI -5.44 to 2.21, P = 0.41). There was no significant difference in the DQ of children exposed to CBZ (n = 172) versus phenytoin (PHT) (n = 87) (MD 3.02, 95% CI -2.41 to 8.46, P = 0.28). The IQ abilities of children exposed to CBZ (n = 75) were not different from the abilities of children exposed to PHT (n = 45) (MD -3.30, 95% CI -7.91 to 1.30, P = 0.16). IQ was significantly lower for children exposed to VPA (n = 74) versus LTG (n = 84) (MD -10.80, 95% CI -14.42 to -7.17, P < 0.00001). DQ was higher in children exposed to PHT (n = 80) versus VPA (n = 108) (MD 7.04, 95% CI 0.44 to 13.65, P = 0.04). Similarly IQ was higher in children exposed to PHT (n = 45) versus VPA (n = 61) (MD 9.25, 95% CI 4.78 to 13.72, P < 0.0001). A dose effect for VPA was reported in six studies, with higher doses (800 to 1000 mg daily or above) associated with a poorer cognitive outcome in the child. We identified no convincing evidence of a dose effect for CBZ, PHT or LTG. Studies not included in the meta-analysis were reported narratively, the majority of which supported the findings of the meta-analyses.

Authors' conclusions: The most important finding is the reduction in IQ in the VPA exposed group, which are sufficient to affect education and occupational outcomes in later life. However, for some women VPA is the most effective drug at controlling seizures. Informed treatment decisions require detailed counselling about these risks at treatment initiation and at pre-conceptual counselling. We have insufficient data about newer AEDs, some of which are commonly prescribed, and further research is required. Most women with epilepsy should continue their medication during pregnancy as uncontrolled seizures also carries a maternal risk.

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Conflict of interest statement

RB has provided expert opinion regarding child outcomes following prenatal exposure to AEDs and has contributed to studies funded by Sanofi Aventis and UCB Pharma. NA has been sponsored to attend educational meetings and conferences in epilepsy over the last five years by UCB Pharma, GSK and Boehringer Ingelheim, and has participated in regional advisory Board meetings for Eisai on their products eslicarbazepine and zonisamide. AM has been sponsored to attend a conference and has had research funding from Pfizer Ltd. Also a consortium of pharmaceutical companies (GSK, EISAI, UCB Pharma) funded the National Audit of Seizure Management in Hospitals (NASH) through grants paid to University of Liverpool. No further conflicts of interests declared.

Clarification statement added from the Co‐ordinating Editor on 8 June 2020: This review was found by the Cochrane Funding Arbiters, post‐publication, to be noncompliant with the Cochrane conflict of interest policy, which includes the relevant parts of the Cochrane Commercial Sponsorship Policy. It will be updated within 12 months. The update will have a majority of authors and lead author free of conflicts

