Research ArticleAnalysis of the Clinical Effects of Sodium Valproate andLevetiracetam in the Treatment of Women withEpilepsy during Pregnancy

Haiqiong Lv,1 Xiaoying Zhao ,2 and Jian Yu 2

1Department of Neurology, Zhuji Hospital Affiliated to Shaoxing University of Arts and Sciences, Shaoxing 311800,Zhejiang, China2Department of Pharmacy, Zhuji Maternal and Child Health Hospital, Shaoxing 311800, Zhejiang, China

Correspondence should be addressed to Jian Yu; atm106@163.com

Received 30 August 2021; Accepted 18 September 2021; Published 29 September 2021

Academic Editor: Songwen Tan

Copyright © 2021 Haiqiong Lv et al. +is is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objective. To explore the clinical effects of sodium valproate and levetiracetam in the treatment of women with epilepsy duringpregnancy.Methods.+e clinical data of 124 women with epilepsy during pregnancy who receivedmonotherapy with antiepilepticdrugs (AEDs) in our hospital from September 2017 to January 2020 were retrospectively analyzed. According to the type ofmedication taken by the patients, they were recorded as the sodium valproate group (the VPA group, n� 56) and the levetiracetamgroup (the LEV group, n� 68 cases).+e effects and the maternal and infant outcomes after treatment were compared between thetwo groups. +e neuron-specific enolase (NSE), cognitive function-related parameters (brain-derived neurotrophic factor(BDNF) and myelin basic protein (MBP)), and related inflammatory factors (tumor necrosis factor- (TNF-) α and interleukin-(IL-) 6) levels were compared between the two groups before and after treatment. Results. After treatment, the total clinicaleffective rate of the LEV group was 91.18% higher than that of the VPA group 73.21%, and the frequency and duration of seizureswere lower than those of the VPA group (P< 0.05). After treatment, the probability of gestational hypertension, depression duringpregnancy, low-weight infants, and neonatal deformities in the LEV group was lower than that in the VPA group (P< 0.05). Aftertreatment, the levels of NSE, MBP, TNF-α, and IL-6 in the two groups decreased, and the levels of BDNF increased, and the LEVgroup changed significantly compared with the VPA group (P< 0.05). Conclusion. Compared with sodium valproate mono-therapy, levetiracetam is more effective in controlling seizures and improving maternal and infant outcomes in women withepilepsy during pregnancy and can effectively regulate their neurological and cognitive functions and reduce the serum in-flammation factor level.

1. Introduction

Epilepsy is a chronic transient brain dysfunction syndromecaused by the abnormally synchronized discharge of the pa-tients’ brain neurons [1]. Patients may present with sudden orrecurrent neurological disorders, twitching of the limbs,temporary sensory failure, unconscious behavior, and othersymptoms [2, 3]. According to statistics from theWorldHealthOrganization, among all epilepsy cases, women of childbearingage account for a larger proportion of epilepsy, about 40%, andin these data, most patients with well-controlled seizures areeager to get pregnant and raise offspring [4]. However, existing

data show that compared with women of normal childbearingage, women of childbearing age with epilepsy have lowermarriage and fertility rates and have a higher risk of com-plications during pregnancy and childbirth [5, 6]. On the onehand, due to the influence of the metabolism of antiepilepticdrugs (AEDs) during pregnancy and the clear or potentialteratogenicity of AEDs to the fetus, it brings difficulties toclinical treatment [7, 8]. On the other hand, with the richselection of AEDs and the increase in the range of indications(such as pain, migraine, and mood disorders), the number offemale patients treated with AEDs during pregnancy has in-creased significantly [9, 10]. Faced with this situation, clinicians

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2021, Article ID 5962200, 8 pageshttps://doi.org/10.1155/2021/5962200

should actively seek countermeasures and choose appropriateAEDs to treat epilepsy during pregnancy, so as to provide afavorable guarantee for the safety of mothers and babies in thisgroup.

