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Ketogenic diet effects on neurobehavioral development of children with intractable epilepsy: A prospective study

Open AccessPublished:January 12, 2016DOI:https://doi.org/10.1016/j.yebeh.2015.12.011

      Highlights

      • KD therapy can improve neurobehavioral development in refractory epilepsy.
      • EEG improvement is correlated with clinical efficacy.
      • KD treatment is safe and effective.

      Abstract

      Objective

      This study aimed to determine the impact of a ketogenic diet (KD) on neurobehavioral development when used to treat children with intractable epilepsy, confirming the efficacy of the KD, as well as the correlation between early electroencephalography (EEG) changes in the early stage with treatment efficacy.

      Methods

      We enrolled 42 children who were starting treatment for intractable epilepsy with the classic KD protocol. The total development quotient as well as the development quotients for adaptability, gross motor movements, fine motor movements, language, and individual–social interaction on the Gesell developmental scales were assessed before and after 3, 6, 12, and 18 months of KD treatment. The efficacy assessment was based on changes in seizure frequency after KD as recorded by the parents. We conducted 24-h video-EEG before and after 1 month of KD treatment.

      Results

      Developmental quotients of five energy regions in the Gesell developmental scales assessment were used to compare adaptability (P1 = 0.000), gross motor movements (P2 = 0.010), and fine motor movements (P3 = 0.000); the results showed significant differences. After KD treatment at different time points, 69.0%, 54.8%, 40.5%, and 33.3% patients, respectively, achieved a ≥50% reduction in seizure frequency. The reduction of epileptiform discharges in the awake state after 1 month of KD treatment correlated with the efficacy after 3 months of KD treatment.

      Conclusions

      Ketogenic diet treatment tends to be associated with improved neurobehavioral development, and more significant improvement can be obtained with prolonged treatment. The KD is safe and effective in treating children with intractable epilepsy. Early EEG changes correlate with clinical efficacy, to a certain degree.

      Keywords

      1. Introduction

      Intractable/refractory epilepsy refers to seizures that remain uncontrolled despite treatment with two or more first-line antiepileptic drugs (AEDs), administered serially as monotherapies or in combination, with the dose reaching the maximum tolerated dose for an appropriate treatment course [
      • Kwan P.
      • Arzimanoglou A.
      • Berg A.T.
      • Brodie M.J.
      • Allen Hauser W.
      • Mathern G.
      Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies.
      ]. Despite the advances in vagus nerve stimulation and other operations and the development and clinical use of new AEDs, 20%–30% of children eventually develop intractable epilepsy [
      • Kwan P.
      • Brodie M.J.
      Definition of refractory epilepsy: defining the indefinable?.
      ].
      A ketogenic diet (KD) is a high-fat, adequate-protein, and low-carbohydrate diet administered under medical supervision, which tends to maintain chronic ketosis in the body as well as provide adequate protein and calories for growth and development [
      • Sharma S.
      • Sankhyan N.
      • Gulati S.
      • Agarwala A.
      Use of the modified Atkins diet for treatment of refractory childhood epilepsy: a randomized controlled trial.
      ]. The KD has become an important treatment for children with intractable epilepsy, and its effectiveness has been demonstrated in numerous studies [
      • Neal E.G.
      • Chaffe H.
      • Schwartz R.H.
      • Lawson M.S.
      • Edwards N.
      • Fitzsimmons G.
      • et al.
      The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial.
      ,
      • Freeman J.M.
      • Vining E.P.
      • Pillas D.J.
      • Pyzik P.L.
      • Casey J.C.
      • Kelly L.M.
      The efficacy of the ketogenic diet—1998: a prospective evaluation of intervention in 150 children.
      ,
      • Lefevre F.
      • Aronson N.
      Ketogenic diet for the treatment of refractory epilepsy in children: a systematic review of efficacy.
      ,
      • Kang H.C.
      • Kim Y.J.
      • Kim D.W.
      • Kim H.D.
      Efficacy and safety of the ketogenic diet for intractable childhood epilepsy: Korean multicentric experience.
      ,
      • Chen W.
      • Kossoff E.H.
      Long-term follow-up of children treated with the modified Atkins diet.
      ]. A broad scope of cognitive deficits and behavioral abnormalities is associated with intractable epilepsy. However, few studies have investigated the effects of add-on therapy with KD on the neurobehavioral development. This study aimed to determine the impact of ketogenic diet (KD) on neurobehavioral development in treating children with intractable epilepsy, confirming the efficacy of KD, as well as the correlation between early electroencephalography (EEG) changes in the early stage with treatment efficacy.

