“To feed or not to feed?”: assessing long-term effects of breastfeeding on mental development of children from mothers with epilepsy

INTRODUCTION / ВВЕДЕНИЕ

Problem description / Описание проблематики

Advances in modern pharmacotherapy of epilepsy, particularly the introduction of safer antiepileptic drugs (AEDs), have created new opportunities for women with epilepsy to give birth to healthy children. Prior to 2008, epilepsy was considered a contraindication to pregnancy due to the risk of increased frequency of uncontrolled seizures and the potentially adverse effects of AEDs on fetal development.

Now there are no absolutely safe AEDs; even the most recent agents carry certain risks for the developing child. One of the key factors mitigating prenatal risks is preconception care – a set of measures aimed, on the one hand, at seizure control and, on the other, at preventing pregnancy complications (toxicosis, anemia, threat of miscarriage, etc.) and neurobehavioral teratogenesis in the child. However, access to preconception care for women with epilepsy remains limited in many regions due to various circumstances [1].

Despite the high practical relevance of this issue, the number of scientific publications assessing the influence of prenatal and perinatal factors on the mental development of children born to mothers with epilepsy is clearly insufficient to form a comprehensive picture [2]. Most existing studies focus on the physical development of offspring affected by teratogenic consequences of maternal antiepileptic therapy. None of these studies have simultaneously analyzed the combined impact of all prenatal and perinatal factors, complicated by maternal epilepsy, on children’s mental development. Without such an integrated approach, it is impossible to ensure the maximum safety of childbirth and to minimize risks for both the child and the mother living with epilepsy.

Previously, we presented the results of our research addressing the effects of prenatal factors [3], preconception care [4], and sex- and age-related factors [5] on the mental development of children born to mothers with epilepsy. In this article, we examine the contribution of intranatal (delivery route) and neonatal (feeding type) factors to their development.

Delivery route and child’s development / Путь родоразрешения и развитие ребенка

Data on the impact of delivery route on subsequent child development are highly fragmentary and primarily concern physical development. A.S. Zhumadullayeva and O.K. Dyisenov (2020) reported that children born via cesarean section more frequently experience disorders of the central nervous and respiratory systems [6].

Other researchers have more often identified in these children problems related to kinesthetic sensitivity, kinetic organization of movements, right-hemispheric processing of visual information, attention deficits, as well as delays in speech and spatial thinking development. They also propose considering such children as a risk group for the emergence of clinical forms of mental developmental disorders [7].

Moreover, long-term consequences have been observed: in a study by I.V. Zelenina (2016), it was shown that at the age of seven, children born by cesarean section demonstrated less developed perception, thinking, speech, and attention compared to their peers [8].

Delivery route in mother’s epilepsy / Путь родоразрешения при эпилепсии у матери

The assessment of the impact of delivery route is not limited to its pathophysiological aspects. Pathological factors determining the safest delivery method for both the fetus and the mother must also be taken into account [9][10].

Historically, cesarean section has been considered the preferred delivery route for women with epilepsy, although clinical indications are not the primary determining factor [11]. Despite the fact that natural childbirth is not contraindicated in epilepsy [1], it should be noted that labor may provoke an epileptic seizure, which leads many patients to opt for surgical delivery.

S.Yu. Zhdanova and E.A. Babina (2021) point out that women often choose surgical intervention not only for medical reasons but also because they perceive it as the least painful and safest method of delivery [12]. Primarily for this reason, the frequency of abdominal delivery among women with epilepsy is higher than that observed in the general population [2].

According to G.I. Naumova et al. (2023), more than 60% of children born to mothers with epilepsy were delivered by cesarean section [13]. However, this practice is not universal, and there are exceptions. For example, among 159 patients with epilepsy at the Moscow Regional Research Institute of Obstetrics and Gynecology named after Academician V.I. Krasnopolsky, cesarean section was performed in only 27 cases, and in just 3 of them was epilepsy itself the direct indication for surgery [14].

More significant factor influencing a child’s physical and mental development is the feeding type.

Effects of breastfeeding / Эффекты грудного вскармливания

Breastfeeding provides significant health benefits for both the mother and the child [15]. Its advantages are determined not only by the composition of breast milk but also by the effects of prolactin on both. Approximately 300 functions of this biologically active hormone have been described. The spectrum of prolactin’s action includes more than 80 biological effects and around 300 functions, exceeding the combined total of all pituitary hormones.