Sodium valproate is a traditional broad-spectrum AED,which is effective for the treatment of many types of epilepsy.Compared with the new AEDs of levetiracetam and oxcar-bazepine, it has the advantage of low price. However, recentstudies have shown that when it is used alone or in combi-nation with other AEDs in patients with epilepsy duringpregnancy, it has a higher probability of causing fetal mal-formations than other AEDs. Levetiracetam is a new type ofAEDs. Compared with traditional AEDs and other new AEDs,it has a lower incidence of malformations associated withmonotherapy in the fetus. +erefore, in recent years, its ap-plication in patients with epilepsy during pregnancy has be-come increasingly widespread. In this study, we observed theclinical effects and safety of sodium valproate and levetiracetamin the treatment of women with peripregnancy epilepsy. +eaim was to explore the effects of the above two monotherapieson epilepsy control, maternal and infant outcomes, neuro-cognitive function, and body inflammatory level in peripreg-nancy women with epilepsy. +e report is as follows.

2. Materials and Methods

2.1. General Data. +is is a retrospective analysis of theclinical data of 124 women with epilepsy during pregnancywho received AEDs monotherapy in our hospital fromSeptember 2017 to January 2020. Case inclusion criteria: metthe diagnostic criteria of the International Anti-EpilepsyLeague [11], 22–38 years old, the patients had a history ofepilepsy and had at least one epilepsy symptom duringpregnancy, the patient without central nervous systemdisease or space-occupying disease, the patient who signedthe consent form, the patient with complete clinical data,and patients who followed doctor’s orders and had goodmedication compliance. Case exclusion criteria: the patientwith allergy to sodium valproate or levetiracetam, the patientwith neurological or mental disorders and unable to com-municate normally, the patient with severe dysfunction suchas the heart, liver, and kidney, the patient with severe un-derlying diseases or tumors, organ transplants, and thepatient with the blood system or immune system diseases.According to the type of medication taken by the patients,they were recorded as the sodium valproate group (the VPAgroup, n� 56) and the levetiracetam group (the LEV group,n� 68 cases). +ere was no statistical difference between thegeneral information in Table 1 between the VPA group andthe LEV group, and they were comparable (P> 0.05).

2.2. Treatment Methods. Both groups of patients receivedroutine antiepileptic care and management during thetreatment period, including reasonable diet arrangements,avoiding patients from eating foods that may induce epi-leptic seizures, and providing psychological counseling in-terventions for patients to relieve the psychological pressureof patients. On this basis, the VPA group received sodium

valproate sustained-release tablets (Sanofi (Hangzhou)Pharmaceutical Co., Ltd., approval number: H20010595,specification: 0.5 g× 30 tablets) monotherapy. Usage anddosage: oral 30min after meal, 2 times/d, initial dose is10mg/kg, increase to 20mg/kg after 1 week, and maintaintreatment. +e LEV group received levetiracetam tablets(UCB Pharma S. A., approval number: J20160085, specifi-cation: 0.5 g× 30 tablets) monotherapy. +e usage anddosage are oral 30min after meal, 2 times/d, the initial doseis 10mg/kg, increased by 10mg/kg every week, so that thepatient’s drug dose at late pregnancy is controlled at1800± 200mg/kg.

2.3. Observation Indicators

(1) +erapeutic effect: the criterion of efficacy was basedon the revised scoring standard of the InternationalAnti-Epilepsy League [12]. Among them, no epi-leptic seizures during treatment and no epileptiformdischarge on EEG examination were fully controlled.After treatment, the number of epileptic seizures wasreduced by 75% or more, and the EEG examinationwas markedly improved as markedly effective. Aftertreatment, the frequency of epileptic seizures de-creased by 50%–<75% and the improvement of EEGwas effective. A reduction of less than 50% in thenumber of seizures was invalid. Total effectivenumber� fully control number +markedly effectivenumber + effective number. Statistics and compari-son of the seizure frequency and seizure duration ofthe two groups of patients.

(2) Maternal and infant outcomes: statistics and com-parison of the number of cases of placenta previa,premature delivery, miscarriage, gestational hyper-tension, and depression during pregnancy betweenthe two groups of patients and statistics and com-parison of the two groups of fetal cases of fetaldistress, stillbirth, low body mass, and neonataldeformities.

(3) Serological indicators: the neuron-specific enolase(NSE), cognitive function-related parameters (brain-derived neurotrophic factor (BDNF) and myelinbasic protein (MBP)), and related inflammatoryfactors (tumor necrosis factor- (TNF-) α and in-terleukin- (IL-) 6) levels were compared between thetwo groups before and after treatment. Detectionmethod: before and after treatment, 6mL of venousblood was drawn in the morning, centrifuged at2800 r/min for 8min, and the supernatant wasseparated and placed in a refrigerator at −30°C fortesting.+e detection was carried out by the enzyme-linked immunosorbent method, and the kit wasprovided by Epson (Shanghai) Biotechnology Co.,Ltd.

