Effect of maternal stress on the risk of development of autoimmune Guillain-Barré syndrome in children: a narrative review

Introduction

Background

Guillain-Barré syndrome (GBS) is a rare, sudden, life-threatening autoimmune neuromuscular condition in which muscle weakness and rapidly progressive muscle paralysis, in severe cases, may proceed to respiratory failure. GBS results from a disturbance in the immune system that is usually provoked by an infection or other immune stimuli attacking myelin sheaths or axons of peripheral nerves (1). This autoimmune damage manifests through impaired nerve conduction, giving rise to the cardinal manifestations of GBS, including ascending flaccid weakness, numbness, areflexia, sometimes cranial nerve affection and may progress to paralysis. The GBS incidence varies across age groups. According to a 2011 study, GBS affects people of all ages and has an incidence of 0.62 to 2.66 cases/100,000 person-years (2). Although the exact pathogenesis is still not fully understood, one important mechanism considered has been molecular mimicry, whereby the immune responses directed against pathogens cross-react with nerve components (2,3).

Stress experienced by the mother during pregnancy has also been shown to have a major influence on fetus’s growth and post-natal health (4). Such complications in pregnancy may be the result of either psychological stressors, such as anxiety and depression or physical stressors like malnutrition and infections, and environmental exposures, including socio-economic adversity and toxin exposure. The response to stress by the mother involves the activation of the hypothalamic-pituitary-adrenal (HPA) axis, releasing large amounts of stress hormones, particularly cortisol. These stress hormones are capable of crossing the intrauterine environment through the placental barrier and acting to influence fetal development (3,5). Chronic maternal stress has been associated with changes in fetal brain development and increased risk of neurodevelopmental disorders in offspring. The fetal HPA axis, which is essential for controlling stress reactions, can be disrupted by prenatal stress. This disruption may lead to an overactive or unregulated HPA axis in the child, increasing the risk of stress-related disorders and impairing the immune system’s proper development and function (6). Moreover, prenatal stress is strongly associated with immune dysregulation in offspring and can thus serve later in life as a relevant factor contributing to autoimmune and inflammatory disorders (7). Maternal stress affects the fetus’s immune system through several mechanisms, including the modification in cytokine production, biases in the balance between subpopulations of T-helper cells, and impairment in the maturation of T-reg (the regulatory population of T) lymphocytes. Such changes often result in the child’s increased vulnerability to infections and allergic diseases, and further to autoimmune diseases (8).

Also, stress during pregnancy can potentially affect the fetus’s blood-brain barrier (BBB) and increase the vulnerability of central nervous system (CNS) to immune-mediated injury. The BBB is a physical barrier made up of endothelial cells that restricts the flow of chemicals to the brain. Its tight junction proteins limit the paracellular flow of hydrophilic molecules, while several transporters control the entrance of various other macromolecules. BBB permeability can be influenced by external cues, such as stress “either acute or chronic” (9). Either acute or chronic stress can alter BBB permeability. Since appropriate structure and function are established by postnatal days, the BBB’s vulnerability to stress is especially relevant throughout development. Given the early postnatal time of BBB induction, it is rational to believe that stress in early life may have a long-term effect on the functioning and structural integrity of the BBB (10). The brains of rats subjected to prenatal maternal forced swim stress and postnatal maternal separation showed increased permeability to dyes and affection of tight junctions expression, providing preliminary proof that both prenatal and postnatal stressors can affect BBB development (11,12). Additionally, the astrocytic profile alters early and permanently because of early stress. Furthermore, maternal stress can impair the maturation of the fetal brain by altering the availability of neurotrophic growth factors, synapse formation, and neurotransmitter levels. Moreover, the growth, survival, differentiation, and intercellular communication of nerve cells can all be impacted by biological processes linked to stress in which there will be impaired myelination and even dysregulated generation of adult neurons (13). However, researchers have reported that the effects of maternal stress vary depending on the stress’s origin, timing, length, and severity, as well as the fetus’s genetic vulnerability and the mother’s stress reactivity (14).