Breast milk contains numerous components that positively influence a child’s long-term physical health. Children who are breastfed are less likely, in adulthood, to develop type 1 diabetes, atherosclerosis, and hematological diseases, and they also experience fewer gastrointestinal disorders [16]. These effects are attributed to the composition of breast milk, which contains essential carbohydrates, fats, and fat-soluble vitamins, immunoglobulins and other infection-protective substances, as well as bifidobacteria and lactobacilli that contribute to the formation of the child’s immune system. Importantly, these components are present in proportions that ensure their optimal absorption by the infant’s body [17].

A. Malhotra (2023) also emphasizes the beneficial influence of immunoglobulins, antibodies, and growth factors contained in maternal milk on both the physical and mental development of the child [18]. Moreover, breast milk is less allergenic than its artificial substitutes [16]. For these reasons, breastfeeding is considered the optimal method of infant feeding during early development [19].

In addition to promoting physical health, breastfeeding has a positive impact on the child’s mental and cognitive development.

Neuroprotective and neurotrophic effects of breastmilk / Нейропротекторные и нейротрофические эффекты грудного молока

The neuroprotective effects of breast milk have been described in several studies on brain development in preterm infants [20]. It has been found that non-coding RNA and stem cells contained in breast milk can cross the blood–brain barrier and positively influence brain formation in preterm infants. Those whose mothers chose breastfeeding exhibited brain white matter volumes close to the norm, in contrast to formula-fed infants.

In a literature review by G. Gialeli et al. (2023), a number of previous studies were summarized, and the mechanisms underlying the neuroprotective action of breast milk were described [21]:

– it is hypothesized that breast milk contributes to epigenetic modifications through its bioactive components (growth factors, microbiota, stem cells, microRNAs, and long non-coding RNAs), which are associated with improved neurological outcomes in both term and preterm infants;

– microRNAs and long non-coding RNAs encapsulated in milk exosomes, as well as stem cells present in breast milk, survive digestion, enter the bloodstream, and are capable of crossing the blood–brain barrier (certain non-coding RNAs potentially regulate genes involved in brain development and function, while nestin-positive stem cells may differentiate into neurons and/or act as epigenetic regulators in the brain);

– the microbiota of breast milk contributes to the formation of the infant’s gut microbiome, which participates in brain development through epigenetic modifications and regulation of key molecular pathways;

– breast milk is classified among biological fluids with a high concentration of microRNAs, encapsulated in exosomes or present as free molecules, with more than 1,400 distinct microRNAs identified (among them, miR-148a, one of the most abundant microRNAs in human milk exosomes, participates in multiple cellular pathways, regulates neuronal development, and exerts neuroprotective effects).

MicroRNAs are small single-stranded non-coding RNA molecules, containing 18–25 nucleotides, capable of regulating up to 60% of gene expression through post-transcriptional mechanisms. Long non-coding RNAs play a crucial role in processes such as neurogenesis, synaptogenesis, and brain development; they are involved in DNA damage response and demonstrate protective functions in mitigating brain injury, neuronal apoptosis, oxidative stress, and inflammation caused by cerebral ischemia/reperfusion injury [22].

Thus, breast milk can modulate the epigenetic mechanisms of infants and influence their health across generations.

Psychological studies also confirm that breastfed children demonstrate higher intellectual development – they generalize information more effectively, show better literacy, and display higher levels of spatial imagination and mathematical ability [23]. At six years of age, these children exhibit more advanced thinking and speech, as well as better school readiness compared to those who were formula-fed [24].

This trend persists into adolescence: according to the study by V.V. Sizykh et al. (2023), children who were breastfed demonstrated significantly higher intelligence scores [25].

Breastfeeding is important not only for the child’s health and emotional well-being but also for that of the mother. The process stimulates the release of oxytocin – the so-called “happiness hormone” – which activates the brain’s “reward zone” [26] and, consequently, promotes maternal bonding with the child. Oxytocin also helps prevent blood loss and subsequent iron-deficiency anemia [27], reduces stress, and improves the mother’s emotional state [28], thereby lowering the risk of postpartum depression [29]. Moreover, breastfeeding has beneficial effects on the mother’s physical health, reducing the risk of cardiovascular disease, type 2 diabetes, and certain cancers [28].

