- Email: [email protected]
Do Anti-Epileptic Drug modifications after first trimester of pregnancy influence fetal malformation or cognitive outcome?
Accepted Manuscript Title: Do Anti-Epileptic Drug modifications after first trimester of pregnancy influence fetal malformation or cognitive outcome? Authors: Ajay Asranna, Manna Jose, Rini M. Philip, Prabhakaran S. Sarma, Sanjeev V. Thomas PII: DOI: Reference:
S0920-1211(18)30201-8 https://doi.org/10.1016/j.eplepsyres.2018.07.017 EPIRES 5999
To appear in:
Epilepsy Research
Received date: Revised date: Accepted date:
24-4-2018 21-7-2018 24-7-2018
Please cite this article as: Asranna A, Jose M, Philip RM, Sarma PS, Thomas SV, Do Anti-Epileptic Drug modifications after first trimester of pregnancy influence fetal malformation or cognitive outcome?, Epilepsy Research (2018), https://doi.org/10.1016/j.eplepsyres.2018.07.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: Do Anti-Epileptic Drug modifications after first trimester of pregnancy influence fetal malformation or cognitive outcome?
Ajay Asranna1
- [email protected]
Manna Jose2
- [email protected] - [email protected]
Prabhakaran S. Sarma3
- [email protected]
Sanjeev V. Thomas 1,2
- [email protected]
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Affiliations and Address:
Department Of Neurology, Sree Chitra Tirunal Institute for Medical Sciences
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1
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Rini M.Philip2
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Authors:
Registry of Epilepsy and Pregnancy, Department of Neurology, Sree
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2 Kerala
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and Technology, Trivandrum, India - 695011
Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum,
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India - - 695011
Achutha Menon Centre for Health Science Studies, Sree Chitra Tirunal
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Institute for Medical Sciences and Technology, Trivandrum, India - 695011 Corresponding Author:
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Prof. Sanjeev V. Thomas, MD, DM Kerala Registry of Epilepsy and Pregnancy, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum 695011, India
Phone +91 471 252468 Email: [email protected]
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HIGHLIGHTS
AED dosage/ regime changes are effected during pregnancy in substantial proportion of Women With Epilepsy
A third of women who were not on AEDs in the first trimester were started on AEDs later in pregnancy
Most Women With Epilepsy (WWE) who were on monotherapy in first trimester remained on the same AED and dosage during the rest of pregnancy period
There was no association between AED modifications in the second/ third trimester and prevalence of major congenital malformations
There was a non-significant trend towards lower DQ with increase in dose or addition of drugs in the second or third trimester for several AEDs
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Objective: The management of Women With Epilepsy (WWE) in pregnancy is a challenge that demands balancing the risks of Major Congenital Malformation (MCM) on one hand with adequate seizure control on the other. While most studies have analysed the risks of Anti-Epileptic Drugs (AED)
exposure in the first trimester, AED changes during the second and third trimester and their effects on fetal outcome has not been studied adequately. Materials and Methods: Data of WWE who were prospectively followed up and completed pregnancy with live birth under the Kerala registry of epilepsy and pregnancy (KREP) between 1998 and 2014 were analysed. The AED
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addition, dose escalation, unchanged continuation, dose reduction or
stoppage during the second or third trimester in comparison to the first
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trimester was tabulated for each drug. The outcome measures evaluated
were malformation status and Developmental Quotient (DQ) at one year as
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extracted from the clinical records of the registry.
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Results: The first trimester AED exposure was nil for 231, monotherapy for
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925 and polytherapy for 391 WWE. WWE on monotherapy in first trimester
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were more likely to remain on the same number of AEDs in second or third trimester than those who were on polytherapy (OR 3.1, 95% CI 2.2 – 4.46).
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AED naïve women had a higher likelihood (OR 16.7; 95% CI 10.9 – 25.8) of
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being started on AED than women on monotherapy being switched to polytherapy. At least one AED was reduced or stopped during second or third
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trimester more often in women on polytherapy (15.1%) than in women on monotherapy (3.7%) (OR 4.7; 95% CI 2.9 – 7.2). Malformation rates for the
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infants of women whose AED dosage was increased or added were not significantly different from those of others. There was no statistically significant change in DQ with increase in dose or addition of drugs in the second or third trimester.
Conclusion: AEDs were reduced in a significant proportion of patients on polytherapy while more than a third of women who were not on AEDs in the first trimester were subsequently started on AEDs. Increase in dose or addition of AEDs after the first trimester is unlikely to influence malformation outcome but the potential adverse effect on the DQ needs to be explored on a
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larger set of data.
ABBREVIATIONS: AED, Anti-epileptic drug; CBZ, Carbamazepine; CI, Confidence Interval; CLB, Clobazam; GTCS, Generalized tonic clonic
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seizures; ILAE, International League Against Epilepsy; KREP, Kerala Registry
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for Epilepsy and Pregnancy; LMP, last menstrual period; LEV, Levetiracetam;
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LTG, Lamotrigine; MCM, Major congenital malformation; OR, Odds Ratio;
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OXC, Oxcarbazepine; PB, Phenobarbitone; PHT, Phenytoin; SPFL,
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With Epilepsy
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Spontaneous fetal loss; TPM, Topiramate; VPA, Valproate; WWE, Women
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Keywords: Epilepsy, Pregnancy, Antiepileptic drugmodifications, Major
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Congenital malformation
1. Introduction: Anti-Epileptic Drug (AED) exposure during pregnancy has been associated with increased risk of major congenital malformations (MCM).(1)(2)(3) Important factors influencing the risk of malformations
include polytherapy, exposure to Valproate (VPA) and higher dosage.(4) The deleterious effects of prenatal AED exposure on cognitive development in children are also well established.(5)(6) Given these considerations, management of epilepsy in pregnancy is a challenge that aims judicious use of AEDs to achieve best seizure control with least risk
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of MCM or developmental problems in the infants. AED adjustments and dosage changes during pregnancy are often carried out and have been
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shown to significantly affect seizure outcomes.(7) However, the differential effect of AED changes / regime between first trimester and rest of
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pregnancy have not been described. Furthermore, the effect of such AED
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changes during the course of pregnancy on fetal outcomes is not known.
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Organogenesis is completed by the first trimester and it is reasonable to
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argue that dosage change in the rest of pregnancy may not have a major effect on malformation risk. Nevertheless the risk of cognitive dysfunction
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related to prenatal exposure to AEDs may still persist. There is no precise data to guide clinicians to change treatment based on malformation/
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cognitive outcomes. Our objective is to analyse the AED regime changes during pregnancy and correlate it with fetal outcomes. The key questions
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we attempt to answer in this study are- ‘How often are AED changes made during pregnancy?’ and ‘how does that influence the fetal outcome?’
