e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 3 7 e4 0
Official Journal of the European Paediatric Neurology Society
Original article
Pregnancy and neurodevelopmental outcomes with in-utero antiepileptic agent exposure. A pilot study Dimitrios Arkilo a,*, Julie Hanna a,b, Deanna Dickens a,b, Lorna Justesen a, Jenny Brunn a, Sarah Garland a, Patricia Penovich a,b Minnesota Epilepsy Group, P.A.® of United Hospital and Children's Hospitals and Clinics of Minnesota, 225 Smith Ave N, # 201, St. Paul, MN 55102, USA b Department of Neurology, University of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455, USA a
article info
abstract
Article history:
Objective: To assess pregnancy outcomes on women exposed to monotherapy with anti-
Received 20 March 2014
epileptic agents.
Received in revised form
Methods: Questionnaires were sent to women with epilepsy in our practice who were
17 July 2014
pregnant between 2006 and 2011. 62/86 patients (72%) who responded were on mono-
Accepted 25 September 2014
therapy. 24 fetuses (63%) were exposed to lamotrigine, 11 (28%) to levetiracetam, 2 (5.2%) to topiramate, 1 (2.6%) to gabapentin, 17 (27%) to carbamazepine, 5 to phenytoin and 2 to
Keywords:
valproate.
Antiepileptic medication
Results: There were 55 (88%) live births and 7 unsuccessful pregnancies (miscarriages/
Pregnancy outcomes
stillbirths). Unsuccessful pregnancies were reported in 2/24 gestations exposed to lamo-
Developmental outcomes
trigine, 2/11 to levetiracetam and 3/17 to carbamazepine. Delayed motor development or speech delay requiring therapy and special programming was noted in 2/24 children prenatally exposed to lamotrigine, 3/17 exposed to carbamazepine and 1/2 children exposed to valproate. Conclusion: Our pilot study of children exposed to antiepileptic drug monotherapy in-utero demonstrated a favorable trend for successful pregnancy outcomes and developmental trajectory. © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
There are multiple reports available correlating the use of traditional antiepileptic drugs during gestation with a higher incidence of unsuccessful pregnancies and their effect of
prenatal exposure on the neurodevelopmental outcome of the child.1e5 The individual impact of each drug on cognitive outcome is different, with recent reports showing that intelligence quotient is affected in children exposed to valproate compared to other antiepileptic drugs.6 Data on the relative
* Corresponding author. Tel.: þ1 6512415290. E-mail address: [email protected] (D. Arkilo). http://dx.doi.org/10.1016/j.ejpn.2014.09.006 1090-3798/© 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
38
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 3 7 e4 0
safety of newer antiepileptic medication in pregnancy are limited due to the relatively short time of commercial availability of the agents and the need for longer clinical and functional follow up required for children exposed to them.7 Our objectives of this pilot study were to assess the pregnancy outcomes and the effect on the development of children of women exposed to antiepileptic drug monotherapy during their gestation.
2.
Material and methods
Questionnaires were sent to women with epilepsy in our practice who were pregnant between 2006 and 2011. Participants signed institutional review board approved informed consents and returned the information in pre-stamped return packets. Eligibility to participate in the survey required antiepileptic medication use for epilepsy at any point during the pregnancy. We investigated expectant mothers on monotherapy. The questionnaire is comprised of twenty five questions including the timing of the onset of the obstetric care, the number of antiepileptic drugs used during the gestation, folate use, pregnancy complications, number of seizures during pregnancy, occurrence of status epilepticus during pregnancy, gestational age at delivery, type of delivery, complications at delivery, neonatal APGAR scores, and neonatal intensive care unit admission. Abnormal developmental outcomes were defined as speech and/or delay requiring special services, including speech, occupational and/or physical therapy. The developmental outcomes were assessed at 2 years of age by developmental specialists assigned by the school districts. Unsuccessful pregnancies were defined as spontaneous miscarriages and stillbirth. Women who were lost to follow up were excluded from the survey.
3.