Breastfeeding in mother’s epilepsy / Грудное вскармливание при эпилепсии у матери

Because of intake of AEDs continuously to control seizures, including during lactation, it is essential to select medications that are both effective and as safe as possible. Unfortunately, this is not always achievable. Studies by S. Karceski and H. Quinn (2023) have shown that women with epilepsy not only breastfeed less frequently but also discontinue breastfeeding much earlier than women without epilepsy. In the United States, 69.1% of mothers with epilepsy breastfeed (compared to 84.6% of healthy women), while in Canada these rates are 50% and 85%, respectively [30].

One of the most important effects of breastfeeding in women with epilepsy is the stimulation of prolactin production. A sharp decline in estrogen levels after childbirth “unblocks” prolactin receptors in the mammary glands, and hyperprolactinemia initiates lactation. Each episode of suckling triggers a three- to fivefold increase in serum prolactin levels. Prolactin contributes to both activation and suppression of microglia and astrocytes and regulates the release of inflammatory and anti-inflammatory cytokines. It has been shown to exert a neuroprotective effect under conditions of neuronal injury and inflammation in disorders such as multiple sclerosis and epilepsy, allowing it to be considered a neuroprotective factor [31].

The first study to investigate the association between epilepsy and elevated serum prolactin levels was published by M.R. Trimble in 1978 [32]. It demonstrated that generalized tonic-clonic seizures cause an increase in serum prolactin, whereas nonepileptic psychogenic seizures do not produce this effect [33].

Hyperprolactinemia during lactation leads to the development of physiological hyperprolactinemic hypogonadism through inhibition of follicle-stimulating hormone-dependent aromatase activity, resulting in decreased estrogen production and slower progesterone synthesis in granulosa cells [34]. Exclusive or predominant breastfeeding during the first six months postpartum prolongs lactational amenorrhea, which is characterized by reduced estrogen levels and, consequently, diminished proconvulsant effects of estrogens. Clinically, based on our experience, this correlates with a reduced risk of seizure recurrence and serves as an additional protective factor against the proconvulsant effects of sleep deprivation in the postpartum period among women with epilepsy.

The necessity of taking AEDs may present an obstacle to initiating breastfeeding. However, results from prospective studies have shown that breastfeeding is safe with many commonly used AEDs, and that breastfed infants of mothers taking AEDs experience additional developmental advantages compared to formula-fed infants – particularly regarding nervous system development [35]. Despite this, according to E.L. Johnson et al. (2018), the proportion of breastfeeding women with epilepsy remains low [36].

The safety profile of AEDs is crucial for women of reproductive age with epilepsy and their children, as AED therapy is often required not only during pregnancy but also throughout lactation [37]. This has significant scientific and clinical relevance due to the risks of teratogenesis resulting from placental transfer of AEDs and their concentrations in breast milk and the infant’s serum. A.K. Birnbaum et al. (2020) reported that AED concentrations in the blood of breastfed infants are substantially lower than in maternal serum [38]. According to available data, very low serum concentrations in infants (approximately 10% or less of maternal levels) are observed for carbamazepine, gabapentin, phenytoin, valproate, and clonazepam. Intermediate levels – up to about 30% of maternal serum concentrations – have been recorded for lamotrigine and topiramate, and occasionally for brivaracetam, lacosamide, and perampanel [39].

However, both concentration and toxicity must be considered. Markedly toxic AED effects on infants and high concentrations in breast milk constitute contraindications to breastfeeding. This primarily applies to older-generation drugs. High infant serum concentrations (ranging from 30% to 100% of maternal levels) have been reported with ethosuximide, phenobarbital, and zonisamide [39].

For lacosamide, the ratios of concentrations in breast milk to maternal serum ranged from 0.77 to 0.93; in infant to maternal serum, from 0.16 to 0.35; and in infant serum to breast milk, from 0.21 to 0.38. None of the measured lacosamide concentrations – maternal, milk, or infant – reached the lower limit of the therapeutic reference range (10–20 mg/l) used for the general epilepsy population [40].

If seizure control cannot be achieved with substitution of older drugs for less toxic and safer AEDs, continued use of older medications may be necessary, in which case the infant is switched to formula feeding.

Thus, the relevance and practical significance of comprehensively studying the effects of delivery route and feeding type in children born to mothers with epilepsy are evident.

Objective: To study an influence of intranatal and neonatal factors on the mental development of children born to mothers with epilepsy.

