Background
Epilepsy is a common chronic neurological disorder marked by a pathological tendency toward recurring and unprovoked seizures [
1]. Epilepsy poses a burden for parents, children, and medical doctors. The annual incidence of epilepsy is 61.4 per 100,000 persons [
2]. Notably, the incidence of epilepsy is highest in the first year of life, with a rate of ~ 150 cases/100,000 persons per year [
3]. Additionally, the occurrence of repeated and unprovoked seizures in childhood reaches 0.8% by the age of 15 [
3]. For those aged under 20, epilepsy can affect 1% of the population [
4]. The etiology of epilepsy can be divided into three types: cryptogenic, symptomatic, and idiopathic [
1]. Meanwhile, the underlying risk factors for epilepsy in childhood and adolescence vary from those associated with epilepsy in adults [
1]. A risk factor for epilepsy is defined as a situation that increases the occurrence of epilepsy [
5]. Although certain risk factors are well documented, such as infection in the central nervous system and metabolic disorders, others remain poorly understood, notably those associated with pregnancy characteristics [
5]. In fact, 20% of epilepsy cases have no identifiable causes [
6]. While extensive research has been conducted to understand the etiology and management of epilepsy, there is a growing interest in investigating the roles of prenatal factors, delivery conditions, and postnatal factors in the development and progression of epilepsy. Understanding the risk factors can help prevent epilepsy onset, decrease epilepsy prevalence in children and adolescents as well as its associated comorbidities, and aid healthcare professionals in identifying high-risk populations and making plausible preventive strategies. Hence, the impacts of prenatal factors, delivery condition and postnatal factors on epilepsy are still a subject of debate, with different studies yielding conflicting results. In this systematic review, we aim to establish the relationships of prenatal characteristics, newborn delivery situations and postnatal conditions with the risk of epilepsy.
Discussion
The present systematic review and meta-analysis is the first to evaluate factors associated with epilepsy occurrence in childhood or adolescence. Meta-analysis based on the 25 studies revealed that the prenatal risk factors for epilepsy included preterm birth (< 37 weeks), smoking during pregnancy, maternal epilepsy, eclampsia, pregnancy metrorrhagia regardless of the term, and maternal infection regardless of the term. Newborn delivery factors that increase the risk of epilepsy were cord prolapse, head trauma and prolonged labor > 6 h. Regarding postnatal factors, the risk of epilepsy was significantly elevated with birth complications, low-weight birth (< 2.5 kg), and male gender.
Prenatal factors were more commonly studied in various papers [
16,
18‐
21,
28,
33]. Of the studies addressing the relationship between preterm/postterm birth and the risk of epilepsy, we identified six case-control studies [
14,
16,
24,
25,
28,
33] and four cohort studies [
19‐
21,
33]. It is worth noting that these studies had comparable weights in terms of their impact on the overall results of the meta-analysis. Subgroup analysis and sensitivity analysis indicated that preterm birth doubled the risk of epilepsy in children or adolescents. The study conducted by Li et al. was in line with our findings, in which the risk was 2.16 times higher in preterm groups [
35]. However, post-term birth was not associated with the risk of epilepsy. Several studies have indicated the association between preterm birth and epilepsy onset at a younger age is mediated by white matter gliosis and hypoxic-ischemic brain injury [
13,
36]. However, in our study, by excluding cerebral palsy and stroke, we emphasize alternative hypotheses. In fact, hippocampal sclerosis, impaired development of brain structure and a higher risk of infection in preterm groups have been reported to contribute to this association [
13]. Given the limited data on the risk of epilepsy occurrence in children and adolescents with preterm, full-term, or post-term births, we were unable to compare the risk of epilepsy between those with preterm and full-term births, and between those with postterm and full-term births.