Results
There were 91 questionnaires sent. 62 of the 86 patients who responded were on monotherapy. All 62 pregnancies reported were singleton. 38 fetuses (69%) were exposed to medication approved after 1990 and 24 fetuses (31%) to older antiepileptic drugs. 24 fetuses were exposed to lamotrigine, 11 to levetiracetam, 2 to topiramate and 1 to gabapentin. Also 17 fetuses were exposed to carbamazepine, 5 to phenytoin and 2 to
valproate. There were no major malformations noted. The average age of the expectant mothers were 22 years for valproate, 28 for levetiracetam, 31 for lamotrigine, 27 for gabapentin, 27 for carbamazepine, 25 for phenytoin and 25 years for topiramate. All women were on folic acid prior to the onset of the pregnancy and received standard prenatal care throughout the gestation starting at the first trimester. Seizures during the pregnancy were reported in 8 expectant mothers on lamotrigine, 3 on levetiracetam, 2 on carbamazepine and 1 on gabapentin of who only 3 children had abnormal development (3/14, 21%). Antiepileptic levels were tested on all the women with breakthrough seizures and notably for lamotrigine were sub therapeutic for 4 of the 8 expectant mothers. Premature delivery (less than 36 weeks gestation) was reported in 3 women on lamotrigine, 2 on levetiracetam and 5 on carbamazepine. There were 55 (88%, 55/62) live births and 7 unsuccessful pregnancies (miscarriages/stillbirths). Unsuccessful pregnancies were reported in 2 gestations exposed to lamotrigine (3% of total, 2/24 exposed to lamotrigine), 2 to levetiracetam (3% of total, 2/11 exposed to levetiracetam) and 3 to carbamazepine (5% of total, 3/17 exposed to carbamazepine). Of the 17 pregnancies exposed to carbamazepine 2 resulted in stillbirths and 1 resulted in spontaneous miscarriage. Maternal ages at the onset of the pregnancy were twentythree and thirty-six years. Neither of these women had seizures during their pregnancies. Of the 24 pregnancies exposed to lamotrigine 2 resulted in spontaneous miscarriages. Maternal ages at conception were twenty-eight and thirty-six years. Neither of these women had seizures during their pregnancies. Of the 11 pregnancies exposed to levetiracetam 2 gestations resulted in stillbirth. Maternal ages at conception were twenty-eight and forty years. The forty year old mother did not have any prior pregnancies. Neither of these women had seizures during their pregnancies (Table 1a). Abnormal development was noted in 6 children: 2/24 prenatally exposed to lamotrigine monotherapy (3.5% of total children), 3/17 exposed to carbamazepine monotherapy (5% of total children) and 1/2 children exposed to valproate monotherapy (2% of total children). Of the children exposed to carbamazepine in-utero, 1 child was diagnosed with autistic spectrum disorder requiring occupational therapy. Maternal age at this conception was twenty-seven years. The pregnancy was complicated by gestational diabetes and two focal onset seizures with
Table 1a e Demographics and pregnancy outcomes. AED
Lamotrigine Levetiracetam Topiramate Gabapentin Carbamazepine Phenytoin Valproate
Number of fetuses exposed
Average age of expectant mothers
# of seizures during pregnancy
Premature delivery
24 11 2 1 17 5 2
31 28 25 27 27 25 22
8 3 e 1 2 e e
3 2 e e 5 e e
Pregnancy outcomes Infant births
Miscarriages/ stillbirths
22 9 2 1 14 5 2
2 2 e e 3 e e
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 3 7 e4 0
dyscognitive changes in the third trimester. Delivery was complicated by fetal bradycardia leading to induction and vaginal delivery. Gestational age at delivery was thirty-eight weeks. Maternal IQ rate was in the mild intellectual disability range. The other 2 children with abnormal development exposed to carbamazepine were diagnosed with hypotonia, delayed speech and motor development, requiring speech and physical therapy. Both women have normal IQs. Maternal ages at conception were thirty-three and thirty-one years respectively. Both pregnancies were unremarkable. Deliveries occurred at thirty two and thirty six weeks respectively. Both children had a brief hospitalization in the neonatal intensive care unit. Both mothers were seizure free during their pregnancies. Of the 2 children with abnormal development exposed to lamotrigine in-utero, 1 child was diagnosed with Goldenhar syndrome with significant delay in the gross motor skills and developmental delay requiring physical occupational and speech therapy. Maternal age at conception was twenty-seven years. The pregnancy was complicated by placenta previa and three generalized tonic clonic seizures in the first and second trimester. Delivery occurred at thirty-nine weeks. The second child was diagnosed with hypotonia and delayed speech and motor development, requiring speech and physical therapy. Maternal age at conception was twenty-seven years. Pregnancy was unremarkable and delivery occurred at thirty-eight weeks. Both maternal IQs are normal. The 1 child with abnormal development who was exposed in-utero to valproate was diagnosed with central hypotonia and had significant delay in the gross motor skills requiring occupational therapy. Maternal age at conception was twenty-nine. The pregnancy was complicated by placenta previa. Nine focal onset seizures without dyscognitive changes were experienced throughout the gestation. Delivery occurred at forty weeks and maternal IQ was normal (Table 1b).