      2. Patients and methods

      2.1 Sample

      This study involved a total of 42 children with intractable epilepsy who visited the Rehabilitation Center of Cerebral Palsy Children in the Third Affiliated Hospital of Zhengzhou University between May 2012 and June 2013 and were treated with a KD (ketogenic products provided by Guangzhou Ketone Co. Ltd.). The inclusion criteria were as follows: (1) patients who were ineligible for surgical treatment and met the diagnostic criteria for intractable epilepsy [
      • Kwan P.
      • Arzimanoglou A.
      • Berg A.T.
      • Brodie M.J.
      • Allen Hauser W.
      • Mathern G.
      Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies.
      ]; (2) patients who were aged ≥6 months and ≤6 years; (3) patients whose average seizure frequency was >4 times per month; (4) patients without a history of treatment with a KD within the past 3 months; (5) children who were treated with a KD for at least 3 months; and (6) children whose family consented to treatment with a KD and provided written informed consent. The exclusion criteria were as follows: (1) those who were in the active stages of fever or infective diseases; (2) those with severe vomiting or severe digestive, cardiovascular, respiratory, hepatic, urinary, or metabolic diseases; and (3) those who could not receive the KD or had contraindications to treatment with a KD. This study was approved by the ethics committee of the Third Affiliated Hospital of Zhengzhou University (approval number: 2012-001).

      2.2 Methods

      2.2.1 KD protocols

      After admission, all children underwent routine blood evaluations, liver-, kidney-, and heart-function tests, blood lipid level determination, urinary system color ultrasonography, 24-h video-electroencephalography (VEEG), electrocardiography, Gesell developmental scales assessments, and other related examinations. The types and doses of the original AEDs taken within 3 months before the KD treatment were maintained. All children eligible to receive KD treatment required hospitalization. Classic KD treatment protocols were used, that is, fasting in the beginning and a 4:1 ratio of fat to combined proteins and carbohydrates. After admission, the KD management group (consisting of physicians, nutritionists, and nurses) educated the children's families (on topics such as the use of a blood ketone meter, blood glucose meter, and electronic balance, the recording of seizure manifestations and frequency, and treatment precautions). Every day, the nurses supervised the families to continue the oral administration of the correct dose of the original AEDs on schedule, and the nutritionists supervised the diet of the children. Children were fasted for 24 h to 48 h, during which blood ketone and blood glucose levels were detected once every 6 h. Patients with blood glucose levels lower than 2.1 mmol/L were given orange juice and underwent continuous blood glucose level monitoring. Fasting was stopped when the blood ketone level reached 3 mmol/L, or the fasting had lasted for 48 h. After the beginning of KD treatment, blood ketone and blood glucose levels were detected once every 8 h, and the caloric requirement was calculated according to height, weight, and other standards in each child by the nutritionists. The planned total amount of calories in the KD was 80% of the amount required for healthy children of the same age, evenly divided into 3 daily portions. Children were given 1/3 of the total amount on the first day of KD treatment, 2/3 on the second day, and the total amount on the third day. If adverse reactions occurred or other special individual conditions were present during the adding-on process, the add-on speed was adjusted. The hospital observation period ranged from 7 to 10 days, during which adverse reactions, seizure frequency, seizure severity, duration, etc. were recorded in detail. During KD treatment, children were given supplements of the appropriate amounts of potassium citrate and various types of vitamins and minerals according to their specific circumstances.

      2.2.2 VEEG

      We performed 24-h VEEG in an environment of quiet, soft lighting, and suitable temperature, including awake, drowsy, and sleeping states. Electrodes were placed according to the International 10–20 system, in which the electrode in the earlobe was considered as the reference electrode, with 19 leads. A bipolar lead was applied as the record electrode. When the recording was started, the children who could cooperate under physician supervision with hyperventilation by blowing paper, flash stimulation of 1–20 Hz, and regular tracings with open and closed eyes. For those children who were unable to cooperate background rhythms were obtained by the physician covering the patients’ eyes when necessary.