2.4. StatisticalMethods. Data analysis was processed by SPSS22.0 software. +e measurement data were expressed as(x± s), and t-test analysis was used for comparison. +e

2 Evidence-Based Complementary and Alternative Medicine

count data were expressed as (%), and χ2-test analysis wasused for comparison. P< 0.05 indicated that the differencewas statistically significant.

3. Results

3.1. Comparison of Efficacy between the VPA Group and LEVGroup. After treatment, the total clinical effective rate of theLEV group was 91.18% higher than that of the VPA group73.21% (P< 0.05) (Table 2).

3.2. Comparison of the Frequency and Duration of Seizuresbetween theVPAGroupandLEVGroup. After treatment, thefrequency of seizures in the LEV group (1.88± 0.25) times/month was less than that in the VPA group (2.41± 0.23)times/month, and the duration of seizures in the LEV group(2.84± 1.01) minutes/time was less than that in the VPAgroup (3.96± 1.21) minutes/time (P< 0.05) (Figure 1).

3.3.ComparisonofMaternal and InfantOutcomesbetween theVPA Group and LEV Group. After treatment, the incidenceof placenta previa, premature delivery, miscarriage, gesta-tional hypertension, and depression during pregnancy in theVPA group was 12.50% (7/56), 16.07% (9/56), 16.07% (9/56), 26.79% (15/56), and 28.57% (16/56), respectively; theincidence of placenta previa, premature delivery, miscar-riage, gestational hypertension, and depression duringpregnancy in the LEV group was 7.35% (5/68), 13.24% (9/68), 10.29% (7/68), 11.76% (8/68), and 11.76% (8/68), re-spectively. +e incidence of fetal distress, stillbirth, low bodymass, and neonatal deformities in the VPA group was17.86% (10/56), 0.00% (0/56), 83.93% (47/56), and 26.79%(15/56), respectively; the incidence of fetal distress, stillbirth,low body mass, and neonatal deformities in the LEV groupwas 8.82% (6/68), 0.00% (0/68), 54.41% (37/68), and 5.88%(4/68), respectively. +e probability of gestational hyper-tension, depression during pregnancy, low-weight infants,and neonatal deformities in the LEV group was lower thanthat in the VPA group (P< 0.05) (Figure 2).

3.4.Comparisonof SerumIndexesbetween theVPAGroupandLEV Group. Before treatment, the NSE levels of the VPAgroup and LEV group were 14.68± 4.36 and 15.01± 4.21 ng/mL, BDNF levels were 20.20± 2.18 and 20.18± 2.21 pg/mL,

MBP levels were 3.62± 0.45 and 3.65± 0.43 μg/mL, IL-6levels were 13.12± 1.66 and 13.15± 1.61 pg/mL, and TNF-αlevels were 3.39± 0.43 and 3.41± 0.43 ng/mL, respectively.After treatment, the NSE levels of the VPA group and LEVgroup were 9.13± 2.37 and 7.11± 2.25 ng/mL, BDNF levelswere 30.24± 3.52 and 33.68± 3.65 pg/mL, MBP levels were2.56± 0.23 and 1.98± 0.20 μg/mL, IL-6 levels were9.42± 1.15 and 8.20± 1.06 pg/mL, and TNF-α levels were1.96± 0.20 and 1.24± 0.14 ng/mL, respectively. After treat-ment, the levels of NSE, MBP, TNF-α, and IL-6 in the twogroups decreased, and the levels of BDNF increased, and theLEV group changed significantly compared with the VPAgroup (P< 0.05) (Figure 3).