Our results showed that smoking during pregnancy significantly increased epilepsy occurrence by 28%. Smoking during pregnancy has been identified as the first environmental risk factor for epilepsy worldwide. Furthermore, it doubles the risk of seizures in children [
37]. Among the few studies exploring the association of smoking at pregnancy with epilepsy onset at an early age, smoking has been found to induce placental inflammation, placenta damage, decreased blood flow in the placenta, remodeling of the uterine vasculature, low birth weight and fetal growth restriction [
38‐
40], which may underlie the increased risk of epilepsy [
38‐
40]. Additionally, tobacco contains various chemicals with proconvulsant effects such as ammonia, hexane, toluene and arsenic; however, it remains unknown whether these chemicals can cross the placental barrier to induce epileptic seizures in children [
40]. Furthermore, some studies have reported brain structural changes associated with maternal smoking, such as cortical thinning in the lateral and perisylvian occipital cortices and a significantly smaller frontal lobe [
40,
41]. Moreover, maternal smoking affects the expression of many genes that are related with epilepsy [
42]. Further research is required to elucidate the pathophysiology of smoking during pregnancy and the risk of epilepsy in children or adolescents.
In our study, children/adolescents born to epileptic mothers were 2.06 times more likely to have epilepsy. Out of the 6 studies that examined the association of maternal epilepsy with epilepsy onset in children or adolescents, two were cross-sectional and case-control studies [
11,
12], three were case-control studies [
27,
30,
32] and one was a cohort study [
20]. Notably, the two studies that exerted the most significant influence on the overall results were those by Ngugi et al. (2013) and Whitehead et al. (37.5% and 30.6% respectively) [
12,
20]. This finding was similar to those reported in various other studies [
12,
16,
43]. In fact, maternal epilepsy was associated with an ~ 45% increased risk of epilepsy in the offspring [
43]. Additionally, antiepileptic drug use during pregnancy is not an explanation for epilepsy occurrence in children/adolescents [
44]. Another hypothesis that can explain this relationship is the genetic origin of epilepsy. In fact, epilepsy can be inherited from the mothers [
43]. Additional studies are needed to fully establish the mechanism behind the association between maternal epilepsy and the risk of epilepsy in children and adolescents.
While preeclampsia was not identified as a risk factor for epilepsy, eclampsia was strongly associated with this risk and conferred an OR of 16.9. The variation in study design has been identified as the origin of heterogeneity in this analysis. Specifically, we integrated two cohort studies [
19,
20] along with one case-control study [
32]. The research conducted by Whitehead et al. carried the greatest significance in the analysis, accounting for 40.1% of the total weight [
20]. Eclampsia is a serious complication that can lead to epilepsy in children/ adolescents through various pathways. In fact, mothers can experience hypoxia, which can affect the normal development of the fetal brain and increase the risk of epilepsy. Rocca et al. showed that eclampsia increases the risk of generalized tonic-clonic seizures, partial seizures and absence seizures by 2 folds; however, this relationship is not significant [
45]. This association may be explained by placental dysfunction, biological changes during eclampsia, premature birth and low-weight birth. Meanwhile, the exact mechanism remains unknown. As preeclampsia precedes eclampsia, prompt diagnosis and treatment of preeclampsia are needed to prevent eclampsia onset and its associated complications.
In our meta-analysis, we found that maternal infection, regardless of the type or term, is the leading cause of epilepsy in children and adolescents. Sun et al. showed that prenatal exposure to maternal cystitis, pyelonephritis, persistent diarrhea, coughing, and vaginal yeast infections is linked to an elevated risk of juvenile epilepsy [
13]. Additionally, Casetta et al. found that maternal illness, notably upper respiratory infections, is linked to an elevated incidence of cryptogenic and idiopathic partial epilepsy [
46]. While the pathophysiological mechanisms remain unclear, a plausible explanation is that the immune response and cytokines might potentially induce placental abnormalities and fetal brain damage. This finding highlights the importance of antenatal care to prevent infection and other pregnancy-related issues. Other factors related to epilepsy occurrence are prolonged labor and cord prolapse. These results could also be explained by the increased risk of infection. Cord prolapses can also lead to oxygen deprivation inducing brain injury [
47]. Glass et al. showed a positive association between cord prolapses and seizure occurrence in children with an OR of 6.9 [95% CI: 5.9–8.1] [
47].