MATERIAL AND METHODS / МАТЕРИАЛ И МЕТОДЫ

The study included 88 children and their mothers diagnosed with epilepsy. Clinical diagnosis and collection of maternal anamnesis data were conducted by neurologists from the Russian Polenov Neurosurgical Institute – branch of Almazov National Medical Research Center¹, – as well as psychiatrists from the City Epileptology Center of City Psychiatric Hospital No. 6 (Hospital with Dispensary) and from the Bekhterev National Medical Research Center for Psychiatry and Neurology (Saint Petersburg).

The assessment included duration of the disease, age at onset, seizure frequency, antiepileptic therapy history and treatment during pregnancy, and the dynamics of clinical manifestations of epilepsy during pregnancy. Additionally, data were collected on the course of pregnancy and delivery, as well as on the somatic health, physical development, and mental development of newborns during the first year of life.

Mothers / Матери

At the moment of the study, the duration of the disease in mothers ranged from 5 to 44 years, with an average of 19 years. The age of epilepsy onset varied from 0 to 37 years (mean age 15 years).

According to the classification of epilepsy by the International League Against Epilepsy (2017) [41], 44 patients (50%) had generalized epilepsy, while 44 (50%) had focal epilepsy. A total of 63 mothers (72%) were in remission. The majority of them had been seizure-free for more than 1 year prior to pregnancy; the remainder experienced rare epileptic seizures.

The mean age of mothers at the time of the study was 28 years (range 18–50 years), with gestational age at delivery ranging from 35 to 42 weeks. Most children were born at term, after the 37^th week. Prematurity was observed in 7 cases of preterm delivery.

Of note, 43 women (49%) delivered vaginally, while 45 cases (51%) required cesarean section.

Children / Дети

The study included 39 female and 49 male children. Their age ranged from 3 years and 1 month to 9 years and 9 months, with a mean age of 5 years and 5 months. Birth weight varied between 1,900 and 4,500 grams.

All children attended preschool educational institutions or schools. During the first year of life, 32 infants (36%) were formula-fed, while 56 (64%) were breastfed.

Clinical and experimental psychological methods / Клинико- и экспериментально-психологические методы

The following structured clinical interviews were used as clinical-psychological methods:

– a medical questionnaire containing biographical information, clinical data on the form, course, and treatment of epilepsy in mothers, the course of pregnancy and childbirth, as well as information about the early development of the child;

– Child Behavior Checklist (CBCL) by T. Achenbach [42];

– a questionnaire for identifying symptoms of attention deficit hyperactivity disorder (ADHD) and other behavioral disorders by N.N. Zavadenko (for children aged 5 years and older), aimed at assessing the level of mental development and adaptation of the child (ADHD and behavioral disorders questionnaire) [43].

The following experimental-psychological methods were used to assess the mental and intellectual development of children:

– two Luria batteries of neuropsychological tests adapted by Zh.M. Glozman (for children aged 3–6 years and 7–12 years) [44][45];

– the intelligence assessment methodology (intelligence subtests) by D. Wechsler (Wechsler Intelligence Scale for Children, WISC) (for children aged 5 years and older) [46].

These methods have been standardized for different age groups of children.

Statistical analysis / Статистический анализ

Statistical data processing was performed using SPSS-23 software (IBM, USA) with the application of the following methods: Contingency tables with calculation of Pearson’s χ² test, non-parametric Mann–Whitney U test, Two-way analysis of variance, correlation analysis, regression analysis, moderator analysis. Statistical significance was considered at the level of p≤0.05, while statistical tendations were determined at p<0.10.

RESULTS AND DISCUSSION / РЕЗУЛЬТАТЫ И ОБСУЖДЕНИЕ

Delivery route / Путь родоразрешения

To assess the impact of delivery route, we compared the neurocognitive development of children born via vaginal delivery and cesarean section (Table 1).

Among children born via cesarean section, more pronounced motor clumsiness was observed (p=0.068, tend.), along with a general delay in speech development (p=0.019) and difficulties in understanding spoken language in particular (p=0.096, tend.).

Children delivered naturally performed better on the “Arithmetic” subtest (p=0.014), but demonstrated poorer results on intellectual tasks assessing comprehension of narrative picture sequences (p=0.038).

Correlation analysis

The results of the correlation analysis confirmed the data of the level analysis: children after cesarean section were more likely to suffer from speech, intelligence, concentration of voluntary attention, and manipulation of numerical material. However, they performed better on intellectual tasks to understand the meaning of plot pictures (Fig. 1).