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2. Materials and Methods 2.1 Study design and setting The Kerala Registry of Epilepsy and Pregnancy is a prospective observational single centre register that enrols women with Epilepsy (WWE) in preconception stage or first trimester of pregnancy and monitors them for
pregnancy outcome including major congenital malformations. Their children are followed up regularly until 18 years of age for neurocognitive and developmental outcome. 2.2: Methodology: For the purpose of this study, we analysed the data of all pregnancies leading
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to live birth in the register from 1998 to 2014. The detailed protocol of
compilation of data and maintenance of registry is documented elsewhere.(8)
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The AED usage and seizure count for the pre-pregnancy month, 9 months of
pregnancy and 3 post-partum months are recorded. The drug compliance was
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ascertained with a pregnancy diary in which the WWE have to document
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usage of AEDs and Folic acid on a daily basis which was reviewed by the
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investigator periodically. The highest daily dose used in any time in a month is
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taken as representative for that month. We extracted the AED usage for each month of pregnancy for all eligible pregnancies from the register and
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computed the minimum, mean and maximum daily dose of AED for the first trimester and rest of pregnancy (second and third trimester) separately. The
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AED usage in the first trimester is taken as the baseline. The AED addition, dose escalation, unchanged continuation, dose reduction or stoppage during
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the second or third trimester in comparison to the first trimester was tabulated for each drug. AED usage in second and third trimester were classified into 3
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groups- AED continued unchanged, AED added or dose increased and AED discontinued or dose reduced. The malformation status of the baby and Developmental Quotient (DQ) at one year were extracted from the clinical records of the registry. Developmental Assessment Scale for Indian Infants (DASII), an adaptation of the Bayley Scale of Infant Development
standardized for Indian infants was administered to each infant under standard conditions. (9) 2.3: Statistical Analysis: The entire data was tabulated and analysed with SPSS 20. Means were
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compared with t tests and proportions with chi square. Mean change in DQ between patient groups under various drugs were compared by t-tests
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assuming the effect of individual drugs are independent.
2.4: Ethical Considerations: The registry has the approval of the Institutional Ethics Committee (IEC) and informed consent was obtained from every
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woman.
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3. Results: A total of 1547 pregnancies in WWE were included in the study.
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The mean maternal age was 26.0 + 4.4 years. The AED usage in first trimester was monotherapy in 925 (59.8%) or polytherapy in 391 (25.3%)
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pregnancies. There were 231 (14.9%) pregnancies without any AED usage in first trimester. There were 685 pregnancies (44.3 %) in women with Idiopathic
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Generalised Epilepsy (IGE) and 862 pregnancies (55.7 %) in women with
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Localisation Related Epilepsy (LRE). Monotherapy was more common with IGE (482/685, OR 1.8, 95% CI 1.4 – 2.2) than with LRE (495/862). MCMs were observed in 105 (6.8 %) pregnancies. Broad changes in AED regime in
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the 2nd and 3rd trimester as a function of the number of AEDs in the first trimester are given in Table 1 and Figure 1. During second / third trimester there was no change in the number of AEDs for 1311 (84.7 %), AEDs were added for 143 (9.2%), and at least one AED was stopped for 93 (6%) pregnancies. WWE who were not on AEDs were more likely (OR 16.7, 95% CI
10.9 – 25.8) to be started on an AED (38.9%) than WWE on monotherapy being shifted to polytherapy (3.7%). The probability of continuing on the same number of AEDs through entire pregnancy period was higher for monotherapy group than polytherapy group (OR 3.1, 95% CI 2.2 – 4.46). AED reduction during second or third trimester occurred more often in WWE on polytherapy
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than in WWE on monotherapy (OR 4.7; 95% CI 2.9 – 7.2). We did not find any significant variation with regard to individual epilepsy syndrome.
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Specific details of frequently used AEDs and their dose changes between first trimester and rest of pregnancy are tabulated in Table 2. With respect to
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individual AEDs, there was no significant difference in the proportion of
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patients in whom a given drug was introduced or stopped. The dose
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escalation after first trimester was least with VPA. The OR (95% confidence
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interval) for dose escalation after first trimester for VPA 1.31 (.37-4.6) as compared to different AEDs were: OXC 3.95 (2.16-7.22), PHT 2.98 (1.93-
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1.7 (.74-3.88).
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4.62), LTG 2.96 (1.48-5.92). CBZ 2.11 (1.45-3.09), PB 1.8 (1.17-2.77), LVT
Malformation rates according to the change in AED usage in second or third
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trimester in comparison to the usage in first trimester individual AEDs are given in Table-3. There was no significant difference in the malformation rates
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between the two groups (AED increased or added versus others). The mean DQ at 1 year was 94.57 ± 33.24 (n=972). The DQ of children where AEDs were added in the second/ third trimester (92.7 + 30.5) was not significantly different from others where AEDs were reduced, unchanged or stopped (93.97 + 37.8).
The mean DQ of children with antenatal exposure to AEDs according to the dose changes in the second or third trimester are given in table 4. Discussion: The setting of the registry provided us the opportunity to prospectively observe the pharmacotherapy of epilepsy during pregnancy on
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a monthly basis. Our key observation is that a majority (84.7%) of WWE did not have any
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change in the number of AEDs during the entire period of pregnancy. In the
second or third trimester AEDs were reduced or stopped in 6% pregnancies while it was increased or added in 9.2% pregnancies. Nevertheless,
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compared to VPA, dosages of OXC, PHT, LTG and CBZ were more likely to
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be escalated. The blood levels of these drugs were not measured in
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pregnancy. The clearance of Lamotrigine and several enzyme inducing AEDs
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are likely to increase during the second and third trimester of pregnancy. (10)
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The dose escalation observed in this study is in line with these principles. We did not observe any significant association between malformation rate and
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change in AED usage in the second or third trimester. This can alleviate the concern of the WWE as well as their caregivers that dose escalation in later
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half of pregnancy may increase the risk of MCM. Previous studies have demonstrated that women who discontinued AEDs before pregnancy or
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patients with untreated epilepsy during pregnancy had a lesser risk of fetal malformations compared to women who continued AEDs throughout the pregnancy.(11)(12) Although organogenesis is completed in the first trimester, structural evolution and malformations risk may continue into the subsequent months. AED regime changes in the second and third trimesters had no
influence on the risk of malformations for any of the individual AEDs. (Table 3) There is also much concern about the potential harm due to AED exposure in the second and third trimester on neurocognitive development. Cerebral maturation, synaptogenesis and neuronal migration are largely seen in the
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second and third trimester.(13) To the best of our knowledge, this is the first study to examine the effect of exposure to AEDs in this period compared to
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the first trimester. In the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, Meader et al prospectively analysed the cognitive effects of
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fetal exposure of AED monotherapy.(14) However, the effect of AED regime
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changes between early and late pregnancies were not examined. We did not
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recognize any significant association between mean DQ and change in the
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AED usage in second or third trimester. Nevertheless there was a non significant trend towards lower DQ with higher dose or addition of AEDs in the
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second or third trimester for several AEDs like PB, LTG, VPA, TPM and LVT.