Rationale and knowledge gap

Several different studies have pinpointed that children born to mothers who experience severe stress during pregnancy are more susceptible to autoimmune ailments such as multiple sclerosis, rheumatoid arthritis, and type 1 diabetes. Such outcomes have raised concern that prenatal stress might also raise the risk for autoimmune neurological disorders like GBS (15-20). Considering the autoimmune nature of GBS, searching for maternal stress as a risk factor may provide critical insight into the early-life determinants of pediatric GBS. Identifying such early risk factors may point to new opportunities for prevention, early diagnosis, and intervention that could reduce the burden of GBS in children (21). Moreover, both establishing maternal stress as a candidate for the development of GBS implies far-reaching consequences in the prevention of other autoimmune diseases because prenatal stress may be a common underlying factor in many immune-mediated conditions. However, the research in this area is scarce.

Objective

This review discloses the possible connection between maternal stress during pregnancy and risk of pediatric autoimmune GBS, contributing to the literature on how early-life exposures influence autoimmune diseases. We present this article in accordance with the Narrative Review reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-25-18/rc).

Methods

As displayed in Table 1, this literature review included many published studies till January 2025. The databases used included Google Scholar, PubMed, Science Direct, and BMC Library using the following keywords “Guillain-Barré syndrome, maternal stress, prenatal immune programming, autoimmune diseases, pediatric health, stress biomarkers”. This review included studies in English that were central to the theme of this study. Articles in languages other than English were excluded. Data extraction was applied to discern patterns, trends, and key findings, contributing to a comprehensive understanding of the review.

Prevalence, demographic insights and pathophysiology of GBS

The overall occurrence of GBS has been estimated to be 1 in 100,000 individuals in different studies worldwide and its rates slightly increase with age, and males are predominant (22). GBS exhibits a statistic where adults and the elderly have the highest frequencies. The male/female ratio of the affected individuals is about 1.25:1, showing a trend not very synonymous with autoimmune but more favorably with immune-related neuropathies (23,24).

The geographical and seasonal factors are additional contributors to the GBS incidence rates. Parts of Asia, Latin America, and North America reported higher rates, with some studies reporting winter months having the highest rates which could be due to respiratory infections (25,26). In Western countries, seasonal changes aren’t clear due to a lack of seasonal patterns of respiratory and enteric infections. Campylobacter jejuni infection, was detected in approximately 41% of cases and allied with more severe cases of GBS, most likely in summer outbreaks among young individuals in northern China (25).

The pathophysiology of GBS is heavily influenced by some factors, one of which is a deviant immune response to the peripheral nervous system (PNS), which is often precipitated by infections. These infectious (environmental) triggers, which are more common among children, can trigger the development of GBS. Per example, the respiratory or gastrointestinal infections, especially with Campylobacter jejuni, cytomegalovirus (CMV) and others, are provocative factors in developing GBS by releasing neurotoxins (27). This abnormal immune response is suggested to be associated with molecular mimicry in which microbial antigens have structural motifs like some nerve tissues which lead to inflammatory response and demyelination or axonal injury and immune responses against antigens resembling components of peripheral nerves, for example, gangliosides. Although vaccines have been linked with a very low risk of developing GBS, infectious agents are still the main consigns associated with the syndrome (28,29). Overall, GBS is the result of the multifaceted interplay of immune responses, genetic traits and environmental factors that work together by disrupting the blood-nerve barrier and activating the innate immune system pathways leading to major motor and sensory deficits (30,31). The complement activation and macrophage infiltration further enhance nerve injury and contribute to the clinical features of GBS. Moreover, the variations in human leukocyte antigen (HLA) class II alleles and immune-regulatory genes, among them those encoding cytokines like interleukin (IL)-10 or tumor necrosis factor-alpha (TNF-α), are examples of genetic predisposition that affects susceptibility to GBS thus provoking the incidence of GBS especially in those prone to an exaggerated immune response (32). These factors put together create a cascade where genetic predisposition and environmental stimuli result in an immune response that mistakenly attacks the PNS, culminating in the manifestations of GBS (33).

Types of GBS

As revealed in Table 2, GBS includes several types such as acute inflammatory demyelinating polyneuropathy (AIDP) (34), acute motor axonal neuropathy (AMAN) (35), acute motor-sensory axonal neuropathy (AMSAN) (36), Miller-Fisher syndrome (MFS) (37), Bickerstaff brainstem encephalitis (BBE) (38) and the pharyngeal cervical-brachial subtype of GBS (39).