4.
Discussion
On average two thirds of women with epilepsy remain seizure free during their pregnancy (66.6%) and pregnancies exposed to lamotrigine are less likely to be seizure free due to the decreased and at times unpredictable levels noted during the gestation.8 Pregnancies complicated by convulsive seizures at any point of the gestation have been associated with prematurity, low birth-weight and small-for-gestational-age.9,10 Therefore it is imperative to attempt to control seizures, but
39
the clinician needs to balance the risks of uncontrolled seizures during pregnancy against potential teratogenic and neurodevelopmental effects of antiepileptic drugs.11 In a previous reports eighty-eight percent of pregnancies of women on antiepileptic medication resulted in a healthy live birth, six percent in a live birth with a birth defect, and four percent in spontaneous abortions and stillbirth.5 The risk of major congenital malformations is more common for valproate (9%), phenobarbital (5.5%) and topiramate (4.2%) compared to carbamazepine (3%), levetiracetam (2.4%) and lamotrigine (2%). The most common malformations are neural tube defects, hypospadias, cardiac defects, and oral clefts for valproate, cardiac defects and oral clefts for phenobarbital and oral clefts for topiramate.7 Furthermore, recent evidence from the NEAD study shows that children exposed in utero to valproate had lower IQ scores at age six compared to carbamazepine, lamotrigine or phenytoin (p ¼ 0.0015, p ¼ 0.0003 and p ¼ 0.0006 respectively) and a dose dependent negative association for verbal ability, non-verbal ability, memory and executive function.6 In our cohort, expectant mothers on antiepileptic medication had good follow up. All pregnant patients received prenatal care during their first trimester of gestation and were supplemented with folate throughout their pregnancies. The pregnancy outcomes were similar to the ones reported in prior studies with 88% of the gestations leading to live births, without any congenital malformations noted. The prevalence of seizures during pregnancy in our group was less compared to reported data (22% versus 34%) and 8 out of the 14 women who experienced seizures were on lamotrigine. This can be explained in part by the erratic lamotrigine levels during the gestation. Unsuccessful pregnancies were reported in two 2/ 11 gestations exposed to levetiracetam, 3/17 to carbamazepine and 2/24 to lamotrigine. Abnormal development was noted in two 2/24 of children exposed in-utero to lamotrigine, 3/17 to carbamazepine and one 1/2 to valproate, with the majority of children having hypotonia and speech delay, requiring physical, occupational and speech therapy. The child diagnosed with Goldenhar syndrome required speech therapy due to his diagnosis and most likely the developmental delays were unrelated to lamotrigine. However, Goldenhar syndrome has multifactorial etiology and for this reason it is included in our report. For the children exposed to carbamazepine there are significant confounders for two out of the three of them, including birth at 32 weeks and the maternal IQ in the intellectual disability range. Notably none of the children exposed to levetiracetam had developmental delays. The percentage of affected total
Table 1b e Developmental outcomes per medication. AED
# of Children with reported abnormal development
Diagnoses
Lamotrigine
2
Carbamazepine
3
Valproate
1
1 ¼ Goldenhar syndrome with significant delay in gross motor skills and developmental delay 1 ¼ Hypotonia and delayed speech & motor development 1 ¼ Autism Spectrum Disorder 2 ¼ Hypotonia and delayed speech & motor development Hypotonia and significant delay in gross motor skills
40
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 3 7 e4 0
children in our cohort is similar to the prevalence of developmental disabilities reported in US.12 Our study has limitations, including the small number of gestations. More specifically for some medication subgroups such as topiramate, gabapentin and valproate due to the small number of participants their influence on gestation and the fetus cannot be assessed. As this was a retrospective evaluation we could not exclude the effect on development of other confounding factors, such as prematurity and levels of anticonvulsant medication. Lastly this study may have reporting bias as there is the possibility that the women who responded represented a portion of the cohort that had good prenatal care and neurological follow up.