Figures

1
1
Study flow diagram.
2
2
1.1
1.1. Analysis
Comparison 1: CBZ versus controls (women without epilepsy), Outcome 1: Development (Griffiths)
1.2
1.2. Analysis
Comparison 1: CBZ versus controls (women without epilepsy), Outcome 2: Development (Bayley)
1.3
1.3. Analysis
Comparison 1: CBZ versus controls (women without epilepsy), Outcome 3: IQ
1.4
1.4. Analysis
Comparison 1: CBZ versus controls (women without epilepsy), Outcome 4: IQ <2SD
1.5
1.5. Analysis
Comparison 1: CBZ versus controls (women without epilepsy), Outcome 5: VIQ
1.6
1.6. Analysis
Comparison 1: CBZ versus controls (women without epilepsy), Outcome 6: PIQ
2.1
2.1. Analysis
Comparison 2: CBZ versus controls (women with epilepsy, no AED treatment), Outcome 1: Development (Griffiths)
2.2
2.2. Analysis
Comparison 2: CBZ versus controls (women with epilepsy, no AED treatment), Outcome 2: Development (Bayley)
2.3
2.3. Analysis
Comparison 2: CBZ versus controls (women with epilepsy, no AED treatment), Outcome 3: IQ
2.4
2.4. Analysis
Comparison 2: CBZ versus controls (women with epilepsy, no AED treatment), Outcome 4: VPA below vs CBZ below IQ > 1SD
2.5
2.5. Analysis
Comparison 2: CBZ versus controls (women with epilepsy, no AED treatment), Outcome 5: IQ > 2SD
2.6
2.6. Analysis
Comparison 2: CBZ versus controls (women with epilepsy, no AED treatment), Outcome 6: VIQ
2.7
2.7. Analysis
Comparison 2: CBZ versus controls (women with epilepsy, no AED treatment), Outcome 7: PIQ
3.1
3.1. Analysis
Comparison 3: VPA versus controls (women without epilepsy), Outcome 1: Development (Griffiths)
3.2
3.2. Analysis
Comparison 3: VPA versus controls (women without epilepsy), Outcome 2: Development (Bayley)
3.3
3.3. Analysis
Comparison 3: VPA versus controls (women without epilepsy), Outcome 3: IQ
3.4
3.4. Analysis
Comparison 3: VPA versus controls (women without epilepsy), Outcome 4: IQ <2SD
3.5
3.5. Analysis
Comparison 3: VPA versus controls (women without epilepsy), Outcome 5: IQ <1SD
3.6
3.6. Analysis
Comparison 3: VPA versus controls (women without epilepsy), Outcome 6: VIQ
3.7
3.7. Analysis
Comparison 3: VPA versus controls (women without epilepsy), Outcome 7: PIQ
4.1
4.1. Analysis
Comparison 4: VPA versus controls (women with epilepsy, no AED treatment), Outcome 1: Development (Griffiths)
4.2
4.2. Analysis
Comparison 4: VPA versus controls (women with epilepsy, no AED treatment), Outcome 2: Development (Bayley)
4.3
4.3. Analysis
Comparison 4: VPA versus controls (women with epilepsy, no AED treatment), Outcome 3: IQ
4.4
4.4. Analysis
Comparison 4: VPA versus controls (women with epilepsy, no AED treatment), Outcome 4: IQ < 1SD
4.5
4.5. Analysis
Comparison 4: VPA versus controls (women with epilepsy, no AED treatment), Outcome 5: IQ <2SD
4.6
4.6. Analysis
Comparison 4: VPA versus controls (women with epilepsy, no AED treatment), Outcome 6: VIQ
4.7
4.7. Analysis
Comparison 4: VPA versus controls (women with epilepsy, no AED treatment), Outcome 7: PIQ
5.1
5.1. Analysis
Comparison 5: PHT versus controls (women without epilepsy), Outcome 1: Development (Bayley)
5.2
5.2. Analysis
Comparison 5: PHT versus controls (women without epilepsy), Outcome 2: IQ
6.1
6.1. Analysis
Comparison 6: PHT versus controls (women with epilepsy, no AED treatment), Outcome 1: Developmental (Bayley)
6.2
6.2. Analysis
Comparison 6: PHT versus controls (women with epilepsy, no AED treatment), Outcome 2: IQ
7.1
7.1. Analysis
Comparison 7: PB versus controls (women without epilepsy), Outcome 1: IQ
8.1
8.1. Analysis
Comparison 8: PB versus controls (women with epilepsy, no AED treatment), Outcome 1: Developmental (Bayley)
8.2
8.2. Analysis
Comparison 8: PB versus controls (women with epilepsy, no AED treatment), Outcome 2: IQ
9.1
9.1. Analysis
Comparison 9: LTG versus controls (women without epilepsy), Outcome 1: Developmental (Griffiths)
9.2
9.2. Analysis
Comparison 9: LTG versus controls (women without epilepsy), Outcome 2: IQ
10.1
10.1. Analysis
Comparison 10: LTG versus controls (women with epilepsy, no AED treatment), Outcome 1: Developmental (Griffiths)
10.2
10.2. Analysis
Comparison 10: LTG versus controls (women with epilepsy, no AED treatment), Outcome 2: IQ
11.1
11.1. Analysis
Comparison 11: LEV versus control (women without epilepsy), Outcome 1: Developmental (Griffiths)
12.1
12.1. Analysis