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This signal needs to be reviewed in a larger set of data. The small sample sizes did not permit to assess the influence of drug
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combinations or interaction of various drugs on DQ. We have not attempted to co-relate the AED modifications with seizure burden during pregnancy as the
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precise timing of AED change and seizure occurrence within a month were not available. The results of our study are clinically relevant and suggests that AED modifications in the second/ third trimester may not adversely affect fetal outcome. Battino et al (7) have called for a more proactive approach to adjusting the dose of AEDs in pregnancy from a perspective of achieving better seizure control. Our study reiterates the safety of such an approach in
terms of fetal outcome and could significantly guide AED changes in pregnancy. An important limitation of our study is the relatively lower number of exposures to newer AEDs such as LTG, LVT,TPM etc. The DQ was not assessed in some children who failed to turn up for the assessment at the
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scheduled time. Further, serum AED levels were not monitored which could
have been a better measure of in- utero exposure. The strengths of the study
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are the considerable sample size and the fact that they reflect AED regime
changes during pregnancy in a real world setting with implications that could
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guide clinical practice.
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Conclusion: Although majority of women had no change in AED usage
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throughout pregnancy, AEDs were reduced in a significant proportion of
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patients on polytherapy and more than a third of women who were not on
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AEDs in the first trimester were subsequently started on AEDs. Increase in dose or addition of AEDs after the first trimester is unlikely to influence
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malformation outcome but the potential adverse effect on the DQ needs to be
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explored on a larger set of data.
ACKNOWLEDGEMENTS KREP Study Group, SCTIMST, Trivandrum, India (1998 – 2016) Ajaykumar B, MD
Research Fellow, KREP, SCTIMST, Trivandrum, India
Ajith Cherian, MD DM
Neurologist, KREP, SCTIMST, Trivandrum, India
Alex Ittiyavirah, MD Imageologist, Ittiyavirah Scan and Research Centre, Trivandrum Anila KM
Clinical Psychologist, KREP, SCTIMST, Trivandrum, India
Arjun S Research Assistant, KREP, SCTIMST, Trivandrum, India
Babu George, MD Ph.D.
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Asha L, MD Research Fellow, KREP, SCTIMST, Trivandrum, India Developmental Paediatrician, Institute of Child
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Development, Trivandrum
Bijoy Thomas, MD Imageologist, SCTIMST, Trivandrum, India
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Research Fellow, KREP, SCTIMST, Trivandrum, India
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BoneyNinan, MD
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Caroline Joshua, MD Research Fellow, KREP, SCTIMST, Trivandrum, India
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Christudas S Research Fellow (social sciences), KREP, SCTIMST,
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Trivandrum, India
Deepa D, Ph.D. Scientist, Department of Biochemistry, SCTIMST,
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Trivandrum, India.
DeethaSantosh, Research Fellow (social sciences), KREP, SCTIMST,
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Trivandrum
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Devi GC, MD Gynecologist, Medical College, Trivandrum Elizebeth KE, MD Ph.D. Shankar Henry PY, MD
Paediatrician, Medical College, Trivandrum
Paediatric geneticist, Medical College, Trivandrum Paediatric surgeon and dysmorphologist, Gokulam
Medical College, Kerala
Indrani L, MD Jacob PP
Research Fellow, KREP, SCTIMST, Trivandrum, India Research Fellow (Social sciences) KREP, SCTIMST,
Trivandrum, India Jacob S, MD Gynecologist, Medical College, Trivandrum Research Fellow, KREP, SCTIMST, Trivandrum, India
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Jisha Joseph, MD
Joseph Samuel, MD DM
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Jitha Jagathan, MD Research Fellow, KREP, SCTIMST, Trivandrum, India
Neurologist, KREP, SCTIMST, Trivandrum, India
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Kesavadas C, MD Imageologist, SCTIMST, Trivandrum, India
Developmental Paediatrician, Institute of Child
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Nair MKC, MD Ph.D.
Research Fellow, KREP, SCTIMST, Trivandrum, India
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Nevin Haroon, MD
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Development, Trivandrum
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Nikita SJ, Research Assistant, KREP, SCTIMST, Trivandrum Rasmi M, Research Assistant, KREP, SCTIMST, Trivandrum
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Reghunath B, MD
Research Fellow, KREP, SCTIMST, Trivandrum, India
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Reni Philip MBBS, Research Fellow, KREP, SCTIMST, Trivandrum, India. Sabarinathan S, Research Fellow (social sciences), KREP, SCTIMST,
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Trivandrum, India Sapna Haridas MD Saramma PP, Ph.D.
Research Fellow, KREP, SCTIMST, Trivandrum, India Nursing Instructor, SCTIMST, Trivandrum, India
Sheeja Varghese Ph D, Research Fellow, KREP, SCTIMST, Trivandrum, India
Shehnaz Begum, MD
Research Fellow, KREP, SCTIMST, Trivandrum,
India Sindhu K, MD
Research Fellow, KREP, SCTIMST, Trivandrum, India
Srirangan R, MD
Research Fellow, KREP, SCTIMST, Trivandrum, India
Neurologist, SCTIMST, Trivandrum, India
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Syam UK, MD DM.
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(Late) Research Fellow, KREP, SCTIMST, Trivandrum, India
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Sucharitha Devi, MD
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DISCLOSURE
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None of the authors has any conflict of interest to disclose.
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FUNDING
This research did not receive any specific grant from funding agencies in the
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public, commercial, or not-for-profit sectors.
References:
1.
Campbell E, Kennedy F, Russell A, Smithson WH, Parsons L, Morrison PJ, et al. Malformation risks of antiepileptic drug monotherapies in pregnancy: Updated results from the UK and Ireland epilepsy and pregnancy registers. J Neurol Neurosurg Psychiatry. 2014;85(9):1029–34.
2.
Thomas S V., Jose M, Divakaran S, Sankara Sarma P. Malformation risk of
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antiepileptic drug exposure during pregnancy in women with epilepsy: Results
3.
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from a pregnancy registry in South India. Epilepsia. 2017;58(2):274–81.
Vajda FJE, O’Brien TJ, Lander CM, Graham J, Eadie MJ. The teratogenicity of the newer antiepileptic drugs - An update. Acta Neurol Scand.
Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Sabers A, et al. Dose-
N
4.
U
2014;130(4):234–8.
A
dependent risk of malformations with antiepileptic drugs: An analysis of data
5.
ED
2011;10(7):609–17.
M
from the EURAP epilepsy and pregnancy registry. Lancet Neurol.
Meador KJ, Baker GA, Browning N, Cohen MJ, Clayton-Smith J, Kalayjian LA,
PT
et al. Foetal antiepileptic drug exposure and verbal versus non-verbal abilities
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at three years of age. Brain. 2011;134(2):396–404. 6.
Elkjær LS, Bech BH, Sun Y, Laursen TM, Christensen J. Association Between
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Prenatal Valproate Exposure and Performance on Standardized Language and Mathematics Tests in School-aged Children. JAMA Neurol [Internet]. 2018; Available from: http://archneur.jamanetwork.com/article.aspx?doi=10.1001/jamaneurol.2017.5 035
7.