Funding All authors did not have any funding sources related to the study and to the article preparation.
Ethical approval This study was reviewed and exempted by the Allina Health IRB.
Acknowledgments 5.
Conclusions
In our pilot study, pregnancy and neurodevelopmental outcomes are similar to the general population for women exposed to antiepileptic drugs during their gestation and it contributes to the existing literature on this issue. Overall it demonstrates a favorable trend with the exception of valproate. Further studies are needed though exploring the effect of antiepileptic medication on neurodevelopmental trajectory of in-utero exposed children.
Disclosures All authors have no commercial, financial or other associations to disclose that poses a conflict of interest in connection with the submitted article.
Author contribution/roles Dimitrios Arkilo was responsible for the concept and design of the study, for the collection of data, interpretation of the data, and for the drafting and editing of the document. Julie Hanna and Deanna Dickens were responsible for the concept and design of the study, and the collection of data. Lorna Justensen, Jenny Brunn and Sarah Garland were responsible for the collection and interpretation of data. Patricia Penovich was responsible for the concept and design, collection and interpretation of data and participated in the drafting and editing of the document. All authors have read and have approved the manuscript as submitted. All authors are responsible for the reported research.
Declaration of conflicting interests The authors and collaborators have no commercial, financial or other associations that pose a conflict of interest.
This study was conducted at the Minnesota Epilepsy Group, St. Paul, MN and was presented as an abstract at AAN's annual meeting, 2013, San Diego, CA.
references
1. Meadow SR. Anticonvulsant drugs and congenital abnormalities. Lancet 1968;2:1296. 2. Battino D, Tomson T. Management of epilepsy during pregnancy. Drugs 2007;67(18):2727e46. 3. Mølgaard-Nielsen D, Hviid A. Newer-generation antiepileptic drugs and the risk of major birth defects. JAMA 2011;305:1996e2002. 4. Meador K, Baker G, Browning N, et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009;360:1597e605. 5. Vajda FJ, O'Brien TJ, Hitchcock A, Graham J, Lander C. The Australian registry of anti-epileptic drugs in pregnancy: experience after 30 months. J Clin Neurosci 2003 Sep;10(5):543e9. 6. Meador KJ, Baker GA, Browning N, et al., NEAD Study Group. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol 2013 Mar;12(3):244e52. ndez-Dı´az S, Smith CR, Shen A, et al., For the North 7. Herna American AED Pregnancy Registry. Comparative safety of antiepileptic drugs during pregnancy. Neurology 2012 May 22;78(21):1692e9. 8. Battino D, Tomson T, Bonizzoni E. Seizure control and treatment changes in pregnancy: observations from the EURAP epilepsy pregnancy registry. Epilepsia 2013 Sep;54(9):1621e7. 9. Chen YH, Chiou HY, Lin HC, Lin HL. Affect of seizures during gestation on pregnancy outcomes in women with epilepsy. Arch Neurol 2009 Aug;66(8):979e84. 10. Rauchenzauner M, Ehrensberger M, Prieschl M, et al. Generalized tonic-clonic seizures and antiepileptic drugs during pregnancy-a matter of importance for the baby? J Neurol 2013 Feb;260(2):484e8. 11. Tomson T, Landmark CJ, Battino D. Antiepileptic drug treatment in pregnancy: changes in drug disposition and their clinical implications. Epilepsia 2013 Mar;54(3):405e14. 12. Boyle C, Boulet S, Schieve L, et al. Trends in the prevalence of developmental disabilities in US children, 1997-2008. Pediatrics 2011, Jun;127(6):1034e42.