4. Discussion

According to incomplete statistics, about 0.3–0.7% of womenof childbearing age in the world have epilepsy during preg-nancy and 0.3–0.5% of children come from women withepilepsy [13–15]. In all patients with epilepsy during preg-nancy, the proportion of patients who choose to receive AEDsmonotherapy can be as high as 98.6% [16]. Among them, thecommonly used AEDs are traditional AEDs such as sodiumvalproate, carbamazepine, and newAEDs such as lamotrigine,levetiracetam, and oxcarbazepine. Different AEDs are ac-companied by different treatment effects and maternal andinfant outcomes. +is study analyzed and compared theclinical efficacy and safety of sodium valproate and levetir-acetammonotherapy.+e results showed that after treatment,the total clinical effective rate of the LEV group was 91.18%higher than that of the VPA group 73.21%. At the same time,the frequency and duration of seizures in the LEV group wereless than those in the VPA group. It shows that comparedwithsodium valproate monotherapy, levetiracetam has a bettertherapeutic effect and can significantly reduce the frequencyand duration of seizures in patients with epilepsy duringpregnancy. +e results also showed that after treatment, theprobability of gestational hypertension, depression duringpregnancy, low-weight infants, and neonatal deformities inthe LEV group was lower than that in the VPA group. +isshows that in addition to effective control of seizures duringpregnancy, levetiracetam can also effectively reduce the risk ofneonatal deformities and low body mass.

Sodium valproate is the first-line AEDs commonly usedin clinical practice. It has the advantages of broad anti-epileptic spectrum, relatively cheap price, low

Table 1: Comparison of general information between the VPA group and LEV group.

Information VPA group (n� 56) LEV group (n� 68) t/χ2 P

Age (years) 28.64± 4.75 29.40± 4.41 0.922 0.358Disease course (years) 0.65± 0.15 0.68± 0.14Maternal type (cases) 0.020 0.888Primiparous 32 39Multiparous 24 29

Epilepsy type (cases) 0.374 0.946Localized 13 15Clonic 17 18Generalized tonic 15 21Generalized tonic-clonic 11 14

Evidence-Based Complementary and Alternative Medicine 3

Table 2: Comparison of efficacy between the VPA group and LEV group (n (%)).

Group n Fully control Markedly effective Valid Invalid Total effectiveVPA group 56 6 (10.71) 14 (25.00) 21 (37.50) 15 (26.79) 41 (73.21)LEV group 68 11 (16.18) 29 (42.65) 22 (32.35) 6 (8.82) 62 (91.18)t 5.343P 0.021

0

2

4

6

Seiz

ure c

ondi

tion

VPA groupLEV group

∗

∗

Seiz

ure f

requ

ency

(tim

es/m

onth

)

Ons

et d

urat

ion

(min

/tim

es)

Figure 1: Comparison of the frequency and duration of seizures between the VPA group and LEV group. ∗Compared with the VPA group,P< 0.05.

0

10

20

30

Inci

denc

e (%

)

∗ ∗

Plac

enta

pre

via

Prem

atur

ede

liver

y

Ges

tatio

nal

hype

rten

sion

Dep

ress

ion

Misc

arria

ge

VPA groupLEV group

(a)

0

20

40

60

80

100

∗

∗

Inci

denc

e (%

)

Feta

l dist

ress

Still

birt

h

Low

bod

ym

ass

Neo

nata

lde

form

ities

VPA groupLEV group

(b)

Figure 2: Comparison of maternal and infant outcomes between the VPA group and LEV group (%). (a) Maternal outcomes. (b) Infantoutcomes. +e incidence of stillbirth in both groups was 0.00%. ∗Compared with the VPA group, P< 0.05.

4 Evidence-Based Complementary and Alternative Medicine

0

5

10

15

20

25

NSE

leve

l (ng

/ml)

∗

∗#

Befo

retr

eatm

ent

Afte

rtr

eatm

ent

VPA groupLEV group

(a)

0

10

20

30

40

BDN

F le

vel (

pg/m

L)

∗

∗#

Befo

retr

eatm

ent

Afte

rtr

eatm

ent

VPA groupLEV group

(b)

0

1

2

3

4

5

MBP

leve

l (μg

/mL)

∗

∗#

Befo

retr

eatm

ent

Afte

rtr

eatm

ent

VPA groupLEV group

(c)

0

5

10

15

20IL

-6 le

vel (

pg/m

L)

∗

∗#Be

fore

trea

tmen

t

Afte

rtr

eatm

ent

VPA groupLEV group

(d)

Figure 3: Continued.