Battino D, Tomson T, Bonizzoni E, Craig J, Lindhout D, Sabers A, et al.
Seizure control and treatment changes in pregnancy: Observations from the EURAP epilepsy pregnancy registry. Epilepsia. 2013;54(9):1621–7. 8.
Thomas S V., Syam U, Devi JS. Predictors of seizures during pregnancy in women with epilepsy. Epilepsia. 2012;53(5). Phathak P. Developmental Assessment Scales for Indian Infants(DASII)
IP T
9.
Revision of 1970 Baroda norms from birth to 30 months onBayley Scales of
10.
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Infant Development (BSID). Baroda: Department ofHDFS, MSUB; 1998
Pariente G, Leibson T, Carls A, Adams-Webber T, Ito S, Koren G. PregnancyAssociated Changes in Pharmacokinetics: A Systematic Review. PLoS Med.
N
Artama M, Auvinen a, Raudaskoski T, Isojärvi I, Isojärvi J. Antiepileptic drug
A
11.
U
2016 Nov 1; 13(11):e1002160.
M
use of women with epilepsy and congenital malformations in offspring. Neurology. 2005;64(11):1874–8.
Weston J, Bromley R, Jackson CF, Adab N, Clayton-Smith J, Greenhalgh J, et
ED
12.
PT
al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane database Syst Rev. 2016;11:CD010224. Tau GZ, Peterson BS. Normal Development of Brain Circuits.
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13.
Neuropsychopharmacol Rev [Internet]. 2010;35115(10):147–68. Available
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from: http://dx.doi.org/10.1038/npp.2009.115
14.
Meador K, Baker G, Browning N. Fetal antiepileptic drug exposure and
cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol [Internet]. 2013;12(3):244–52. Available from: http://www.sciencedirect.com/science/article/pii/S147444221270323X
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Figure 1
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Table 1: Changes in AED usage in second and third trimester in comparison to first trimester AED usage in second and third trimester
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AEDs used in first
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trimester Stopped or
Continued
unchanged
141
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34
90
857
34
313
19
1311
143
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Monotherapy
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(925)
(391)
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Total (1547)
59
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Polytherapy
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reduced Nil (231)
AED added
93
Table 2. AED specific changes in usage during second and third trimester in comparison to first trimester of pregnancy
AED used in first trimeste r (n)
Change in usage the AED in second or third trimester compared to first trimester n (%) Dose Increa sed
Dose Uncha nged
PB(319)
10(3.1 %)
57 (17.9% )
222 (69.6% )
21 (6.6 %)
9 (2.8%)
LTG(53)
0 (0%)
14 (26.4% )
33 (62.3% )
2 (3.8 %)
4 (7.5%)
PHT(230 )
12(5.3 %)
61 (26.5% )
125(54. 3%)
19(8 .3%)
13(5.7 %)
CLB(172 )
17 (9.9%)
25 (14.5% )
112(65. 1%)
9(5. 2%)
9 (5.2%)
CBZ (619)
26(4.2 %)
126(20. 4%)
393(62. 5%)
44(7 .1%)
30(4.8 %)
VPA(380 )
26(6.8 %)
41(10.8 %)
254(66. 8%)
35(8 .6%)
24(6.3 %)
0
3(13.6 %)
17(77.3 %)
1(4. 5%)
1(4.5% )
LVT (47)
0
8(17.8 %)
31(68.9 %)
3(6. 7%)
3(6.7% )
OXC (68)
0
22(32.4 %)
38(55.9 %)
3(4. 4%)
5(7.4% )
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TPM (22)
Dos e Dec reas ed
AED Stoppe d
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AED Added
AED: anti epileptic drug, PB: Phenobabitone, LTG: Lamotrigine, PHT: phenytoin, CLB: Clobazam, CBZ: Carbamazepine, VPA: Valproate, TPM : Topiramate, LVT: Levetiracetam, OXC: Oxcarbazepine
Table 3. Malformation rates according to the change in AED usage in second or third trimester in comparison to the usage in first trimester individual AEDs Malformations (Y)
Significance
16 (6.3%) 8 (11.9%)
0.103
0 0
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8 (5.1 %) 3 (4.1 %)
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Number of pregnancies 319 252 67 53 39 14 230 157 73 172 130 42
12 (9.2 %) 4 (9.5 %)
0.518
0.581
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AED change PB Dec/stop/un Inc/add LTG Dec/stop/un Inc/add PHT Dec/stop/un Inc/ad CLB Dec/stop/un Inc/add
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CBZ 619 Dec/stop/un 467 33 (7.1 %) 0.191 Inc/add 152 7 (4.6 %) VPA 380 Dec/stop/un 313 32 (10.2 %) 0.201 Inc/add 67 4 (6 %) TPM 22 Dec/stop/un 19 5 (26.3 %) 0.636 Inc/add 3 1 (33.3%) LVT 45 Dec/stop/un 37 2 (5.4 %) 0.673 Inc/add 8 0 OXC 68 Dec/stop/un 46 5 (10.9 %) 0.361 Inc/add 22 1 (4.1 %) PB: Phenobabitone, LTG: Lamotrigine, PHT: phenytoin, CLB: Clobazam, CBZ: Carbamazepine, VPA: Valproate, TPM : Topiramate, LVT: Levetiracetam, OXC: Oxcarbazepine Dec: Dose Decreased, stop: AED stopped, un: Dose continued unchanged, Inc: Dose Increased, Add: AED Added
Table 4: Development Quotient (DQ) of children according to the change in
AED usage in second or third trimester in comparison to the first trimester of pregnancy for individual AEDs AED change
Number of
DQ
pregnancies
mean
143
88.49
P value
PB
Inc/add
31
0.297
(33.39)
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Dec/stop/un
85.42
LTG 24
99.37
Inc/add
8
(30.91)
N
82
0.496
U
Dec/stop/un
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(30.31)
(38.49)
Inc/add
42
PT
CLB
M
89
ED
Dec/stop/un
A
PHT
91 (31.45) 93.58 (32.65)
Dec/stop/un
95
93.17
Inc/add
29
(31.87)
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0.614
0.749
95.66 (30.64)
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CBZ
Dec/stop/un
319
94.39
Inc/add
90
(33.24) 95.48 (30.38)
0.396
VPA Dec/stop/un
211
Inc/add
87.14
45
0.343
(35.44) 80.07 (32.40)
TPM 15
108.05
Inc/add
1
(22.12)
-
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Dec/stop/un
LVT 28
108.06
Inc/add
5
(36.04)
0.081
U
Dec/stop/un
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78.46
96.24
N
(17.80)
Inc/add
18
106.98
M
35
ED
Dec/stop/un
A
OXC
0.403
(32.24) 109.03 (28.26)
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PB: Phenobabitone, LTG: Lamotrigine, PHT: phenytoin, CLB: Clobazam, CBZ: Carbamazepine, VPA: Valproate, TPM : Topiramate, LVT: Levetiracetam, OXC: Oxcarbazepine.