Comparison 12: CBZ versus LTG, Outcome 1: Development (Bayley)
12.2
12.2. Analysis
Comparison 12: CBZ versus LTG, Outcome 2: IQ
12.3
12.3. Analysis
Comparison 12: CBZ versus LTG, Outcome 3: IQ>1SD
13.1
13.1. Analysis
Comparison 13: CBZ versus PHT, Outcome 1: Development (Bayley)
13.2
13.2. Analysis
Comparison 13: CBZ versus PHT, Outcome 2: IQ
13.3
13.3. Analysis
Comparison 13: CBZ versus PHT, Outcome 3: DQ>1SD
14.1
14.1. Analysis
Comparison 14: VPA versus LTG, Outcome 1: Development (Bayley)
14.2
14.2. Analysis
Comparison 14: VPA versus LTG, Outcome 2: IQ
14.3
14.3. Analysis
Comparison 14: VPA versus LTG, Outcome 3: IQ>1SD
15.1
15.1. Analysis
Comparison 15: LEV versus VPA, Outcome 1: Development (Griffiths)
16.1
16.1. Analysis
Comparison 16: PHT versus VPA, Outcome 1: Development (Bayley)
16.2
16.2. Analysis
Comparison 16: PHT versus VPA, Outcome 2: IQ
16.3
16.3. Analysis
Comparison 16: PHT versus VPA, Outcome 3: DQ>1SD
17.1
17.1. Analysis
Comparison 17: CBZ versus VPA, Outcome 1: Development (Bayley)
17.2
17.2. Analysis
Comparison 17: CBZ versus VPA, Outcome 2: IQ
17.3
17.3. Analysis
Comparison 17: CBZ versus VPA, Outcome 3: VIQ
17.4
17.4. Analysis
Comparison 17: CBZ versus VPA, Outcome 4: PIQ
17.5
17.5. Analysis
Comparison 17: CBZ versus VPA, Outcome 5: DQ>1SD
17.6
17.6. Analysis
Comparison 17: CBZ versus VPA, Outcome 6: DQ>2SD
17.7
17.7. Analysis
Comparison 17: CBZ versus VPA, Outcome 7: IQ>2SD
17.8
17.8. Analysis
Comparison 17: CBZ versus VPA, Outcome 8: IQ>1SD
18.1
18.1. Analysis
Comparison 18: PHT versus LTG, Outcome 1: Developmental (Bayley)
18.2
18.2. Analysis
Comparison 18: PHT versus LTG, Outcome 2: IQ
19.1
19.1. Analysis
Comparison 19: CBZ versus PB, Outcome 1: Developmental (Bayley)
19.2
19.2. Analysis
Comparison 19: CBZ versus PB, Outcome 2: IQ
19.3
19.3. Analysis
Comparison 19: CBZ versus PB, Outcome 3: DQ >1SD
20.1
20.1. Analysis
Comparison 20: VPA versus PB, Outcome 1: Developmental (Bayley)
20.2
20.2. Analysis
Comparison 20: VPA versus PB, Outcome 2: IQ
21.1
21.1. Analysis
Comparison 21: PHT versus PB, Outcome 1: Developmental (Bayley)
21.2
21.2. Analysis
Comparison 21: PHT versus PB, Outcome 2: IQ
21.3
21.3. Analysis
Comparison 21: PHT versus PB, Outcome 3: DQ >1SD
22.1
22.1. Analysis
Comparison 22: Monotherapy versus controls (women without epilepsy), Outcome 1: Developmental (Griffiths)
22.2
22.2. Analysis
Comparison 22: Monotherapy versus controls (women without epilepsy), Outcome 2: Developmental (Bayley)
22.3
22.3. Analysis
Comparison 22: Monotherapy versus controls (women without epilepsy), Outcome 3: IQ
23.1
23.1. Analysis
Comparison 23: Monotherapy versus controls (women with epilepsy, no AED treatment), Outcome 1: Development (Griffiths)
23.2
23.2. Analysis
Comparison 23: Monotherapy versus controls (women with epilepsy, no AED treatment), Outcome 2: Developmental (Bayley)
23.3
23.3. Analysis
Comparison 23: Monotherapy versus controls (women with epilepsy, no AED treatment), Outcome 3: IQ
24.1
24.1. Analysis
Comparison 24: Polytherapy versus controls (women without epilepsy), Outcome 1: Developmental (Griffiths)
24.2
24.2. Analysis
Comparison 24: Polytherapy versus controls (women without epilepsy), Outcome 2: Developmental (Bayley)
24.3
24.3. Analysis
Comparison 24: Polytherapy versus controls (women without epilepsy), Outcome 3: IQ
25.1
25.1. Analysis
Comparison 25: Polytherapy versus controls (women with epilepsy, no AED treatment), Outcome 1: Developmental (Griffiths)
25.2
25.2. Analysis
Comparison 25: Polytherapy versus controls (women with epilepsy, no AED treatment), Outcome 2: Developmental (Bayley)
25.3
25.3. Analysis
Comparison 25: Polytherapy versus controls (women with epilepsy, no AED treatment), Outcome 3: IQ
26.1
26.1. Analysis
Comparison 26: Monotherapy versus polytherapy, Outcome 1: Developmental (Griffiths)
26.2
26.2. Analysis
Comparison 26: Monotherapy versus polytherapy, Outcome 2: Developmental (Bayley)
26.3
26.3. Analysis
Comparison 26: Monotherapy versus polytherapy, Outcome 3: IQ
27.1
27.1. Analysis
Comparison 27: VPA monotherapy versus VPA polytherapy, Outcome 1: Developmental (Bayley)
27.2
27.2. Analysis
Comparison 27: VPA monotherapy versus VPA polytherapy, Outcome 2: IQ
28.1
28.1. Analysis
Comparison 28: VPA polytherapy versus non‐VPA polytherapy, Outcome 1: IQ
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References