Evidence-Based Complementary and Alternative Medicine 5

concentration of drug required, and long action time. Itsmechanism of action is related to the promotion of the highexpression of the inhibitory neurotransmitter c-amino-butyric acid in the brain, inhibiting the abnormal dischargeof neurons, preventing the influx of calcium ions, andmaintaining the stability of neuronal cell membranes [17].At the same time, it is effective in treating bipolar disorder,and it is also the drug of choice for many patients withpartial epileptic seizures and has a wide range of clinicalapplications. However, with the increasing expansion ofthe scope of clinical application of sodium valproate, itsadverse reactions are gradually exposed. Its common ad-verse effects on patients include skin allergies, thrombo-cytopenia, personality changes, memory decline, brain cellhypoxia, and liver damage [18]. +e adverse effects on thefetus include major congenital malformations (MCMs)such as heart development malformations, bone malfor-mations, urogenital malformations, cleft palate, and neuraltube defects [19]. +erefore, it is classified as D-level in thepregnancy safety level by the US Drug and Food Admin-istration. Research on whether the teratogenic risk of AEDsis related to the type of drug, multidrug therapy, andapplied dose has found that when the multidrug combi-nation or drug regimen contains sodium valproate, theprobability of fetal MCMs is significantly increased [20]. Astudy comparing the incidence of MCMs during mono-therapy found that the incidence of sodium valproate wasthe highest at 10.3%, which was much higher than the 2.8%of levetiracetam [21]. In this study, the rates of neonataldeformities treated with sodium valproate and levetir-acetam were 26.79% and 5.88%, respectively, slightly higherthan the study by Meador et al. [20]. +is may be caused bythe inclusion of some newborns with small deformities inthis sample.

Levetiracetam is a pyrrolidone derivative, which canspecifically bind to the central nerve synaptic vesicle protein2A subunit to inhibit the release of neurotransmitters, blockthe abnormal discharge of neurons, and ultimately reduceseizures [22]. In addition, compared with traditional AEDssuch as sodium valproate, it has better drug metabolism,longer action time, and fewer adverse reactions (less impacton the liver, no cognitive impairment, no risk of weight gain,and low probability of skin rash) and other characteristics[23]. +erefore, in recent years, its application in many typesof epilepsy has become increasingly widespread, and its usein patients with epilepsy during pregnancy has graduallyincreased. According to the latest Chinese guidelines for themanagement of women with epilepsy during peripregnancy,it is recommended that women of childbearing age shouldgive priority to new AEDs for treatment when preparing forpregnancy, but for patients who have used sodium valproatefor antiepileptic therapy during pregnancy, if the seizures arewell controlled, the applied dose should be adjusted to alower range, and when the control is not good, you can try toreplace or add new AEDs for treatment. It can be seen fromthe above that although sodium valproate has the advantagesof broad-spectrum antiepileptic, it is not recommended asthe first-line treatment option for patients with epilepsyduring pregnancy. For such patients, levetiracetam has ahigher application value in controlling epilepsy and im-proving maternal and infant outcomes due to its excellentpharmacological and pharmacokinetic properties.

Epilepsy is mostly caused by the abnormal discharge ofbrain neurons. Long-term repeated seizures can triggerevents such as hippocampal neuron regeneration and othercentral nervous system damage, which in turn leads tocognitive decline in patients [24]. In addition, the release ofinflammatory mediators can also increase the excitability of

0

1

2

3

4

5

TNF-α

leve

l (ng

/mL)

∗

∗#

Befo

retr

eatm

ent

Afte

rtr

eatm

ent

VPA groupLEV group

(e)

Figure 3: Comparison of serum indexes between the VPA group and LEV group. (a) NSE level. (b) BDNF level. (c) MBP level. (d) TNF-αlevel. (e) IL-6 level. ∗Compared with the same group before treatment, P< 0.05. #Compared with the VPA group after treatment, P< 0.05.

6 Evidence-Based Complementary and Alternative Medicine

neurons, so it also plays a key role in promoting epilepticseizures [25]. NSE is a marker of nerve damage, and itsserum content is positively correlated with the number ofneuronal damage [26]. MBP is an important part of myelinsheath, which can reflect the degree of brain nerve damage;when the central nervous system is damaged, its serum levelrises; BDNF can prevent neuronal damage and is of greatsignificance to the growth and survival of neurons, and bothare important parameters reflecting the cognitive level ofpatients with epilepsy [27, 28]. Elevated levels of TNF-α canexcite neurotransmitters, and elevated levels of IL-6 canchange neuronal action potentials. +e interaction betweenthe two can excite neurons, cause hippocampal damage, andaggravate epilepsy [29]. After treatment, in this study, thelevels of NSE, MBP, TNF-α, and IL-6 in the two groupsdecreased, and the levels of BDNF increased, and the LEVgroup changed significantly compared with the VPA group.It is suggested that compared with sodium valproatemonotherapy, levetiracetam monotherapy is more effectivein improving neurocognitive function and serum inflam-mation levels in women with epilepsy during pregnancy.+is once again confirmed the good prospects of levetir-acetam in the treatment of women with epilepsy duringperipregnancy.