Official Journal of the European Paediatric Neurology Society
Original article
Pregnancy and neurodevelopmental outcomes with in-utero antiepileptic agent exposure. A pilot study Dimitrios Arkilo a,*, Julie Hanna a,b, Deanna Dickens a,b, Lorna Justesen a, Jenny Brunn a, Sarah Garland a, Patricia Penovich a,b Minnesota Epilepsy Group, P.A.® of United Hospital and Children's Hospitals and Clinics of Minnesota, 225 Smith Ave N, # 201, St. Paul, MN 55102, USA b Department of Neurology, University of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455, USA a
article info
abstract
Article history:
Objective: To assess pregnancy outcomes on women exposed to monotherapy with anti-
Received 20 March 2014
epileptic agents.
Received in revised form
Methods: Questionnaires were sent to women with epilepsy in our practice who were
17 July 2014
pregnant between 2006 and 2011. 62/86 patients (72%) who responded were on mono-
Accepted 25 September 2014
therapy. 24 fetuses (63%) were exposed to lamotrigine, 11 (28%) to levetiracetam, 2 (5.2%) to topiramate, 1 (2.6%) to gabapentin, 17 (27%) to carbamazepine, 5 to phenytoin and 2 to
Keywords:
valproate.
Antiepileptic medication
Results: There were 55 (88%) live births and 7 unsuccessful pregnancies (miscarriages/
Pregnancy outcomes
stillbirths). Unsuccessful pregnancies were reported in 2/24 gestations exposed to lamo-
Developmental outcomes
trigine, 2/11 to levetiracetam and 3/17 to carbamazepine. Delayed motor development or speech delay requiring therapy and special programming was noted in 2/24 children prenatally exposed to lamotrigine, 3/17 exposed to carbamazepine and 1/2 children exposed to valproate. Conclusion: Our pilot study of children exposed to antiepileptic drug monotherapy in-utero demonstrated a favorable trend for successful pregnancy outcomes and developmental trajectory. © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
There are multiple reports available correlating the use of traditional antiepileptic drugs during gestation with a higher incidence of unsuccessful pregnancies and their effect of
prenatal exposure on the neurodevelopmental outcome of the child.1e5 The individual impact of each drug on cognitive outcome is different, with recent reports showing that intelligence quotient is affected in children exposed to valproate compared to other antiepileptic drugs.6 Data on the relative
* Corresponding author. Tel.: þ1 6512415290. E-mail address: [email protected] (D. Arkilo). http://dx.doi.org/10.1016/j.ejpn.2014.09.006 1090-3798/© 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
38
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 3 7 e4 0
safety of newer antiepileptic medication in pregnancy are limited due to the relatively short time of commercial availability of the agents and the need for longer clinical and functional follow up required for children exposed to them.7 Our objectives of this pilot study were to assess the pregnancy outcomes and the effect on the development of children of women exposed to antiepileptic drug monotherapy during their gestation.
2.
Material and methods
Questionnaires were sent to women with epilepsy in our practice who were pregnant between 2006 and 2011. Participants signed institutional review board approved informed consents and returned the information in pre-stamped return packets. Eligibility to participate in the survey required antiepileptic medication use for epilepsy at any point during the pregnancy. We investigated expectant mothers on monotherapy. The questionnaire is comprised of twenty five questions including the timing of the onset of the obstetric care, the number of antiepileptic drugs used during the gestation, folate use, pregnancy complications, number of seizures during pregnancy, occurrence of status epilepticus during pregnancy, gestational age at delivery, type of delivery, complications at delivery, neonatal APGAR scores, and neonatal intensive care unit admission. Abnormal developmental outcomes were defined as speech and/or delay requiring special services, including speech, occupational and/or physical therapy. The developmental outcomes were assessed at 2 years of age by developmental specialists assigned by the school districts. Unsuccessful pregnancies were defined as spontaneous miscarriages and stillbirth. Women who were lost to follow up were excluded from the survey.
3.