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AED change: change in AED usage in second or third trimester compared to first trimester. Dec: Dose Decreased, stop: AED stopped, un: Dose continued unchanged, Inc: Dose Increased,
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Add: AED Added
S0920-1211(18)30201-8 https://doi.org/10.1016/j.eplepsyres.2018.07.017 EPIRES 5999
To appear in:
Epilepsy Research
Received date: Revised date: Accepted date:
24-4-2018 21-7-2018 24-7-2018
Please cite this article as: Asranna A, Jose M, Philip RM, Sarma PS, Thomas SV, Do Anti-Epileptic Drug modifications after first trimester of pregnancy influence fetal malformation or cognitive outcome?, Epilepsy Research (2018), https://doi.org/10.1016/j.eplepsyres.2018.07.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: Do Anti-Epileptic Drug modifications after first trimester of pregnancy influence fetal malformation or cognitive outcome?
Ajay Asranna1
- [email protected]
Manna Jose2
- [email protected] - [email protected]
Prabhakaran S. Sarma3
- [email protected]
Sanjeev V. Thomas 1,2
- [email protected]
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Affiliations and Address:
Department Of Neurology, Sree Chitra Tirunal Institute for Medical Sciences
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1
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Rini M.Philip2
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Authors:
Registry of Epilepsy and Pregnancy, Department of Neurology, Sree
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2 Kerala
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and Technology, Trivandrum, India - 695011
Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum,
3
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India - - 695011
Achutha Menon Centre for Health Science Studies, Sree Chitra Tirunal
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Institute for Medical Sciences and Technology, Trivandrum, India - 695011 Corresponding Author:
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Prof. Sanjeev V. Thomas, MD, DM Kerala Registry of Epilepsy and Pregnancy, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum 695011, India
Phone +91 471 252468 Email: [email protected]
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HIGHLIGHTS
AED dosage/ regime changes are effected during pregnancy in substantial proportion of Women With Epilepsy
A third of women who were not on AEDs in the first trimester were started on AEDs later in pregnancy
Most Women With Epilepsy (WWE) who were on monotherapy in first trimester remained on the same AED and dosage during the rest of pregnancy period
There was no association between AED modifications in the second/ third trimester and prevalence of major congenital malformations
There was a non-significant trend towards lower DQ with increase in dose or addition of drugs in the second or third trimester for several AEDs
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Objective: The management of Women With Epilepsy (WWE) in pregnancy is a challenge that demands balancing the risks of Major Congenital Malformation (MCM) on one hand with adequate seizure control on the other. While most studies have analysed the risks of Anti-Epileptic Drugs (AED)
exposure in the first trimester, AED changes during the second and third trimester and their effects on fetal outcome has not been studied adequately. Materials and Methods: Data of WWE who were prospectively followed up and completed pregnancy with live birth under the Kerala registry of epilepsy and pregnancy (KREP) between 1998 and 2014 were analysed. The AED
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addition, dose escalation, unchanged continuation, dose reduction or
stoppage during the second or third trimester in comparison to the first
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trimester was tabulated for each drug. The outcome measures evaluated
were malformation status and Developmental Quotient (DQ) at one year as
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extracted from the clinical records of the registry.
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Results: The first trimester AED exposure was nil for 231, monotherapy for
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925 and polytherapy for 391 WWE. WWE on monotherapy in first trimester
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were more likely to remain on the same number of AEDs in second or third trimester than those who were on polytherapy (OR 3.1, 95% CI 2.2 – 4.46).
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AED naïve women had a higher likelihood (OR 16.7; 95% CI 10.9 – 25.8) of
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being started on AED than women on monotherapy being switched to polytherapy. At least one AED was reduced or stopped during second or third
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trimester more often in women on polytherapy (15.1%) than in women on monotherapy (3.7%) (OR 4.7; 95% CI 2.9 – 7.2). Malformation rates for the
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infants of women whose AED dosage was increased or added were not significantly different from those of others. There was no statistically significant change in DQ with increase in dose or addition of drugs in the second or third trimester.
Conclusion: AEDs were reduced in a significant proportion of patients on polytherapy while more than a third of women who were not on AEDs in the first trimester were subsequently started on AEDs. Increase in dose or addition of AEDs after the first trimester is unlikely to influence malformation outcome but the potential adverse effect on the DQ needs to be explored on a
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larger set of data.
ABBREVIATIONS: AED, Anti-epileptic drug; CBZ, Carbamazepine; CI, Confidence Interval; CLB, Clobazam; GTCS, Generalized tonic clonic
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seizures; ILAE, International League Against Epilepsy; KREP, Kerala Registry
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for Epilepsy and Pregnancy; LMP, last menstrual period; LEV, Levetiracetam;
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LTG, Lamotrigine; MCM, Major congenital malformation; OR, Odds Ratio;
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OXC, Oxcarbazepine; PB, Phenobarbitone; PHT, Phenytoin; SPFL,
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With Epilepsy
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Spontaneous fetal loss; TPM, Topiramate; VPA, Valproate; WWE, Women
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Keywords: Epilepsy, Pregnancy, Antiepileptic drugmodifications, Major
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Congenital malformation
1. Introduction: Anti-Epileptic Drug (AED) exposure during pregnancy has been associated with increased risk of major congenital malformations (MCM).(1)(2)(3) Important factors influencing the risk of malformations
include polytherapy, exposure to Valproate (VPA) and higher dosage.(4) The deleterious effects of prenatal AED exposure on cognitive development in children are also well established.(5)(6) Given these considerations, management of epilepsy in pregnancy is a challenge that aims judicious use of AEDs to achieve best seizure control with least risk
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of MCM or developmental problems in the infants. AED adjustments and dosage changes during pregnancy are often carried out and have been
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shown to significantly affect seizure outcomes.(7) However, the differential effect of AED changes / regime between first trimester and rest of
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pregnancy have not been described. Furthermore, the effect of such AED
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changes during the course of pregnancy on fetal outcomes is not known.
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Organogenesis is completed by the first trimester and it is reasonable to
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argue that dosage change in the rest of pregnancy may not have a major effect on malformation risk. Nevertheless the risk of cognitive dysfunction
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related to prenatal exposure to AEDs may still persist. There is no precise data to guide clinicians to change treatment based on malformation/
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cognitive outcomes. Our objective is to analyse the AED regime changes during pregnancy and correlate it with fetal outcomes. The key questions
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we attempt to answer in this study are- ‘How often are AED changes made during pregnancy?’ and ‘how does that influence the fetal outcome?’