      2.2.3 Follow-up

      After discharge, data on the children's seizures and diet (seizure time, manifestation, frequency, duration, KD conditions, and adverse reactions) were recorded by their families. The urine ketone level was detected daily, and blood ketone and blood glucose levels were detected once a week. The nutritionists performed a weekly telephone follow-up of the parameters specified above and adjusted the diet. Children were required to attend outpatient visits and undergo repeat tests for liver and kidney functions, blood glucose levels, and urinary system color ultrasonography at 1, 2, 3, 6, 12, and 18 months of KD treatment. They underwent 24-h VEEG before the treatment and after 1 month of the treatment. The Gesell developmental scales scores were repeated after 3, 6, 12, and 18 months of KD treatment. The results of the 24-h VEEG and Gesell developmental scales assessments before and after the treatment were analyzed by physicians with 10 and 13 years of experience in electroencephalographic and Gesell developmental scales assessments, respectively.

      2.3 Efficacy assessment

      Assessment of neurobehavioral development was also performed. The total development quotient as well as the development quotients for adaptability, gross motor movements, fine motor movements, language, and individual–social interaction on the Gesell developmental scales were determined before and after 3, 6, 12, and 18 months of KD treatment. Improvements were observed in each quotient after KD treatment. The total development quotient (DQ) was divided into 6 grades: normal (DQ > 85), boundary situation (76 ≤ DQ ≤ 85), mild growth retardation (55 ≤ DQ ≤ 75), moderate growth retardation (40 ≤ DQ ≤ 54), severe growth retardation (25 ≤ DQ ≤ 39), and extremely severe growth retardation (DQ < 25). An improvement of ≥1 grade in the total development quotient was considered to indicate improvement in neurobehavioral development.
      Reduction in clinical seizure frequency was assessed by determining the Engel grade [
      • Engel Jr., J.
      Surgery for seizures.
      ] at 3, 6, 12, and 18 months of KD treatment: grade I (no seizures): complete control of seizures; grade II (significant effect): ≥75% reduction in seizure frequency; grade III (effectiveness): ≥50% reduction in seizure frequency; and grade IV (ineffectiveness): <50% reduction in seizure frequency. The total efficiency was defined as the number of patients with favorable results (no seizures + significant effectiveness + effectiveness) divided by the total number of patients and multiplied by 100%.
      We also analyzed the correlation of changes in the epileptiform discharges index corresponding to the awake and sleeping states on 24-h VEEG before and after 1 month of KD with clinical efficacy after 3 months of KD treatment. The epileptiform discharge indexes at 1 h after the children woke up and 1 h after they went to sleep were calculated (the total time of epileptiform wave discharge(s) / total observation time × 100%). The onset of sleep was defined as the disappearance of occipital brain waves or falling asleep and closing the eyes. Epileptiform discharges within 30 min of each clinical seizure were excluded to avoid changes due to the seizure. The EEG was performed before and after KD treatment, at the same time of day as much as possible to reduce the effects of circadian rhythms and AED concentrations on epileptiform activity. Effective KD treatment was defined as a ≥50% reduction in clinical seizure frequency after 3, 6, 12, or 18 months of KD treatment; a reduction of <50% indicated ineffective treatment.

      2.4 Statistical analysis

      Statistical analyses were performed using SPSS 17.0 software. Count data were expressed as the number of cases (%), and measurement data were expressed as mean ± standard deviation (χ ± s) or median and interquartile range. The normality of the measurement data was tested using the Kolmogorov–Smirnov test. Changes in neurobehavioral development in each energy region before and after KD treatment were assessed using analysis of variance. Pairwise comparisons were performed using the least significant difference-t method, while heterogeneity of variance was analyzed using the Tamhane's method. The epileptiform discharge index before KD treatment was compared with that after 1 month of KD treatment by using the Mann–Whitney U test, and the correlation of changes in epileptiform discharge indexes with KD efficacy was determined using the Spearman rank correlation. P <0.05 was considered statistically significant.