In summary, compared with sodium valproate mono-therapy, levetiracetam is more effective in controlling sei-zures and improving maternal and infant outcomes inwomen with epilepsy during pregnancy and can effectivelyregulate their neurological and cognitive functions andreduce the serum inflammation factor level.

Data Availability

+edata used to support the results of this study are availablefrom the corresponding author upon request.

Ethical Approval

+is study is approved by the Ethics Committee of ZhujiHospital Affiliated to Shaoxing University of Arts andScience and Zhuji Maternal and Child Health Hospital.

Conflicts of Interest

+e authors declare that there are no conflicts of interest.

References

[1] C. C. Shen and J. F. Jiang, “Auricular electroacupuncture forlate posttraumatic epilepsy after severe brain injury: a ret-rospective study,” Evidence-based Complementary and Al-ternative Medicine: eCAM, vol. 2019, Article ID 5798912,9 pages, 2019.

[2] A. M. Pack, “Epilepsy overview and revised classification ofseizures and epilepsies,” Continuum: Lifelong Learning inNeurology, vol. 25, no. 2, pp. 306–321, 2019.

[3] A. Bernasconi, F. Cendes, W. H. +eodore et al., “Recom-mendations for the use of structural magnetic resonanceimaging in the care of patients with epilepsy: a consensusreport from the international league against epilepsy

neuroimaging task force,” Epilepsia, vol. 60, no. 6,pp. 1054–1068, 2019.

[4] C.-Y. Kuo, Y.-H. Liu, I.-J. Chou et al., “Shifting valproic acidto levetiracetam in women of childbearing age with epilepsy: aretrospective investigation and review of the literature,”Frontiers in Neurology, vol. 11, p. 330, 2020.

[5] S. Li, J. Chen, A. T. A. Abdulaziz et al., “Epilepsy in China:factors influencing marriage status and fertility,” Seizure,vol. 71, pp. 179–184, 2019.

[6] C. Harden and C. Lu, “Epilepsy in pregnancy,” NeurologicClinics, vol. 37, no. 1, pp. 53–62, 2019.

[7] P. E. Voinescu, S. Park, L. Q. Chen et al., “Antiepileptic drugclearances during pregnancy and clinical implications forwomen with epilepsy,” Neurology, vol. 91, no. 13,pp. e1228–1236, 2018.

[8] T. Tomson, D. Battino, and E. Perucca, “Teratogenicity ofantiepileptic drugs,” Current Opinion in Neurology, vol. 32,no. 2, pp. 246–252, 2019.

[9] S. R. Sharma, N. Sharma, and M. Hussain, “Levetiracetam useduring pregnancy in women with active epilepsy: a hospital-based, retrospective study from a tertiary care hospital innorth eastern India,” Neurology India, vol. 69, no. 3,pp. 692–697, 2021.

[10] J. D. Cardoso-Vera, G. A. Elizalde-Velazquez, H. Islas-Flores,A. Mejıa-Garcıa, J. M. Ortega-Olvera, and L. M. Gomez-Olivan, “A review of antiepileptic drugs: Part 1 occurrence,fate in aquatic environments and removal during differenttreatment technologies,”;e Science of the Total Environment,vol. 768, Article ID 145487, 2021.

[11] I. E. Scheffer, S. Berkovic, G. Capovilla et al., “ILAE classi-fication of the epilepsies: position paper of the ILAE com-mission for classification and terminology,” Epilepsia, vol. 58,no. 4, pp. 512–521, 2017.

[12] A. T. Berg, S. F. Berkovic, and M. J. Brodie, “Revised ter-minology and concepts for organization of seizures and ep-ilepsies: report of the ILAE commission on classification andterminology,” Epilepsia, vol. 51, no. 4, pp. 676–685, 2010.

[13] S. F. Reiter, G. Veiby, A.-K. Daltveit, B. A. Engelsen, andN. E. Gilhus, “Psychiatric comorbidity and social aspects inpregnant women with epilepsy-the norwegian mother andchild cohort study,” Epilepsy and Behavior, vol. 29, no. 2,pp. 379–385, 2013.