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2. Materials and Methods 2.1 Study design and setting The Kerala Registry of Epilepsy and Pregnancy is a prospective observational single centre register that enrols women with Epilepsy (WWE) in preconception stage or first trimester of pregnancy and monitors them for
pregnancy outcome including major congenital malformations. Their children are followed up regularly until 18 years of age for neurocognitive and developmental outcome. 2.2: Methodology: For the purpose of this study, we analysed the data of all pregnancies leading
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to live birth in the register from 1998 to 2014. The detailed protocol of
compilation of data and maintenance of registry is documented elsewhere.(8)
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The AED usage and seizure count for the pre-pregnancy month, 9 months of
pregnancy and 3 post-partum months are recorded. The drug compliance was
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ascertained with a pregnancy diary in which the WWE have to document
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usage of AEDs and Folic acid on a daily basis which was reviewed by the
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investigator periodically. The highest daily dose used in any time in a month is
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taken as representative for that month. We extracted the AED usage for each month of pregnancy for all eligible pregnancies from the register and
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computed the minimum, mean and maximum daily dose of AED for the first trimester and rest of pregnancy (second and third trimester) separately. The
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AED usage in the first trimester is taken as the baseline. The AED addition, dose escalation, unchanged continuation, dose reduction or stoppage during
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the second or third trimester in comparison to the first trimester was tabulated for each drug. AED usage in second and third trimester were classified into 3
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groups- AED continued unchanged, AED added or dose increased and AED discontinued or dose reduced. The malformation status of the baby and Developmental Quotient (DQ) at one year were extracted from the clinical records of the registry. Developmental Assessment Scale for Indian Infants (DASII), an adaptation of the Bayley Scale of Infant Development
standardized for Indian infants was administered to each infant under standard conditions. (9) 2.3: Statistical Analysis: The entire data was tabulated and analysed with SPSS 20. Means were
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compared with t tests and proportions with chi square. Mean change in DQ between patient groups under various drugs were compared by t-tests
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assuming the effect of individual drugs are independent.
2.4: Ethical Considerations: The registry has the approval of the Institutional Ethics Committee (IEC) and informed consent was obtained from every
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woman.
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3. Results: A total of 1547 pregnancies in WWE were included in the study.
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The mean maternal age was 26.0 + 4.4 years. The AED usage in first trimester was monotherapy in 925 (59.8%) or polytherapy in 391 (25.3%)
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pregnancies. There were 231 (14.9%) pregnancies without any AED usage in first trimester. There were 685 pregnancies (44.3 %) in women with Idiopathic
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Generalised Epilepsy (IGE) and 862 pregnancies (55.7 %) in women with
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Localisation Related Epilepsy (LRE). Monotherapy was more common with IGE (482/685, OR 1.8, 95% CI 1.4 – 2.2) than with LRE (495/862). MCMs were observed in 105 (6.8 %) pregnancies. Broad changes in AED regime in
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the 2nd and 3rd trimester as a function of the number of AEDs in the first trimester are given in Table 1 and Figure 1. During second / third trimester there was no change in the number of AEDs for 1311 (84.7 %), AEDs were added for 143 (9.2%), and at least one AED was stopped for 93 (6%) pregnancies. WWE who were not on AEDs were more likely (OR 16.7, 95% CI
10.9 – 25.8) to be started on an AED (38.9%) than WWE on monotherapy being shifted to polytherapy (3.7%). The probability of continuing on the same number of AEDs through entire pregnancy period was higher for monotherapy group than polytherapy group (OR 3.1, 95% CI 2.2 – 4.46). AED reduction during second or third trimester occurred more often in WWE on polytherapy
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than in WWE on monotherapy (OR 4.7; 95% CI 2.9 – 7.2). We did not find any significant variation with regard to individual epilepsy syndrome.
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Specific details of frequently used AEDs and their dose changes between first trimester and rest of pregnancy are tabulated in Table 2. With respect to
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individual AEDs, there was no significant difference in the proportion of
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patients in whom a given drug was introduced or stopped. The dose
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escalation after first trimester was least with VPA. The OR (95% confidence
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interval) for dose escalation after first trimester for VPA 1.31 (.37-4.6) as compared to different AEDs were: OXC 3.95 (2.16-7.22), PHT 2.98 (1.93-
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1.7 (.74-3.88).
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4.62), LTG 2.96 (1.48-5.92). CBZ 2.11 (1.45-3.09), PB 1.8 (1.17-2.77), LVT
Malformation rates according to the change in AED usage in second or third
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trimester in comparison to the usage in first trimester individual AEDs are given in Table-3. There was no significant difference in the malformation rates
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between the two groups (AED increased or added versus others). The mean DQ at 1 year was 94.57 ± 33.24 (n=972). The DQ of children where AEDs were added in the second/ third trimester (92.7 + 30.5) was not significantly different from others where AEDs were reduced, unchanged or stopped (93.97 + 37.8).
The mean DQ of children with antenatal exposure to AEDs according to the dose changes in the second or third trimester are given in table 4. Discussion: The setting of the registry provided us the opportunity to prospectively observe the pharmacotherapy of epilepsy during pregnancy on
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a monthly basis. Our key observation is that a majority (84.7%) of WWE did not have any
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change in the number of AEDs during the entire period of pregnancy. In the
second or third trimester AEDs were reduced or stopped in 6% pregnancies while it was increased or added in 9.2% pregnancies. Nevertheless,
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compared to VPA, dosages of OXC, PHT, LTG and CBZ were more likely to
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be escalated. The blood levels of these drugs were not measured in
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pregnancy. The clearance of Lamotrigine and several enzyme inducing AEDs
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are likely to increase during the second and third trimester of pregnancy. (10)
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The dose escalation observed in this study is in line with these principles. We did not observe any significant association between malformation rate and
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change in AED usage in the second or third trimester. This can alleviate the concern of the WWE as well as their caregivers that dose escalation in later
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half of pregnancy may increase the risk of MCM. Previous studies have demonstrated that women who discontinued AEDs before pregnancy or
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patients with untreated epilepsy during pregnancy had a lesser risk of fetal malformations compared to women who continued AEDs throughout the pregnancy.(11)(12) Although organogenesis is completed in the first trimester, structural evolution and malformations risk may continue into the subsequent months. AED regime changes in the second and third trimesters had no
influence on the risk of malformations for any of the individual AEDs. (Table 3) There is also much concern about the potential harm due to AED exposure in the second and third trimester on neurocognitive development. Cerebral maturation, synaptogenesis and neuronal migration are largely seen in the
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second and third trimester.(13) To the best of our knowledge, this is the first study to examine the effect of exposure to AEDs in this period compared to
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the first trimester. In the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, Meader et al prospectively analysed the cognitive effects of
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fetal exposure of AED monotherapy.(14) However, the effect of AED regime
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changes between early and late pregnancies were not examined. We did not
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recognize any significant association between mean DQ and change in the
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AED usage in second or third trimester. Nevertheless there was a non significant trend towards lower DQ with higher dose or addition of AEDs in the
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second or third trimester for several AEDs like PB, LTG, VPA, TPM and LVT.