Clinical presentation of pediatric GBS

In pediatric GBS, neurologic symptoms occur after classic signs such as fever, respiratory infections, or gastrointestinal issues, suggesting that the acute phase of the disease has begun (26). AIDP is commonly seen in approximately 50% of cases and is significantly related to upper respiratory infections. However, a greater incidence of sensory symptoms, pain in particular, is more common in the axonal forms of GBS, including AMAN and AMSAN (40). Figure 1 depicts the progression of pediatric GBS with different symptoms in different stages. Moreover, bulbar weakness including lacrimation and multiple cranial palsies, including oculomotor and facial nerve palsies, was present in up to 69% of the pediatric cases (41). Proper diagnosis and treatment of GBS lowers the need for respiratory support and improves the outcomes, which are positive in most subtypes (42).

Figure 1 Clinical presentation of pediatric GBS in different stages. AIDP, acute inflammatory demyelinating polyneuropathy; AMAN, acute motor axonal neuropathy; GBS, Guillain-Barré syndrome.

Maternal stress and fetal development

Prenatal maternal stress and HPA axis

The HPA axis is activated during stress, and it is also documented as an important factor during fetal development (43). The anterior pituitary releases adrenocorticotropic hormone (ACTH) and subsequently, cortisol is released from the adrenal cortex in response to the hypothalamus’s release of corticotropin-releasing hormone (CRH) during maternal stress. However, during pregnancy, there is a placental CRH that is associated with maternal cortisol, leading to a positive feedback loop that escalates the concentrations of blood cortisol in pregnant women, especially in the last trimester (44).

Worth mentioning, the placenta has been shown to contain enzymes such as 11β-hydroxysteroid dehydrogenase (11β-HSD2), which deactivate almost all the maternal cortisol, thus it functions as a protective glucocorticoid (GC) barrier. The 11β-HSD2 transforms cortisol into its inactive form, cortisone (45). However, during pregnancy, the placenta’s expression amounts of 11β-HSD2 vary according to the duration of both induced and natural stress exposure (46). Furthermore, this enzyme is extensively expressed in the kidney, stomach, lung, and most significantly in the brain of the fetus, where it may control how GCs affect neurological development. Also, 11β-HSD2’s abundance and expression pattern besides promoting the placental development and function, which is essential for optimal fetal growth and development, shield mitotically active brain cells from the maturational effects of GCs, too soon (47). Yet still, roughly 20% of cortisol gets absorbed within the fetal circulation. This influx of cortisol is, however, important for fetal growth since it plays important roles, including timely support of the lung and brain development (44).

Chronic stress during pregnancy, however, may result in decreased amounts and levels of 11β-HSD2, which leads to higher rates of cortisol to which the fetus is exposed, resulting in behavioral and cognitive disorders as well as decreased fetal growth and predetermined outcomes in adult life (48). Additionally, taking an inhibitor of 11β-HSD2 enzyme changed the activity of the HPA axis (49). Notably, for mothers of girls compared to mothers of boys, maternal psychological stress throughout pregnancy was somewhat linked to higher placental 11β-HSD2 methylation and lower 11β-HSD2 expression (50). In support, pregnant women producing excess cortisol showed many complications like fetal growth restriction, birth preterm and lower birth weight (50,51).

Maternal stress-induced-uterine artery resistance effect on fetus

Another route in which a pregnant woman’s stress can have an impact on fetal health is through altered uterine arterial blood flow during pregnancy. Stress or anxiety has been shown to increase uterine artery resistance, which limits the amount of fetal blood flow that could explain the low-birth-weight babies, as well as a wide spectrum of poor fetal outcomes. Elevated levels of maternal anxiety are associated with both maximum and mean uterine artery resistance scores. It is thought that this response may be due to the sympathetic-adrenal system. Nevertheless, additional research is required to confirm this link and examine how the HPA axis and other physiological elements function in this process (52).