Results
There were 91 questionnaires sent. 62 of the 86 patients who responded were on monotherapy. All 62 pregnancies reported were singleton. 38 fetuses (69%) were exposed to medication approved after 1990 and 24 fetuses (31%) to older antiepileptic drugs. 24 fetuses were exposed to lamotrigine, 11 to levetiracetam, 2 to topiramate and 1 to gabapentin. Also 17 fetuses were exposed to carbamazepine, 5 to phenytoin and 2 to
valproate. There were no major malformations noted. The average age of the expectant mothers were 22 years for valproate, 28 for levetiracetam, 31 for lamotrigine, 27 for gabapentin, 27 for carbamazepine, 25 for phenytoin and 25 years for topiramate. All women were on folic acid prior to the onset of the pregnancy and received standard prenatal care throughout the gestation starting at the first trimester. Seizures during the pregnancy were reported in 8 expectant mothers on lamotrigine, 3 on levetiracetam, 2 on carbamazepine and 1 on gabapentin of who only 3 children had abnormal development (3/14, 21%). Antiepileptic levels were tested on all the women with breakthrough seizures and notably for lamotrigine were sub therapeutic for 4 of the 8 expectant mothers. Premature delivery (less than 36 weeks gestation) was reported in 3 women on lamotrigine, 2 on levetiracetam and 5 on carbamazepine. There were 55 (88%, 55/62) live births and 7 unsuccessful pregnancies (miscarriages/stillbirths). Unsuccessful pregnancies were reported in 2 gestations exposed to lamotrigine (3% of total, 2/24 exposed to lamotrigine), 2 to levetiracetam (3% of total, 2/11 exposed to levetiracetam) and 3 to carbamazepine (5% of total, 3/17 exposed to carbamazepine). Of the 17 pregnancies exposed to carbamazepine 2 resulted in stillbirths and 1 resulted in spontaneous miscarriage. Maternal ages at the onset of the pregnancy were twentythree and thirty-six years. Neither of these women had seizures during their pregnancies. Of the 24 pregnancies exposed to lamotrigine 2 resulted in spontaneous miscarriages. Maternal ages at conception were twenty-eight and thirty-six years. Neither of these women had seizures during their pregnancies. Of the 11 pregnancies exposed to levetiracetam 2 gestations resulted in stillbirth. Maternal ages at conception were twenty-eight and forty years. The forty year old mother did not have any prior pregnancies. Neither of these women had seizures during their pregnancies (Table 1a). Abnormal development was noted in 6 children: 2/24 prenatally exposed to lamotrigine monotherapy (3.5% of total children), 3/17 exposed to carbamazepine monotherapy (5% of total children) and 1/2 children exposed to valproate monotherapy (2% of total children). Of the children exposed to carbamazepine in-utero, 1 child was diagnosed with autistic spectrum disorder requiring occupational therapy. Maternal age at this conception was twenty-seven years. The pregnancy was complicated by gestational diabetes and two focal onset seizures with
Table 1a e Demographics and pregnancy outcomes. AED
Lamotrigine Levetiracetam Topiramate Gabapentin Carbamazepine Phenytoin Valproate
Number of fetuses exposed
Average age of expectant mothers
# of seizures during pregnancy
Premature delivery
24 11 2 1 17 5 2
31 28 25 27 27 25 22
8 3 e 1 2 e e
3 2 e e 5 e e
Pregnancy outcomes Infant births
Miscarriages/ stillbirths
22 9 2 1 14 5 2
2 2 e e 3 e e
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 3 7 e4 0
dyscognitive changes in the third trimester. Delivery was complicated by fetal bradycardia leading to induction and vaginal delivery. Gestational age at delivery was thirty-eight weeks. Maternal IQ rate was in the mild intellectual disability range. The other 2 children with abnormal development exposed to carbamazepine were diagnosed with hypotonia, delayed speech and motor development, requiring speech and physical therapy. Both women have normal IQs. Maternal ages at conception were thirty-three and thirty-one years respectively. Both pregnancies were unremarkable. Deliveries occurred at thirty two and thirty six weeks respectively. Both children had a brief hospitalization in the neonatal intensive care unit. Both mothers were seizure free during their pregnancies. Of the 2 children with abnormal development exposed to lamotrigine in-utero, 1 child was diagnosed with Goldenhar syndrome with significant delay in the gross motor skills and developmental delay requiring physical occupational and speech therapy. Maternal age at conception was twenty-seven years. The pregnancy was complicated by placenta previa and three generalized tonic clonic seizures in the first and second trimester. Delivery occurred at thirty-nine weeks. The second child was diagnosed with hypotonia and delayed speech and motor development, requiring speech and physical therapy. Maternal age at conception was twenty-seven years. Pregnancy was unremarkable and delivery occurred at thirty-eight weeks. Both maternal IQs are normal. The 1 child with abnormal development who was exposed in-utero to valproate was diagnosed with central hypotonia and had significant delay in the gross motor skills requiring occupational therapy. Maternal age at conception was twenty-nine. The pregnancy was complicated by placenta previa. Nine focal onset seizures without dyscognitive changes were experienced throughout the gestation. Delivery occurred at forty weeks and maternal IQ was normal (Table 1b).