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This signal needs to be reviewed in a larger set of data. The small sample sizes did not permit to assess the influence of drug
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combinations or interaction of various drugs on DQ. We have not attempted to co-relate the AED modifications with seizure burden during pregnancy as the
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precise timing of AED change and seizure occurrence within a month were not available. The results of our study are clinically relevant and suggests that AED modifications in the second/ third trimester may not adversely affect fetal outcome. Battino et al (7) have called for a more proactive approach to adjusting the dose of AEDs in pregnancy from a perspective of achieving better seizure control. Our study reiterates the safety of such an approach in
terms of fetal outcome and could significantly guide AED changes in pregnancy. An important limitation of our study is the relatively lower number of exposures to newer AEDs such as LTG, LVT,TPM etc. The DQ was not assessed in some children who failed to turn up for the assessment at the
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scheduled time. Further, serum AED levels were not monitored which could
have been a better measure of in- utero exposure. The strengths of the study
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are the considerable sample size and the fact that they reflect AED regime
changes during pregnancy in a real world setting with implications that could
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guide clinical practice.
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Conclusion: Although majority of women had no change in AED usage
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throughout pregnancy, AEDs were reduced in a significant proportion of
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patients on polytherapy and more than a third of women who were not on
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AEDs in the first trimester were subsequently started on AEDs. Increase in dose or addition of AEDs after the first trimester is unlikely to influence
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malformation outcome but the potential adverse effect on the DQ needs to be
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explored on a larger set of data.
ACKNOWLEDGEMENTS KREP Study Group, SCTIMST, Trivandrum, India (1998 – 2016) Ajaykumar B, MD
Research Fellow, KREP, SCTIMST, Trivandrum, India
Ajith Cherian, MD DM
Neurologist, KREP, SCTIMST, Trivandrum, India
Alex Ittiyavirah, MD Imageologist, Ittiyavirah Scan and Research Centre, Trivandrum Anila KM
Clinical Psychologist, KREP, SCTIMST, Trivandrum, India
Arjun S Research Assistant, KREP, SCTIMST, Trivandrum, India
Babu George, MD Ph.D.
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Asha L, MD Research Fellow, KREP, SCTIMST, Trivandrum, India Developmental Paediatrician, Institute of Child
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Development, Trivandrum
Bijoy Thomas, MD Imageologist, SCTIMST, Trivandrum, India
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Research Fellow, KREP, SCTIMST, Trivandrum, India
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BoneyNinan, MD
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Caroline Joshua, MD Research Fellow, KREP, SCTIMST, Trivandrum, India
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Christudas S Research Fellow (social sciences), KREP, SCTIMST,
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Trivandrum, India
Deepa D, Ph.D. Scientist, Department of Biochemistry, SCTIMST,
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Trivandrum, India.
DeethaSantosh, Research Fellow (social sciences), KREP, SCTIMST,
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Trivandrum
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Devi GC, MD Gynecologist, Medical College, Trivandrum Elizebeth KE, MD Ph.D. Shankar Henry PY, MD
Paediatrician, Medical College, Trivandrum
Paediatric geneticist, Medical College, Trivandrum Paediatric surgeon and dysmorphologist, Gokulam
Medical College, Kerala
Indrani L, MD Jacob PP
Research Fellow, KREP, SCTIMST, Trivandrum, India Research Fellow (Social sciences) KREP, SCTIMST,
Trivandrum, India Jacob S, MD Gynecologist, Medical College, Trivandrum Research Fellow, KREP, SCTIMST, Trivandrum, India
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Jisha Joseph, MD
Joseph Samuel, MD DM
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Jitha Jagathan, MD Research Fellow, KREP, SCTIMST, Trivandrum, India
Neurologist, KREP, SCTIMST, Trivandrum, India
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Kesavadas C, MD Imageologist, SCTIMST, Trivandrum, India
Developmental Paediatrician, Institute of Child
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Nair MKC, MD Ph.D.
Research Fellow, KREP, SCTIMST, Trivandrum, India
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Nevin Haroon, MD
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Development, Trivandrum
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Nikita SJ, Research Assistant, KREP, SCTIMST, Trivandrum Rasmi M, Research Assistant, KREP, SCTIMST, Trivandrum
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Reghunath B, MD
Research Fellow, KREP, SCTIMST, Trivandrum, India
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Reni Philip MBBS, Research Fellow, KREP, SCTIMST, Trivandrum, India. Sabarinathan S, Research Fellow (social sciences), KREP, SCTIMST,
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Trivandrum, India Sapna Haridas MD Saramma PP, Ph.D.
Research Fellow, KREP, SCTIMST, Trivandrum, India Nursing Instructor, SCTIMST, Trivandrum, India
Sheeja Varghese Ph D, Research Fellow, KREP, SCTIMST, Trivandrum, India
Shehnaz Begum, MD
Research Fellow, KREP, SCTIMST, Trivandrum,
India Sindhu K, MD
Research Fellow, KREP, SCTIMST, Trivandrum, India
Srirangan R, MD
Research Fellow, KREP, SCTIMST, Trivandrum, India
Neurologist, SCTIMST, Trivandrum, India
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Syam UK, MD DM.
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(Late) Research Fellow, KREP, SCTIMST, Trivandrum, India
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Sucharitha Devi, MD
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DISCLOSURE
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None of the authors has any conflict of interest to disclose.
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FUNDING
This research did not receive any specific grant from funding agencies in the
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public, commercial, or not-for-profit sectors.
References:
1.
Campbell E, Kennedy F, Russell A, Smithson WH, Parsons L, Morrison PJ, et al. Malformation risks of antiepileptic drug monotherapies in pregnancy: Updated results from the UK and Ireland epilepsy and pregnancy registers. J Neurol Neurosurg Psychiatry. 2014;85(9):1029–34.
2.
Thomas S V., Jose M, Divakaran S, Sankara Sarma P. Malformation risk of
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antiepileptic drug exposure during pregnancy in women with epilepsy: Results
3.
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from a pregnancy registry in South India. Epilepsia. 2017;58(2):274–81.
Vajda FJE, O’Brien TJ, Lander CM, Graham J, Eadie MJ. The teratogenicity of the newer antiepileptic drugs - An update. Acta Neurol Scand.
Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Sabers A, et al. Dose-
N
4.
U
2014;130(4):234–8.
A
dependent risk of malformations with antiepileptic drugs: An analysis of data
5.
ED
2011;10(7):609–17.
M
from the EURAP epilepsy and pregnancy registry. Lancet Neurol.
Meador KJ, Baker GA, Browning N, Cohen MJ, Clayton-Smith J, Kalayjian LA,
PT
et al. Foetal antiepileptic drug exposure and verbal versus non-verbal abilities
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at three years of age. Brain. 2011;134(2):396–404. 6.
Elkjær LS, Bech BH, Sun Y, Laursen TM, Christensen J. Association Between
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Prenatal Valproate Exposure and Performance on Standardized Language and Mathematics Tests in School-aged Children. JAMA Neurol [Internet]. 2018; Available from: http://archneur.jamanetwork.com/article.aspx?doi=10.1001/jamaneurol.2017.5 035
7.
Battino D, Tomson T, Bonizzoni E, Craig J, Lindhout D, Sabers A, et al.
Seizure control and treatment changes in pregnancy: Observations from the EURAP epilepsy pregnancy registry. Epilepsia. 2013;54(9):1621–7. 8.