Regression analysis

Regression analysis showed (Fig. 2) that polytherapy of AEDs and early diseases of the child are predictors of delayed development of praxis (finger postures), manifested at an older age. However, this pattern is not typical for children born naturally.

Feeding type / Тип вскармливания

Comparative analysis strategies

Since women with epilepsy must take AEDs continuously to prevent seizures, many choose to forego breastfeeding in favor of formula feeding due to concerns about potential adverse effects of AEDs on the child’s development. However, T. Tomson et al. argue that with appropriate selection of AEDs – those with the lowest concentrations in breast milk – breastfeeding has beneficial effects on both the child’s development and the mother’s health [39].

To verify this conclusion and avoid bias in evaluating the effects of AED exposure during lactation on subsequent child development, 13 children whose mothers were in remission and did not take AEDs during pregnancy and lactation were excluded from the sample. Therefore, the comparative analysis included only children whose mothers were taking AEDs while breastfeeding (n=75).

The results of the comparison between 44 breastfed children and 31 formula-fed children are presented in Table 2.

Children who were breastfed during the first six months of life subsequently exhibited less pronounced emotional and volitional disorders (p=0.041).

In neuropsychological testing, these children demonstrated overall more mature behavior (p=0.021)² in particular, they were more adequate in their responses (p=0.043) and showed better orientation within the testing situation (p=0.003). They also made fewer errors in object gnosis tasks (p=0.045) and performed better on reciprocal coordination tests (p=0.048), indicating better interhemispheric integration.

Moreover, breastfed children displayed more advanced spontaneous speech (p=0.047), improved comprehension of spoken language (p=0.025), and a better understanding of logical constructions in speech (p=0.053, tend.).

When assessing intelligence, it was found that infants who were breastfed had a higher level of nonverbal intelligence (p=0.029): in particular, they performed better on the “arithmetic” (p=0.012), “folding shapes” (p=0.006) and “encryption” (p=0.059, tend.) subtests.

Correlation analysis

Correlation analysis revealed links between artificial feeding and the severity of the following developmental disorders in children (Fig. 3):

– emotional and volitional disorders;

– insufficient orientation, criticality and adequacy in the examination situation for their age;

– errors in performing tests for subject gnosis, the development of spontaneous speech and the understanding of reversed speech;

– lower level of non-verbal intelligence, poorer ability to operate with numerical material (“arithmetic” subtest), correlate parts and the whole (“adding shapes” subtest);

– mental retardation.

Relationship between delivery route and feeding type / Связь между путем родоразрешения и типом вскармливания

One of the hypotheses of the study was the assumption that the feeding type may depend on the delivery route, since very often women after abdominal childbirth have problems with lactation – insufficient milk or no milk at all. To test this hypothesis, we compared two groups of women with epilepsy who gave birth naturally and by caesarean section, and who are on antiepileptic therapy. It was found that there were significantly more nursing mothers among women who gave birth naturally (p=0.002) than after cesarean section (Table 3).

Two-way analysis of variance

Since these two factors are interrelated (the feeding type is often a consequence of the physician’s decision regarding the delivery route or the mother’s own choice), a two-way analysis of variance (ANOVA) was applied to assess their combined effect on the subsequent mental development of children. Specifically, we aimed to determine which developmental domains of the child are most influenced by the interaction between the delivery route and the feeding type – a clinical situation frequently observed in practice (cesarean delivery followed by artificial feeding).

Undoubtedly, the obstetrician’s decision in favor of abdominal delivery is primarily determined by the totality of preceding factors – the mother’s and fetus’s condition (presence of seizures, comorbidities, pregnancy complications, etc.), which we analyzed in detail in our previous publications [3][4]. However, the choice to breastfeed – despite persistent concerns among physicians – most often depends on the mother herself, on her motivation and determination to continue lactation.

To avoid bias, as in the previous stage of analysis, data from 13 children whose mothers did not take AEDs during lactation were excluded. The remaining 75 children were divided, for two-way ANOVA, into four groups combining different delivery routes and feeding types. As a result, eight parameters of mental development were identified as being dependent on the simultaneous influence of these two factors, demonstrating a similar pattern of outcomes. The most pronounced developmental difficulties were observed in the subgroup of children delivered by cesarean section and subsequently fed artificially (Fig. 4).