      3. Results

      3.1 General information

      Among the 42 enrolled children, there were 26 boys and 16 girls, aged 7 to 68 months, with a median age of 25.2 months. The course of the disease before the treatment ranged from 2 to 51 months, with a median of 14.4 months. The AEDs used during KD treatment included sodium valproate oral liquid/tablets (32 patients), clonazepam tablets (21 patients), lamotrigine tablets (16 patients), levetiracetam (27 patients), topiramate (19 patients), and prednisone acetate tablets (6 patients). The seizure types included 6 cases of tonic–clonic seizures, 5 cases of atonic seizures, 2 cases of typical absence seizures, 6 cases of partial seizures, 20 cases of West syndrome, and 3 cases of Lennox–Gastaut syndrome. All children underwent brain magnetic resonance imaging or computed tomography. The brain imaging findings were normal in 15 patients, while abnormalities were detected in 27 patients, including pachygyria (1 patient), gray matter heterotopia (4 patients), cerebral hypoplasia (9 patients), intracranial cyst (5 patients), and cortical and subcortical softening focus (8 patients). The Gesell developmental scales assessments revealed that 41 patients had psychomotor retardation, including 24 with extremely severe retardation, 12 with severe retardation, and 5 with moderate retardation. There were 4 patients with cerebral palsy and 1 patient with tuberous sclerosis.

      3.2 Neurobehavioral development

      Among the 42 children receiving KD treatment, 14 children achieved ≥1 grade improvement in the total development quotient on the Gesell developmental scale. The development quotients of the 5 energy regions on the Gesell developmental scales after KD treatment for 3, 6, 12, and 18 months are shown in Table 1.
      Table 1Comparison of each development quotient before KD treatment and after 3, 6, 12, and 18 months of KD treatment (χ¯ ± s, score).
      Development quotient in energy regionBefore KD treatment3 months of KD treatment6 months of KD treatment12 months of KD treatment18 months of KD treatmentF valueP value
      Adaptability19.79 ± 15.3621.48 ± 15.4622.19 ± 8.7030.56 ± 11.99
      P<0.05, compared with 6months of KD treatment.
      40.67 ± 9.71
      P<0.05, compared with 6months of KD treatment.
      P<0.05, compared with 12months of KD treatment.
      8.2760.000
      Gross motor29.19 ± 16.2730.21 ± 16.0230.2 ± 12.4533.28 ± 8.8844.33 ± 10.72
      P<0.05, compared with 6months of KD treatment.
      P<0.05, compared with 12months of KD treatment.
      3.4850.010
      Fine motor25.98 ± 18.5127.83 ± 18.5129.9 ± 14.4840.50 ± 14.89
      P<0.05, compared with 6months of KD treatment.
      52.67 ± 13.27
      P<0.05, compared with 6months of KD treatment.
      P<0.05, compared with 12months of KD treatment.
      8.7810.000
      Language23.19 ± 15.0724.76 ± 15.3126.0 ± 11.9428.83 ± 10.8531.80 ± 10.521.3750.246
      Individual–social interaction23.24 ± 14.4425.45 ± 14.5828.0 ± 12.8129.94 ± 12.4333.73 ± 12.402.0420.092
      KD, ketogenic diet.
      a P < 0.05, compared with 6 months of KD treatment.
      b P < 0.05, compared with 12 months of KD treatment.

      3.3 Clinical efficacy

      A ≥50% reduction in seizure frequency was observed in 69.0% (29/42), 54.8% (23/42), 40.5% (17/42), and 33.3% (14/42) patients after 3, 6, 12, and 18 months of KD treatment, respectively. The seizure control and retention rates in the children with epilepsy receiving KD treatment for different durations are listed in Table 3. After receiving KD treatment for 3–6 months, 7 patients quit because of unsatisfactory efficacy, 6 patients stopped the treatment because of antifeeding (diet nonadherence) (in 2 of these, the treatment was effective), 2 patients stopped treatment because of poor compliance of their parents, and 1 patient died. After receiving KD treatment for 6–12 months, 4 patients stopped treatment because of poor efficacy, 2 stopped treatment because of other diseases, and 1 because of antifeeding. After receiving KD treatment for 12–18 months, 1 and 2 patients stopped the treatment because of recurrent seizures and poor efficacy, respectively (Fig. 1). The main adverse reactions during KD treatment were gastrointestinal symptoms, such as vomiting, diarrhea, and constipation. Most of these were relieved after symptomatic treatment. Long-term adverse reactions were one case of kidney stones. One patient died during KD treatment. The immediate cause of death was speculated to be airway obstruction due to sputum, leading to suffocation, and was not directly related to KD treatment.
      Table 2Clinical control of seizures and retention rate in children with intractable epilepsy receiving KD treatment for different durations (n = 42).
      3 months of KD treatment6 months of KD treatment12 months of KD treatment18 months of KD treatment
      Number of casesRetention rate (%)Number of casesRetention rate (%)Number of casesRetention rate (%)Number of casesRetention rate (%)
      Grade I921.41126.21126.21023.8
      Grade II511.9819.137.124.8
      Grade III1535.749.537.124.8
      Grade IV1331.037.112.412.4
      Sum42100.02661.91842.81535.8
      Table 3Epileptiform discharge indexes in the awake and sleeping states before KD treatment and after 1 month of KD treatment.
      Before KD treatment1 month of KD treatmentP value
      MedianInterquartileMedianInterquartile
      Epileptiform discharge index in the awake state (%)57.449.9450.6947.900.31
      Epileptiform discharge index in the sleeping state (%)60.2335.5851.8237.690.33
      Figure thumbnail gr1
      Fig. 1Exit KD during the treatment period flow chart.