Thomas S V., Syam U, Devi JS. Predictors of seizures during pregnancy in women with epilepsy. Epilepsia. 2012;53(5). Phathak P. Developmental Assessment Scales for Indian Infants(DASII)
IP T
9.
Revision of 1970 Baroda norms from birth to 30 months onBayley Scales of
10.
SC R
Infant Development (BSID). Baroda: Department ofHDFS, MSUB; 1998
Pariente G, Leibson T, Carls A, Adams-Webber T, Ito S, Koren G. PregnancyAssociated Changes in Pharmacokinetics: A Systematic Review. PLoS Med.
N
Artama M, Auvinen a, Raudaskoski T, Isojärvi I, Isojärvi J. Antiepileptic drug
A
11.
U
2016 Nov 1; 13(11):e1002160.
M
use of women with epilepsy and congenital malformations in offspring. Neurology. 2005;64(11):1874–8.
Weston J, Bromley R, Jackson CF, Adab N, Clayton-Smith J, Greenhalgh J, et
ED
12.
PT
al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane database Syst Rev. 2016;11:CD010224. Tau GZ, Peterson BS. Normal Development of Brain Circuits.
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13.
Neuropsychopharmacol Rev [Internet]. 2010;35115(10):147–68. Available
A
from: http://dx.doi.org/10.1038/npp.2009.115
14.
Meador K, Baker G, Browning N. Fetal antiepileptic drug exposure and
cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol [Internet]. 2013;12(3):244–52. Available from: http://www.sciencedirect.com/science/article/pii/S147444221270323X
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Figure 1
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Table 1: Changes in AED usage in second and third trimester in comparison to first trimester AED usage in second and third trimester
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AEDs used in first
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trimester Stopped or
Continued
unchanged
141
N
34
90
857
34
313
19
1311
143
A
Monotherapy
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(925)
(391)
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Total (1547)
59
ED
Polytherapy
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reduced Nil (231)
AED added
93
Table 2. AED specific changes in usage during second and third trimester in comparison to first trimester of pregnancy
AED used in first trimeste r (n)
Change in usage the AED in second or third trimester compared to first trimester n (%) Dose Increa sed
Dose Uncha nged
PB(319)
10(3.1 %)
57 (17.9% )
222 (69.6% )
21 (6.6 %)
9 (2.8%)
LTG(53)
0 (0%)
14 (26.4% )
33 (62.3% )
2 (3.8 %)
4 (7.5%)
PHT(230 )
12(5.3 %)
61 (26.5% )
125(54. 3%)
19(8 .3%)
13(5.7 %)
CLB(172 )
17 (9.9%)
25 (14.5% )
112(65. 1%)
9(5. 2%)
9 (5.2%)
CBZ (619)
26(4.2 %)
126(20. 4%)
393(62. 5%)
44(7 .1%)
30(4.8 %)
VPA(380 )
26(6.8 %)
41(10.8 %)
254(66. 8%)
35(8 .6%)
24(6.3 %)
0
3(13.6 %)
17(77.3 %)
1(4. 5%)
1(4.5% )
LVT (47)
0
8(17.8 %)
31(68.9 %)
3(6. 7%)
3(6.7% )
OXC (68)
0
22(32.4 %)
38(55.9 %)
3(4. 4%)
5(7.4% )
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ED
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TPM (22)
Dos e Dec reas ed
AED Stoppe d
IP T
AED Added
AED: anti epileptic drug, PB: Phenobabitone, LTG: Lamotrigine, PHT: phenytoin, CLB: Clobazam, CBZ: Carbamazepine, VPA: Valproate, TPM : Topiramate, LVT: Levetiracetam, OXC: Oxcarbazepine
Table 3. Malformation rates according to the change in AED usage in second or third trimester in comparison to the usage in first trimester individual AEDs Malformations (Y)
Significance
16 (6.3%) 8 (11.9%)
0.103
0 0
SC R
8 (5.1 %) 3 (4.1 %)
IP T
Number of pregnancies 319 252 67 53 39 14 230 157 73 172 130 42
12 (9.2 %) 4 (9.5 %)
0.518
0.581
U
AED change PB Dec/stop/un Inc/add LTG Dec/stop/un Inc/add PHT Dec/stop/un Inc/ad CLB Dec/stop/un Inc/add
A
CC E
PT
ED
M
A
N
CBZ 619 Dec/stop/un 467 33 (7.1 %) 0.191 Inc/add 152 7 (4.6 %) VPA 380 Dec/stop/un 313 32 (10.2 %) 0.201 Inc/add 67 4 (6 %) TPM 22 Dec/stop/un 19 5 (26.3 %) 0.636 Inc/add 3 1 (33.3%) LVT 45 Dec/stop/un 37 2 (5.4 %) 0.673 Inc/add 8 0 OXC 68 Dec/stop/un 46 5 (10.9 %) 0.361 Inc/add 22 1 (4.1 %) PB: Phenobabitone, LTG: Lamotrigine, PHT: phenytoin, CLB: Clobazam, CBZ: Carbamazepine, VPA: Valproate, TPM : Topiramate, LVT: Levetiracetam, OXC: Oxcarbazepine Dec: Dose Decreased, stop: AED stopped, un: Dose continued unchanged, Inc: Dose Increased, Add: AED Added
Table 4: Development Quotient (DQ) of children according to the change in
AED usage in second or third trimester in comparison to the first trimester of pregnancy for individual AEDs AED change
Number of
DQ
pregnancies
mean
143
88.49
P value
PB
Inc/add
31
0.297
(33.39)
IP T
Dec/stop/un
85.42
LTG 24
99.37
Inc/add
8
(30.91)
N
82
0.496
U
Dec/stop/un
SC R
(30.31)
(38.49)
Inc/add
42
PT
CLB
M
89
ED
Dec/stop/un
A
PHT
91 (31.45) 93.58 (32.65)
Dec/stop/un
95
93.17
Inc/add
29
(31.87)
CC E
0.614
0.749
95.66 (30.64)
A
CBZ
Dec/stop/un
319
94.39
Inc/add
90
(33.24) 95.48 (30.38)
0.396
VPA Dec/stop/un
211
Inc/add
87.14
45
0.343
(35.44) 80.07 (32.40)
TPM 15
108.05
Inc/add
1
(22.12)
-
IP T
Dec/stop/un
LVT 28
108.06
Inc/add
5
(36.04)
0.081
U
Dec/stop/un
SC R
78.46
96.24
N
(17.80)
Inc/add
18
106.98
M
35
ED
Dec/stop/un
A
OXC
0.403
(32.24) 109.03 (28.26)
PT
PB: Phenobabitone, LTG: Lamotrigine, PHT: phenytoin, CLB: Clobazam, CBZ: Carbamazepine, VPA: Valproate, TPM : Topiramate, LVT: Levetiracetam, OXC: Oxcarbazepine.
CC E
AED change: change in AED usage in second or third trimester compared to first trimester. Dec: Dose Decreased, stop: AED stopped, un: Dose continued unchanged, Inc: Dose Increased,
A
Add: AED Added