Among children born by cesarean section and subsequently fed artificially, higher levels of anxiety, fears, and obsessive behaviors were observed (p=0.082, tend.), as well as more pronounced motor clumsiness (p=0.076, tend.), emotional–volitional disturbances (p=0.092, trend), and particularly attention deficit (p=0.038), compared with breastfed children. In contrast, children delivered naturally did not show significant differences in the severity of these syndromes regardless of the feeding type, which further supports the advantages of natural delivery.

Thus, the combination of cesarean section and artificial feeding has a more negative impact on children’s mental development, whereas breastfeeding in infants born by cesarean section partially mitigates the severity of developmental disorders—including when compared with naturally born, artificially fed children. In this context, breastfeeding appears to act as a kind of “psychostimulant” for subsequent child development, compensating for possible prenatal and intranatal impairments.

Similar patterns were revealed in the performance of neuropsychological tests and intellectual subtests (Fig. 5). The positive effect of breastfeeding on psychological and personal maturation was particularly evident among children born by cesarean section: those who were artificially fed demonstrated significantly poorer orientation (p=0.010) and lower adequacy and self-criticism during testing (p=0.022). Their overall impairment index (summarizing errors across all neuropsychological domains) was also higher, indicating poorer development of cognitive functions (gnosis, praxis, speech, neurodynamics, and reasoning) compared with breastfed children born by cesarean section (p=0.072, tend.).

Children delivered naturally did not differ significantly from those who were breastfed, even when they were artificially fed, which supports the safety of vaginal delivery in women with epilepsy. Similarly, among breastfed children, the delivery route had little impact on subsequent mental development, as the differences between groups were not statistically significant.

This pattern – reflecting the stimulating and compensatory influence of breastfeeding on the further intellectual development of children born by cesarean section – was also confirmed by the results of the “arithmetic” subtest. Children born by cesarean section and artificially fed demonstrated poorer numerical reasoning skills than those who were breastfed (p=0.044). Moreover, they performed worse than breastfed children delivered naturally (p=0.012). Arithmetic abilities among naturally born children did not differ significantly depending on the feeding type, which again supports the safety and developmental advantages of vaginal delivery in women with epilepsy.

Thus, the development of the intellectual ability to memorize and manipulate numerical material in children born to mothers with epilepsy depended on both the delivery route and the feeding type (p=0.008). The results of the two-way analysis of variance clearly demonstrated the importance of maintaining breastfeeding – even when mothers are taking antiepileptic drugs – particularly after cesarean delivery. Furthermore, they confirmed the advantages and safety of natural childbirth for the subsequent mental development of children, even when breastfeeding cannot be maintained.

Regression analysis

According to the results of regression analysis, the following predictors of developmental and adaptation disorders were identified in children born to mothers with epilepsy.

The predictors of the appearance of emotional-volitional disorders in a child were epileptic seizures in the mother before pregnancy and artificial feeding, but this pattern was not typical for girls (Fig. 6).

Inadequate behavior was typical for those children whose mothers suffered from anemia and epileptic seizures during pregnancy and who were on artificial feeding (Fig. 7).

A large number of errors when performing praxis tests were typical for older children who were on artificial feeding (Fig. 8).

Breastfed children made the least mistakes when performing tests for subject gnosis (Fig. 9).

The predictors of disorders in the development of the gnostic sphere in general were artificial feeding, the presence of seizures before pregnancy, and maternal intake of valproic acid (Fig. 10).

Artificial feeding, maternal intake of valproic acid, and anemia during pregnancy became predictors of disorders in the development of spontaneous speech in older children (Fig. 11).

Artificial feeding, along with seizures in the third trimester of pregnancy, taking valproic acid and anemia in the mother, became predictors of the appearance of difficulties in understanding spoken speech in children (Fig. 12).

Artificial feeding, along with maternal intake of valproic acid and anemia during pregnancy, became predictors of the neuropsychological syndrome of left temporal region malformation in children (Fig. 13).

Predictors of successful numerical treatment of children were the mother's pre-gravidar training in the focal form of maternal epilepsy, but not for those children who were on artificial feeding (Fig. 14).

The results of the regression analysis demonstrate the multifactorial nature of mental development disorders in children born to mothers with epilepsy. Artificial feeding, in combination with prenatal risk factors (seizures before and during pregnancy, maternal anemia, and valproic acid intake), has significant prognostic value in the formation of various developmental impairments in these children – including emotional and volitional disorders, delays in the development of praxis, gnosis, spontaneous speech, and comprehension of spoken language, as well as the syndrome of functional immaturity of the left temporal lobe. Moreover, artificial feeding does not contribute to the social maturity of these children, who exhibit insufficient orientation, adequacy, and critical awareness for their age during neuropsychological assessment.