Associations between maternal stress and pregnancy outcomes

Several studies have documented a link between stress experienced before birth and negative pregnancy outcomes, especially regarding fetal activity and development (50,51). Women who reported high level of stress were at risk of pre-term delivery as well as restricted fetal growth by about double, putting them on par with other obstetric risks (53). Preterm birth is recognized as being related to the susceptibility to develop psychological issues later in life, while low birth weight increases susceptibility to chronic medical and psychiatric disorders in adulthood. The association between stressful pregnancy events and a higher risk of premature labor has been confirmed by a number of investigations for a long time. Stress within the third trimester has been shown to cause premature uterine activity and shorter pregnancy duration. Serum levels of pCRH are elevated in preterm pregnant women between weeks 15 and 20 of pregnancy. Recent studies have shown that substantial anxiety and depression are the cause of the lower birth weight and microcephaly (54,55). Moreover, there is an association between maternal stress during childbirth and a higher chance of constraints for the infant, including infections, and even structural deformities such as craniofacial abnormalities and heart defects in some instances. Recent life events have been recognized to be psychosocial stressors that can exacerbate the risk of spontaneous abortion even in chromosomally normal fetuses. The following potential mechanisms could expose the fetus to maternal stress: (I) decreased uterine blood supply; (II) transplacental transfer of maternal stress hormones; and (III) stress-induced release of pCRH into the peri-fetal environment. The muscular tone of peripheral blood vessels is strongly impacted by corticosteroids, catecholamines (CAs), and decreased uteroplacental blood supply. According to recent studies, the placenta’s production of 5-hydroxytryptamine (5-HT) is essential for the maturation of the embryonic brain (56,57). There is proof that various placental functions are disrupted in offspring under stress during pregnancy. For instance, following exposure to prolonged prenatal stress, the expression of placental glucose transporters was altered significant consequences for the growth and metabolism of the fetus, placenta O-GlcNAc transferase, which plays a variety of roles in brain growth and development, was suppressed, and placental oxidative stress markers were elevated because the placenta is always in a mild oxidative state because of its high metabolic needs; hence, any further stress could cause it to malfunction (58). Furthermore, during maternal stress, micro ribonucleic acids released from the placenta into the fetal blood may target and alter the expression of important genes related to development in the fetal brain (59). Also, the restrictive fetal growth may result from stress-induced sympathetic nervous system stimulation, which lowers blood supply to the uterus and fetus (60). At around 32 weeks of pregnancy, Doppler blood flow tests show that women with high anxiety levels had greater uterine artery resistance (61). However, due to different methodologies used in various studies, all possible causal relations are still uncertain (62).

Moreover, the incidence of preeclampsia in the last trimester of pregnancy is increased by depression and anxiety during the first trimester (63,64). From 18–20 weeks of gestation forward, patients with preeclampsia have elevated serum concentrations of placental corticotropin-releasing hormone (pCRH). Furthermore, pregnancy-related depression and anxiety can boost the release of neuroendocrine transmitters as well as vasoactive hormones that increase uterine artery resistance and predispose to preeclampsia (63). Also, the sympathetic nervous system is overactivated by psychological triggers and stressors leading to preeclampsia. Five percent of preeclamptic individuals experienced really severe anxiety, according to the Kordi et al.’s study (64). Additionally, after controlling for the confounding variables, Kurki et al.’s study highlighted the link between early pregnancy anxiety and depression and the incidence of preeclampsia in nulliparous women (63).

Impact of maternal stress on neurodevelopmental outcomes

Maternal stress affects the neurological processes and milestones of the fetus and increases the chance of many neurodevelopmental disorders such as Tourette’s syndrome, autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) (65). Moreover, stressors during pregnancy have been specifically linked to a greater probability of schizophrenia (66) and cognitive delay (67). Additionally, the emergence of emotional regulating mechanisms may be disrupted if the fetus is exposed to maternal stress. Later in life, this may show up as increased anxiety and depression (65), and a subtle impact on a person’s temperament and personality characteristics, such as increased shyness, introversion, irritability, poor social interaction due to low frustration tolerance and behavioral avoidance in offspring (62,68).