4.
Discussion
On average two thirds of women with epilepsy remain seizure free during their pregnancy (66.6%) and pregnancies exposed to lamotrigine are less likely to be seizure free due to the decreased and at times unpredictable levels noted during the gestation.8 Pregnancies complicated by convulsive seizures at any point of the gestation have been associated with prematurity, low birth-weight and small-for-gestational-age.9,10 Therefore it is imperative to attempt to control seizures, but
39
the clinician needs to balance the risks of uncontrolled seizures during pregnancy against potential teratogenic and neurodevelopmental effects of antiepileptic drugs.11 In a previous reports eighty-eight percent of pregnancies of women on antiepileptic medication resulted in a healthy live birth, six percent in a live birth with a birth defect, and four percent in spontaneous abortions and stillbirth.5 The risk of major congenital malformations is more common for valproate (9%), phenobarbital (5.5%) and topiramate (4.2%) compared to carbamazepine (3%), levetiracetam (2.4%) and lamotrigine (2%). The most common malformations are neural tube defects, hypospadias, cardiac defects, and oral clefts for valproate, cardiac defects and oral clefts for phenobarbital and oral clefts for topiramate.7 Furthermore, recent evidence from the NEAD study shows that children exposed in utero to valproate had lower IQ scores at age six compared to carbamazepine, lamotrigine or phenytoin (p ¼ 0.0015, p ¼ 0.0003 and p ¼ 0.0006 respectively) and a dose dependent negative association for verbal ability, non-verbal ability, memory and executive function.6 In our cohort, expectant mothers on antiepileptic medication had good follow up. All pregnant patients received prenatal care during their first trimester of gestation and were supplemented with folate throughout their pregnancies. The pregnancy outcomes were similar to the ones reported in prior studies with 88% of the gestations leading to live births, without any congenital malformations noted. The prevalence of seizures during pregnancy in our group was less compared to reported data (22% versus 34%) and 8 out of the 14 women who experienced seizures were on lamotrigine. This can be explained in part by the erratic lamotrigine levels during the gestation. Unsuccessful pregnancies were reported in two 2/ 11 gestations exposed to levetiracetam, 3/17 to carbamazepine and 2/24 to lamotrigine. Abnormal development was noted in two 2/24 of children exposed in-utero to lamotrigine, 3/17 to carbamazepine and one 1/2 to valproate, with the majority of children having hypotonia and speech delay, requiring physical, occupational and speech therapy. The child diagnosed with Goldenhar syndrome required speech therapy due to his diagnosis and most likely the developmental delays were unrelated to lamotrigine. However, Goldenhar syndrome has multifactorial etiology and for this reason it is included in our report. For the children exposed to carbamazepine there are significant confounders for two out of the three of them, including birth at 32 weeks and the maternal IQ in the intellectual disability range. Notably none of the children exposed to levetiracetam had developmental delays. The percentage of affected total
Table 1b e Developmental outcomes per medication. AED
# of Children with reported abnormal development
Diagnoses
Lamotrigine
2
Carbamazepine
3
Valproate
1
1 ¼ Goldenhar syndrome with significant delay in gross motor skills and developmental delay 1 ¼ Hypotonia and delayed speech & motor development 1 ¼ Autism Spectrum Disorder 2 ¼ Hypotonia and delayed speech & motor development Hypotonia and significant delay in gross motor skills
40
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 3 7 e4 0
children in our cohort is similar to the prevalence of developmental disabilities reported in US.12 Our study has limitations, including the small number of gestations. More specifically for some medication subgroups such as topiramate, gabapentin and valproate due to the small number of participants their influence on gestation and the fetus cannot be assessed. As this was a retrospective evaluation we could not exclude the effect on development of other confounding factors, such as prematurity and levels of anticonvulsant medication. Lastly this study may have reporting bias as there is the possibility that the women who responded represented a portion of the cohort that had good prenatal care and neurological follow up.