Moderator analysis

The moderator's analysis revealed the role of breastfeeding as a moderator of the negative impact of maternal anemia on the further mental development of their children.

The children of mothers who suffered from anemia during pregnancy were characterized by social and personal immaturity – orientation, adequacy, and criticality in the study situation that did not correspond to their age. Anemia became a predictor of a delay in the development of a child's social and personal maturity, and breastfeeding significantly reduced the predictive power of it (Fig. 15).

The children of mothers suffering from anemia experienced the greatest difficulties in performing neuropsychological tests, i.e. they showed a greater number of problems in various areas of mental development. Anemia is a predictor of further neuropsychological disorders in a child, and breastfeeding partially eliminates (reduces). This is a negative effect (Fig. 16).

An interdisciplinary approach to studying the mental health of the “mother–child” dyad in such a specific context as motherhood in epilepsy is applied extremely rarely. The present study, focused on the effects of antenatal and perinatal factors on the child’s mental development, utilized several types of statistical analyses, which allowed for a comprehensive examination of the problem. Despite the clinical relevance and practical importance of this topic, the issue of breastfeeding while a mother is undergoing antiepileptic therapy remains controversial among specialists.

Meanwhile, the need for evidence-based answers to these questions continues to grow, as patients experience anxiety regarding the risks and developmental prospects of their children. Since 2019, the first publications have begun to appear that investigate the effects of certain new and emerging AEDs on the mental development of children born to mothers with epilepsy. However, to date, there are still no studies that provide a comparative analysis of the long-term effects of various AEDs on children’s mental development, despite a clear demand for such data from both clinicians and patients.

In addition to prenatal, intranatal, and perinatal factors, it is also necessary to consider the child’s own developmental characteristics, since mental developmental disorders demonstrate gender and age specificity, manifesting more prominently in certain sexes at specific developmental stages [5]. In our study, the male fetus was found to be more vulnerable to prenatal influences; consequently, boys exhibited more pronounced mental developmental disturbances (motor clumsiness, hyperactivity, attention deficits, speech disorders) and adaptation difficulties (impaired socialization, emotional-volitional instability, aggressiveness, oppositional behavior, and conduct problems). Developmental delays in mental functions – “precursors of intelligence” and speech – were more characteristic of younger children; however, over time, some of these deficits were compensated for, while behavioral and socialization problems became more evident.

Only by considering the multifactorial nature of these influences can the problem of neurobehavioral teratogenesis in children born to mothers with epilepsy be adequately addressed, paving the way for strategies aimed at prevention and compensation of developmental impairments.

CONCLUSION / ЗАКЛЮЧЕНИЕ

Breastfeeding reduces perinatal risks by creating more favorable conditions for both the physical and mental health of children born to mothers with epilepsy. Infants who receive breast milk during the first year of life subsequently demonstrate a higher level of development – both in the basic cognitive domains (“precursors of intelligence” such as gnosis, praxis, and memory) and in integrative functions (speech and nonverbal intelligence).

In contrast, artificial feeding, especially when combined with other prenatal factors (maternal seizures, exposure to toxic AEDs, or anemia), serves as a predictor of mental developmental and adaptive impairments in these children. Breastfeeding acts as a moderating factor that mitigates the negative impact of maternal anemia on the likelihood of neuropsychological deficits in various domains – praxis, gnosis, speech, memory, and intelligence – as well as on social and personal immaturity.

Although our findings indicate that children born via cesarean section more frequently exhibit motor clumsiness and delays in speech and nonverbal intellectual development, these results require further investigation. It is essential to consider a wide range of factors influencing the choice of delivery route – such as maternal seizures, toxicosis, fetoplacental insufficiency, and threatened miscarriage. A comprehensive analysis of antenatal and intranatal factors that increase the risk of cerebral pathology in children delivered by cesarean section is needed.

Only an integrated assessment of all risk factors can provide a full understanding of their combined impact on the child’s subsequent mental development, as these factors are linked not only to the course and treatment of maternal epilepsy during pregnancy but also to the postpartum period, which plays a crucial role in the biological and psychological maturation of the child and the formation of the “mother–child” relationship.

Further studies are also required to assess the effects of new-generation antiepileptic drugs on the neuropsychological development of children born to mothers with epilepsy.