[14] A. Verrotti, E. Mencaroni, M. Castagnino, and G. Zaccara,“Foetal safety of old and new antiepileptic drugs,” ExpertOpinion on Drug Safety, vol. 14, no. 10, pp. 1563–1571, 2015.

[15] J. Jedrzejczak, D. Bomba-Opon, G. Jakiel, A. Kwasniewska,and D. Mirowska-Guzel, “Managing epilepsy in women ofchildbearing age-polish society of epileptology and polishgynecological society guidelines,” Ginekologia Polska, vol. 88,no. 5, pp. 278–284, 2017.

[16] H. Kim, E. Faught, D. J. +urman, J. Fishman, and L. Kalilani,“Antiepileptic drug treatment patterns in women of child-bearing age with epilepsy,” JAMA Neurology, vol. 76, no. 7,pp. 783–790, 2019.

[17] S. M. Jankovic and S. V. Jankovic, “Lessons learned from thediscovery of sodium valproate and what has this meant tofuture drug discovery efforts?” Expert Opinion on DrugDiscovery, vol. 15, no. 11, pp. 1355–1364, 2020.

[18] C. Pirozzi, A. Lama, C. Annunziata et al., “Butyrate preventsvalproate-induced liver injury: in vitro and in vivo evidence,”;e FASEB Journal, vol. 34, no. 1, pp. 676–690, 2020.

[19] T. Tomson, D. Battino, E. Bonizzoni et al., “Declining mal-formation rates with changed antiepileptic drug prescribing:

Evidence-Based Complementary and Alternative Medicine 7

an observational study,” Neurology, vol. 93, no. 9,pp. e831–840, 2019.

[20] K. Meador, M. W. Reynolds, S. Crean, K. Fahrbach, andC. Probst, “Pregnancy outcomes in women with epilepsy: asystematic review and meta-analysis of published pregnancyregistries and cohorts,” Epilepsy Research, vol. 81, no. 1,pp. 1–13, 2008.

[21] T. Tomson, D. Battino, E. Bonizzoni et al., “Comparative riskof major congenital malformations with eight different an-tiepileptic drugs: a prospective cohort study of the EURAPregistry,” ;e Lancet Neurology, vol. 17, no. 6, pp. 530–538,2018.

[22] P. Howard, J. Remi, C. Remi et al., “Levetiracetam,” Journal ofPain and Symptom Management, vol. 56, no. 4, pp. 645–649,2018.

[23] J. M. Chamberlain, J. Kapur, S. Shinnar et al., “Efficacy oflevetiracetam, fosphenytoin, and valproate for establishedstatus epilepticus by age group (ESETT): a double-blind,responsive-adaptive, randomised controlled trial,” Lancet(London, England), vol. 395, no. 10231, pp. 1217–1224, 2020.

[24] V. E. De Knegt, C. E. Hoei-Hansen, M. Knudsen et al.,“Increase in cognitive function is seen in many single-oper-ated pediatric patients after epilepsy surgery,” Seizure, vol. 81,pp. 254–262, 2020.

[25] S. Tao, J. Sun, F. Hao et al., “Effects of sodium valproatecombined with lamotrigine on quality of life and serum in-flammatory factors in patients with poststroke secondaryepilepsy,” Journal of Stroke and Cerebrovascular Diseases,vol. 29, no. 5, Article ID 104644, 2020.

[26] A. Bindra, A. Kaushal, H. Prabhakar et al., “Neuroprotectiverole of dexmedetomidine in epilepsy surgery: a preliminarystudy,” Neurology India, vol. 67, no. 1, pp. 163–168, 2019.

[27] P. Sharma, A. Kumar, and D. Singh, “Dietary flavonoidsinteraction with CREB-BDNF pathway: an unconventionalapproach for comprehensive management of epilepsy,”Current Neuropharmacology, vol. 17, no. 12, pp. 1158–1175,2019.

[28] R. He, W. Han, and X. Song, “Knockdown of Lingo-1 by shorthairpin RNA promotes cognitive function recovery in a statusconvulsion model,” 3 Biotech, vol. 11, no. 7, p. 339, 2021.

[29] Y. Wan and Z.-Q. Yang, “LncRNA NEAT1 affects inflam-matory response by targeting miR-129-5p and regulatingNotch signaling pathway in epilepsy,” Cell Cycle, vol. 19, no. 4,pp. 419–431, 2020.

8 Evidence-Based Complementary and Alternative Medicine