Furthermore, prenatally stressed children may be delayed in achieving the developmental milestones of their age (62). The neurodevelopmental consequences emphasize what has been pointed out regarding maternal stress during gestation, as early life stress can potentially determine mental health in the short term or throughout life. Fetal development can be impacted by environmental influences, particularly in the first week of pregnancy. While some of these factors, including drugs, alcohol, and long-term conditions like depression, are clearly recognized, others, like prenatal maternal stress disorder (PNMS), are more individualized and rely on the kind, level, and period of exposure to stress (69). Notably, the extent and nature of later neurodevelopmental effects are significantly influenced by the timing of prenatal stress exposures. Per example, Collins et al. found that the motor development of children is adversely affected by late gestational stress whereas the cognitive function of the child is adversely affected by early prenatal stress. However, stress during pregnancy does not affect speech or language. Additionally, they discovered the risk of schizophrenia and ADHD in the progeny is increased by early and late gestational stress, respectively (70). Therefore, perceived stress during pregnancy has important implications for the growing fetus, depending on what stage it occurs. This might result from changes in maternal hormones that are specific to the timing of pregnancy and are triggered by stress. The first trimester is when the immune system first develops, however, after 16 weeks, maternal antibodies begin to pass through the placenta, with the majority of immunoglobulin G (IgG) passage taking place in the last 4 weeks (71). According to research on animals, prolonged prenatal stress in the latter stages of pregnancy can result in lower levels of IgG in both the mother and the male neonate, as well as lower innate immune cell function and lower child white blood cell counts. There is evidence linking a lower adaptive immune response to vaccinations in human infants to higher levels of anxiety in later pregnancy (72).

Overall, the improper regulation of the prenatal environment can therefore increase the embryo’s risk of establishing a variety of illnesses, among them psychiatric disorders (like autism, schizophrenia, ADHD, anxiety, and depression) during late childhood or adulthood, or fetal development disruptions (like intrauterine growth restriction and congenital malformations) in addition to adverse pregnancy outcomes (like miscarriages and preeclampsia). These disorders underscore the importance of addressing prenatal stressors to prevent long-term mental health problems in offspring. Promoting ideal fetal development and lowering the risk of psychiatric illnesses requires effective treatment of maternal stress.

Environmental imprinting and fetal conditioning

The fetus adjusts to the mother’s physiological changes during pregnancy, which can have significant consequences on the way it develops. The placenta is essential for controlling the mother-fetus exchange of nutrients and hormones. The release of hormones like progesterone and human chorionic gonadotropin (hCG), which are essential for sustaining pregnancy and promoting fetal growth, can be impacted by changes in the stress levels of the mother (73). Fetal growth can also be impacted by changes in maternal hormones, such as oxytocin, which is linked to stress alleviation and bonding. Increased oxytocin levels may improve the development of the prenatal brain and encourage favorable emotional experiences in the future. Collectively, pregnancy-related physiological factors, such as the mother’s heart rate, stress hormone levels, and placental hormone fluctuations, all have a significant impact on the fetus’s development and long-term health results (69,74).

However, pregnancy-related environmental variables, such as maternal gestational stress, might affect fetal development and programming, enabling offspring to adjust to postpartum conditions “environmental imprinting”. These adaptations, nevertheless, may be detrimental if the environment runs short of expectancies or if the external triggers are greater than what is tolerated (75). An infant’s immune system may be impacted by maternal stress during pregnancy, which may result in elevated immunoglobulin E, pro-inflammatory cytokines, and changes in the mother’s circulating cytokine levels. These changes may predict atopic diseases in early childhood and raise the likelihood of allergies in adulthood (76,77). The ontogeny of immune cells is directly impacted by maternal GCs and neuromediators, which are released during maternal stress and reach fetal organs (78). Also, environmental influences may promote long-lasting modulation of gene expression in immune cells by epigenetic regulation, such as gene silence through DNA methylation and/or histone deacetylation/methylation (79). Moreover, the HPA malfunction may result in immunological abnormalities in prenatally stressed children, with reduced gut maturation and lower sensitivity to GCs, impairing the acquisition of immunoglobulins after birth. Additionally, excessive CRH production also activates the fetal HPA axis and raises the levels of GCs in the fetus’s circulation. Also, maternal stress impacts placental iron transport, resulting in anemia in infants aged 4 to 8 months, which is associated with a decrease in natural killer cells’ activity (80). It has been established that physiological changes following maternal stress can act as stimuli to the fetus and this may alter the developing fetus’s autonomic nervous system (ANS) and CNS’s postnatal functioning for some time (81).