Funding All authors did not have any funding sources related to the study and to the article preparation.
Ethical approval This study was reviewed and exempted by the Allina Health IRB.
Acknowledgments 5.
Conclusions
In our pilot study, pregnancy and neurodevelopmental outcomes are similar to the general population for women exposed to antiepileptic drugs during their gestation and it contributes to the existing literature on this issue. Overall it demonstrates a favorable trend with the exception of valproate. Further studies are needed though exploring the effect of antiepileptic medication on neurodevelopmental trajectory of in-utero exposed children.
Disclosures All authors have no commercial, financial or other associations to disclose that poses a conflict of interest in connection with the submitted article.
Author contribution/roles Dimitrios Arkilo was responsible for the concept and design of the study, for the collection of data, interpretation of the data, and for the drafting and editing of the document. Julie Hanna and Deanna Dickens were responsible for the concept and design of the study, and the collection of data. Lorna Justensen, Jenny Brunn and Sarah Garland were responsible for the collection and interpretation of data. Patricia Penovich was responsible for the concept and design, collection and interpretation of data and participated in the drafting and editing of the document. All authors have read and have approved the manuscript as submitted. All authors are responsible for the reported research.
Declaration of conflicting interests The authors and collaborators have no commercial, financial or other associations that pose a conflict of interest.
This study was conducted at the Minnesota Epilepsy Group, St. Paul, MN and was presented as an abstract at AAN's annual meeting, 2013, San Diego, CA.
references
1. Meadow SR. Anticonvulsant drugs and congenital abnormalities. Lancet 1968;2:1296. 2. Battino D, Tomson T. Management of epilepsy during pregnancy. Drugs 2007;67(18):2727e46. 3. Mølgaard-Nielsen D, Hviid A. Newer-generation antiepileptic drugs and the risk of major birth defects. JAMA 2011;305:1996e2002. 4. Meador K, Baker G, Browning N, et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009;360:1597e605. 5. Vajda FJ, O'Brien TJ, Hitchcock A, Graham J, Lander C. The Australian registry of anti-epileptic drugs in pregnancy: experience after 30 months. J Clin Neurosci 2003 Sep;10(5):543e9. 6. Meador KJ, Baker GA, Browning N, et al., NEAD Study Group. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol 2013 Mar;12(3):244e52. ndez-Dı´az S, Smith CR, Shen A, et al., For the North 7. Herna American AED Pregnancy Registry. Comparative safety of antiepileptic drugs during pregnancy. Neurology 2012 May 22;78(21):1692e9. 8. Battino D, Tomson T, Bonizzoni E. Seizure control and treatment changes in pregnancy: observations from the EURAP epilepsy pregnancy registry. Epilepsia 2013 Sep;54(9):1621e7. 9. Chen YH, Chiou HY, Lin HC, Lin HL. Affect of seizures during gestation on pregnancy outcomes in women with epilepsy. Arch Neurol 2009 Aug;66(8):979e84. 10. Rauchenzauner M, Ehrensberger M, Prieschl M, et al. Generalized tonic-clonic seizures and antiepileptic drugs during pregnancy-a matter of importance for the baby? J Neurol 2013 Feb;260(2):484e8. 11. Tomson T, Landmark CJ, Battino D. Antiepileptic drug treatment in pregnancy: changes in drug disposition and their clinical implications. Epilepsia 2013 Mar;54(3):405e14. 12. Boyle C, Boulet S, Schieve L, et al. Trends in the prevalence of developmental disabilities in US children, 1997-2008. Pediatrics 2011, Jun;127(6):1034e42.