      3.4 Correlation of EEG changes in the early stage with clinical efficacy

      The epileptiform discharge indexes in the awake and sleeping states before and after 1 month of KD treatment did not show statistically significant differences (Table 2). The reduction in the epileptiform discharge index in the awake state after 1 month of KD treatment was correlated with the efficacy after 3 months of KD treatment (P = 0.029, r = 0.337), while the reduction in the epileptiform discharge index in the sleeping state after 1 month of KD treatment was not correlated with the efficacy after 3 months of KD treatment (P = 0.119).

      4. Discussion

      Epilepsy is one of the most common problems among patients with cerebral palsy, autism, mental retardation, and other forms of intellectual disability. It has been used as a marker of severity and often worsens the quality of life of patients. At the same time, epileptic seizures often cause various neuropsychological problems for children, such as movement retardation, decline in social adaptiveness, anxiety, and sleep disorder. To our knowledge, this study is the first to use the Gesell developmental scales administered to children to assess the neurobehavioral development after 18 months. Because of the unknown effects of KD on neurobehavioral development, comprehensive Gesell developmental scales assessment includes adaptability, gross motor movements, fine motor movements, language, and individual–social interaction. In this study, 42 children receiving a KD were assessed using the Gesell developmental scale, and the neurobehavioral development was found to be significantly improved in 14 children. Compared with the data before KD treatment, adaptability, gross motor movement, and fine motor movement energy regions after KD treatment for 3, 6, 12, and 18 months showed statistically significant differences. Furthermore, pairwise comparisons revealed that the energy regions of adaptability and fine motor movement after KD treatment for 6 months were significantly different from those observed after KD treatment for 12 and 18 months. The gross motor movement energy region showed statistically significant differences between patients receiving 12 and 18 months of KD treatment. Among these, the adaptability region is the most important energy region and is the antecedent of future “intelligence.” The language and individual–social interaction did not show significant differences in patients before and after KD treatment but did improve over time, indicating that short-term KD treatment is unlikely to significantly improve neurobehavioral development, and the improvement in neurobehavioral development is more significant with clinical control of seizures and prolonged KD treatment. Some studies have reported that neurobehavioral development could be improved to some extent with KD treatment [
      • Farasat S.
      • Kossoff E.H.
      • Pillas D.J.
      • Rubenstein J.E.
      • Vining E.P.
      • Freeman J.M.
      The importance of parental expectations of cognitive improvement for their children with epilepsy prior to starting the ketogenic diet.
      ,
      • Pulsifer M.B.
      • Gordon J.M.
      • Brandt J.
      • Vining E.P.
      • Freeman J.M.
      Effects of ketogenic diet on development and behavior: preliminary report of a prospective study.
      ,
      • Hallböök T.
      • Lundgren J.
      • Rosén I.
      Ketogenic diet improves sleep quality in children with therapy-resistant epilepsy.
      ]. Peuscher et al. [
      • Peuscher R.
      • Dijsselhof M.E.
      • Abeling N.G.
      • Van Rijn M.
      • Van Spronsen F.J.
      • Bosch A.M.
      The ketogenic diet is well tolerated and can be effective in patients with argininosuccinate lyase deficiency and refractory epilepsy.
      ] found that the neurobehavioral development of children with intractable epilepsy was improved by a reduction in clinical seizure frequency after KD treatment, mainly manifesting as improvements in social and life abilities. At the same time, Lambrechts et al. [
      • Lambrechts D.A.
      • Bovens M.J.
      • de la Parra N.M.
      • Hendriksen J.G.
      • Aldenkamp A.P.
      • Majoie M.J.
      Ketogenic diet effects on cognition, mood, and psychosocial adjustment in children.