Notably, maternal relaxation methods such as guided imagery led to notable drops in respiratory and heart rates, suggesting a more tranquil physiological state. Furthermore, the relaxation resulted in a decrease in salivary cortisol levels, indicating a lessened stress reaction. This is important because high cortisol might harm fetal development. The study implies that relaxation may have an impact on placental hormones, which are essential for fetal growth. Additionally, the relaxation process may change bonding and stress-reduction-promoting maternal chemicals like oxytocin, which could be advantageous for fetal neurodevelopment. Taking everything into considered, the results lend credence to the assumption that maternal relaxation has advantageous physiological impacts that enhance the health of both the mother and the fetus (82).

Potential pathophysiological mechanisms: maternal stress and GBS

Inflammatory markers and immune dysregulation during pregnancy

It has been shown that psychological stress pertains to excessive pro-inflammatory cytokine release in the later months of pregnancy. These issues have been further discussed by examining the relationship between psychological stress and serum cytokines in the first, second and last trimesters, and the impact of stress and emotional support on the production of cytokines by stimulated lymphocytes in the last months of pregnancy (83).

Furthermore, an analysis was done on the correlation between stress, support and C-reactive protein (CRP) during pregnancy. During the initial stages of pregnancy, high levels of stress were linked with lower IL-10 and higher IL-6 in the serum, which was also evident in late pregnancy. There was no clear correlation between stress and cytokines in the second trimester of pregnancy. Increased serum levels of CRP were linked with increased stress during the second trimester and less emotional support during the third trimester further implying that psychological factors can facilitate increased inflammation during pregnancy. Significantly, increased stress during pregnancy was linked to increased secretion of proinflammatory cytokines IL-1B and IL-6 by activated lymphocytes in the last trimester. These findings lend more credence to the idea that prenatal stress alters a mother’s immune system and psychology, increasing her risk of pregnancy problems, including early delivery and hypertension (84).

The levels of leptin, TNF-α, IL-6 and IL-8 in pre-eclamptic subjects were elevated drastically in comparison with healthy control pregnant and non-pregnant. The concentration of IL-10 has exhibited different patterns when compared to control participants (pregnant and non-pregnant), as its level generally dropped significantly in pre-eclamptic women (85).

According to recent research, two primary stress hormones, CAs and GCs, enhance the synthesis of transforming growth factor-beta (TGF-β) and IL-10 while suppressing IL-12, TNF-α, and interferon-gamma (INF-γ). Since the stress pathway is activated by a T helper lymphocyte 2 (Th2) shift, the organism is thus shielded from systemic “overshooting” with T helper lymphocyte 1 (Th1)/proinflammatory cytokines during immunological and inflammatory reactions. Nevertheless, in some local reactions and under specific situations, stress hormones may help inflammation by activating the CRH/substance P (SP)-histamine axis and inducing the generation of IL-1, IL-6, IL-8, IL-18, TNF-α, and CRP (86). Figure 2 below depicts important cytokines that are responsible for the pathogenesis of GBS.

Figure 2 Different factors affecting the development of GBS. CRP, C-reactive protein; GBS, Guillain-Barré syndrome; IL-6, interleukin-6; IL-10, interleukin-10.

As revealed in Figure 3, A discrepancy in the pro/anti-inflammatory and Th1/Th2 cytokine homeostasis is a hallmark of atherosclerosis, persistent infections, severe depression, and autoimmunity. Thus, the pathophysiology of these disorders may be supported by an overactive or less active stress system, a defective neuroendocrine-immune interface associated with impairment of the systemic anti-inflammatory feedback, and overactivity of the local pro-inflammatory components (86,87). Stress alters the synthesis of innate and T helper (Th) cytokines through stress hormones, which impacts the risk, course, and outcome of numerous immune disorders (88).