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    1. Thomas S, Ajaykumar B, Singhu K, Nair M, George B, Sarma P. Motor and mental development of infants exposed to antiepileptic drugs in utero. Epilepsy and Behavior 2008;13:229-36. - PubMed
Veiby 2013 {published data only}
    1. Veiby G, Daltveit A, Schjolberg S, Stoltenberg C, Oyen A-S, Vollset S et al. Exposure to antiepileptic drugs in utero and child development: a prospective population-based study. Epilepsia 2013;54(8):1462-72. - PMC - PubMed
Wide 2002 {published data only (unpublished sought but not used)}
    1. Wide K, Henning E, Eomson T, Winbladh B. Psychomotor development in preschool children exposed to antiepileptic drugs in utero. Acta Paediatrica 2002;91:409-14. - PubMed
    1. Wide K, Winbladh B, Tomson T, Sars-Zimmer K, Berggren E. Psychomotor development and minor anomalies in children exposed to antiepileptic drugs in utero: a prospective population-based study. Developmental Medicine and Child Neurology 2000;42:87-92. - PubMed

References to studies excluded from this review

Annegers 1974 {published data only}
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Antiga 2010 {published data only}
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Dean 2002 {published data only}
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Dessens 2000 {published data only}
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Forsberg 2011 {published data only}
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Holmes 2000 {published data only}
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Holmes 2005 {published data only}
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Jakubowska 1981 {published data only}
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Kelly 1984 {published data only}
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Kozhokaru 2010 {published data only}
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Latis 1982 {published data only}
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Lekwuwa 1995 {published data only}
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Majewski 1981 {published data only}
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Meador 2010 {published data only}
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Moore 2000 {published data only}
    1. Moore S, Turnpenny P, Quinn A et al. A clinical study of 57 children with fetal anticonvulsant syndromes. Journal of Medical Genetics 2000;37:489-97. - PMC - PubMed
Mortensen 1996 {published data only}
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Mortensen 2003 {published data only}
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Oyen 2007 {published data only}
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Parisi 2003 {published data only}
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Perinola 1992 {published data only}
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Rasalam 2005 {published data only}
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Sereno‐Colo 1984 {published data only}
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Steinhausen 1982 {published data only}
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Vanoverloop 1992 {published data only}
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Vert 1982 {published data only}
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    1. Vert P, Deblay M, Andre M. Follow-up study on growth and neurologic development of children born to epileptic mothers. In: Janz et al, editors(s). Epilepsy, Pregnancy, and the Child. New York: Raven Press, 1982:433-6.
Yamatogi 1993 {published data only}
    1. Yamatogi Y, Oka E, Satoh M, Kobayashi K, Yoshinaga H, Ohtahara S. A prospective follow-up of the offspring of epileptic patients. The Japanese Journal of Psychiatry and Neurology 1993;47(2):309-11. - PubMed

References to studies awaiting assessment

Adams 2000 Abstract {unpublished data only}
    1. Adams JHE, Holmes LB. Cognitive deficits following gestational monotherapy with phenobarbital and carbamazepine. Neurotoxicology and Teratology 2000;22:466.
Jovic 2011 Abstract {unpublished data only}
    1. Jovic N, Knezevic-Pogancev M, Ignjatovic MP. Cognitive functions at 6 years of age after fetal exposure to antiepileptic drugs used in mothers with juvenile myoclonic epilepsy. European Neuropsychopharmacology 2011;21(2):169.
Nadebaum 2011 Abstract {unpublished data only}
    1. Nadebaum C, Anderson V, Vajda F, Wood A. Academic achievement of Australian children prenatally exposed to antiepileptic drugs. International Epilepsy Congress. 2011. - PubMed
Wood 2011 Abstract {unpublished data only}
    1. Wood AG, Nadebaum C, Anderson VA, Reutens D, Barton S, O'Brien T, Vajda FV. Valproate dose is an independent risk factor for autism spectrum disorder: Evidence from prospective assessments in the Australian brain, cognition and antiepileptic drugs study. 29th International Epilepsy Congress .

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References to other published versions of this review

Abab 2004
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Publication types