      ] conducted neurobehavioral development tests in children with intractable epilepsy before and after KD treatment, and the results showed no indication that the KD has a negative impact on cognition or social adaptation in the short term. There is a tendency towards an increase in mood problems. Pulsifer et al. [
      • Pulsifer M.B.
      • Gordon J.M.
      • Brandt J.
      • Vining E.P.
      • Freeman J.M.
      Effects of ketogenic diet on development and behavior: preliminary report of a prospective study.
      ] described the effects of the KD on development and behavior, and found a significant improvement in cognition and behavior. In our follow-up, some parents reflected that impulsive and aggressive behavior were reduced in children, self-care ability and the quality of sleep improved, and social activities and concentrating on learning increased, but we did not do further statistical analysis.
      The KD also exhibits good efficacy in treating glucose transporter glut syndrome, infantile spasm, and other diseases. Sinha et al. [
      • Sinha S.R.
      • Kossoff E.
      The ketogenic diet.
      ] performed a meta-analysis and found that about 37% of children with epilepsy achieved ≥90% reduction in seizures; among these, 30% achieved a seizure reduction of 50%–90%. Suo et al. [
      • Suo C.
      • Liao J.
      • Lu X.
      • Fang K.
      • Hu Y.
      • Chen L.
      • et al.
      Efficacy and safety of the ketogenic diet in Chinese children.
      ] assessed 317 children with intractable epilepsy treated with KD and found that 35.0%, 26.2%, and 18.6% of the patients achieved a >50% seizure reduction after 3, 6, and 12 months of treatment. In our earlier study [
      • Zhu D.N.
      • Xie M.M.
      • Wang J.H.
      • Wang J.
      • Ma D.Y.
      • Sun L.
      • et al.
      Therapeutic effect of ketogenic diet for refractory epilepsy in children: a prospective observational study.
      ] of 20 children with intractable epilepsy treated with KD, the efficiency at 3, 6, and 9 months was 65%, 55%, and 55%, respectively. In this study, among the 42 children with intractable epilepsy, the retention rate was close to that reported in the above literature, while the clinical efficiency and rate of complete seizure control were slightly higher, which might be associated with the greater number of patients with infantile spasm and relatively good compliance of the children's families.
      Whether or not the long-term clinical efficacy of KD treatment can be predicted by observing the relationship between the early improvements on EEG remains to be determined. Ebus et al. [
      • Ebus S.C.
      • Lambrechts D.A.
      • Herraets I.J.
      • Majoie M.J.
      • de Louw A.J.
      • Boon P.J.
      • et al.
      Can an early 24-hour EEG predict the response to the ketogenic diet? A prospective study in 34 children and adults with refractory epilepsy treated with the ketogenic diet.
      ] found that a reduction in epileptiform discharge index in the sleeping state after 6 weeks of KD treatment was correlated with the clinical efficacy after 6 months of KD treatment. In this study, we found that the epileptiform discharge index in the awake state was correlated with the clinical efficacy (P = 0.029, r = 0.337), which differs from the above results. This difference may be associated with the limited seizure types and short EEG observation time.

      5. Summary and conclusions

      In summary, KD treatment tends to be associated with improved neurobehavioral development in children with intractable epilepsy, and the improvement is more significant with prolonged treatment. Ketogenic diet treatment is safe and effective, without significant adverse reactions. An EEG improvement in the early stage is correlated with clinical efficacy to a certain extent. However, because of the small sample size and short follow-up duration, the relationship between neurobehavioral development and quality of life and school performance and other issues require further investigation in large, multi-center, randomized control studies.

      Acknowledgments

      This work was supported by the Health Department of scientific and technological projects in Henan Province ( 45000RMB ).
      Conflict of interest
      The authors declared no conflicts of interest with respect to the research, authorship, and/or publication of this article.

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