The occurrence of epilepsy following head trauma has been extensively studied in both children/adolescents and adults [
45,
48]. We found that children/adolescents with a history of head trauma had a 2.31-fold increased risk of epilepsy. This finding aligns with the results of previous studies. In fact, this association can be linked to neuroinflammation, glial scars and brain injuries induced by head trauma.
After sensitivity analysis by excluding the study of McDermott et al. [
16], the risk of epilepsy occurrence was shown to be higher in male newborns (56% vs 50.7%, pooled OR = 1.18 [95% CI: 1.06–1.32]). We excluded this particular study because it was the primary source of variations of results. Our findings are consistent with those of other studies [
49,
50]. Two potential explanations for our findings are as follows: sex differences in cerebral connectivity and in astrocyte structure [
51‐
53]. The male brain typically has a larger amygdala and thalamus, while the female brain features a larger hippocampus, caudate nuclei, regional gray matter, and cortices [
54]. Studies have shown that men exhibit stronger right-side connectivity in the amygdala, while women display more prominent left-side connections [
54]. These sex-related distinctions in brain development, influenced by steroid hormones, impact the susceptibility to seizures [
54]. Additionally, astrocyte structural variations may contribute to the sex difference in epilepsy, as cultured astrocytes and microglia from male and female rats display distinct functional responses and inflammatory marker expression [
52,
53]. Further research is needed to uncover the structural and neuroendocrine factors contributing to the sex differences in epilepsy.
In our study, birth complications including feeding complications, crying, respiratory complications, infection (excluding central nervous system infection) and Apgar < 6, are significantly associated with a higher risk of epilepsy occurrence (pooled OR = 3.91 [95% CI: 2.43–6.29]). This discovery aligns with previous research. Indeed, the presence of respiratory complications and an Apgar score below 6 increase the likelihood of neurodevelopmental issues and the risk of epilepsy development [
55]. Hypoxia can result in energy depletion, oxidative stress, and inflammation, ultimately causing cellular death, which can contribute to the development of cerebral palsy and epileptic lesions [
56]. Additionally, Frederik et al. discovered that the likelihood of an epilepsy diagnosis is elevated not only after central nervous system infections but also after a wide variety of peripheral infections [
57]. Some infections can enhance the likelihood of experiencing seizures, particularly in individuals who already have a pre-existing susceptibility to epilepsy [
58]. Infections, particularly those linked to inflammation, have the potential to alter the immune responses in the brain and disrupt the equilibrium of neurotransmitters [
59], which may potentially elevate the likelihood of epilepsy development [
58]. Conversely, adequate nutrition is essential for healthy brain development. Insufficient intake of vital nutrients can have adverse effects on brain growth and development, increasing the vulnerability to various neurological disorders, including epilepsy [
59]. Moreover, difficulties with feeding can give rise to metabolic imbalances, such as hypoglycemia or disruptions in electrolytes. These metabolic irregularities can impact brain function and potentially provoke seizures [
59].
We assume that multiple factors during the prenatal, delivery and postnatal periods interact synergistically and dynamically, elevating the risk of epilepsy in children or adolescents. For instance, eclampsia can contribute to premature birth and low-weight birth, which, in turn, can lead to frequent newborn infections and complications. Additionally, maternal infection can be linked to cord prolapse and prolonged labor. A better understanding of these factors is critical for advancing effective preventive and treatment measures to reduce the likelihood of epilepsy.
While our study is novel and represents the first meta-analysis on prenatal, delivery and postnatal factors, it has some limitations. First, our research included 25 studies with various study designs. Second, some data were unavailable, such as the exact term and the quantity or severity of pregnancy metrorrhagia, which prevented us from establishing a stronger relationship between these factors and epilepsy onset. Furthermore, the inclusion and exclusion criteria varied across the studies. The age of children/adolescents included in different studies ranged from 0 to 20 years, potentially introducing bias. Third, our study only examined children and adolescents, excluding adults. It is essential to acknowledge that the factors we examined may have implications for epilepsy in adulthood [
60,
61].