Figure 3 Pathophysiology of GBS. GBS, Guillain-Barré syndrome; IL-10, interleukin-10; IL-12, interleukin-12; TGF-β, transforming growth factor-beta; Th2, T helper cell 2; TNF-α, tumor necrosis factor-alpha.

Postnatal infections triggering GBS in stress-primed children

Research suggests that children’s susceptibility to infectious diseases increases later in life due to perinatal maternal stress (89). Perinatal stress may have an effect on a variety of offspring health outcomes by reducing offspring cluster of differentiation 8 (CD8) T-cell activity and rendering them more vulnerable to bacterial infections (90). Stress exposure during pregnancy has the potential to have widespread consequences since the fetal and infancy stages are known to be delicate times for the development of organs and system function (91). After adjusting for postpartum stress, notably, there was a moderate correlation between prenatal stress and postnatal depression and health issues. These correlations were shown in a lower socioeconomic group with a varied range of races and ethnicities (71). Also, the development of the fetal HPA axis is impacted by maternal stress (92).

Additionally, prenatal stress overactivates the infant’s ANS responsiveness and influences the development of the offspring’s immune system by modifying the gut microbiome (93).

Furthermore, fundamental molecular processes with functional implications that may affect a wide range of health outcomes are indicated by maternal prenatal stress and the epigenetic control of FKBP5, which has been connected to inflammation and mental and physical health issues (94).

These findings, which demonstrate maternal stress relationships with the incidence of a variety of offspring illness types—both infectious and noninfectious—are consistent with proof of such broad interactions with offspring brain and organ development and function, as well as growing knowledge of the organ cross-talk and related inflammatory reactions that participate in pathogenesis. In addition to predicting a higher prevalence of infectious and noninfectious diseases, maternal stress additionally foresees whether the child will have a variety of ailments. This element expands the interpretation of the results and is consistent with additional data supporting extensive systemic impacts of disrupted stress response systems, which may span immunologic, cardiovascular, neurohormonal, and limbic alterations along an intergenerational pathway (71,95,96).

Stress is regarded as revoking viral latency, allowing viruses to act as infectious environmental activators for autoimmune diseases (97). Eighty percent of patients with autoimmune disorders reported atypical emotional stress before disease onset. Therefore, to prevent stress-related immune imbalance, stress management and behavioral interventions should be considered in the treatment of autoimmune diseases (98). According to the Rezazadeh and colleagues’ study, mindfulness therapy can help people with autoimmune illnesses feel less depressed and anxious (99). Essentially, mindfulness enhances self-awareness, lessens stress reactions, and controls brain activity related to emotion processing, all of which diminish depressive and anxious symptoms. Additionally, mindfulness has been demonstrated to help manage pain and reduce inflammation by reducing pro-inflammatory cytokine levels (100). It is especially helpful for those who suffer from autoimmune illnesses, which frequently cause chronic pain (101). Significantly, mindfulness enhances sleep quality, which is important for autoimmune patients because sleep disorders worsen symptoms (102). Worth mentioning, psychotherapy of patients with GBS was associated with better functional outcomes (103).

Current evidence and gaps in research

Research in recent years suggests a correlation between GBS and maternal stress. Studies showed that there is a remarkable increase in the risk of GBS within the first month postpartum, while the risk appears to be lower during pregnancy (104,105) with an incidence rate of around 0.06% (106). It is believed that GBS typically affects unvaccinated middle-aged women, in the 3^rd trimester, preceded by respiratory infections (1). Maternal and fetal complications concerning GBS are not very common, but they can be serious, including respiratory failure, up to death (107,108). Research regarding prenatal stress and pediatric GBS faces several challenges. While studies have shown a relation between the two, the definite cause of the disease is still mysterious (109). Pediatric GBS has a heterogeneous clinical presentation with various neurophysiological subtypes, making it difficult to diagnose despite the disease being considered the most frequent contributing factor to children’s acute flaccid paralysis (110). Previous studies showed significant rates of morbidity and mortality associated with GBS in pregnancy, but there have been improvements in patient outcomes due to the new developments in intensive care and treatment routes (111,112). Prospective cohort studies are very important in understanding the etiology of GBS, as shown by a plethora of research like the International GBS Outcome Study, which is a worldwide prospective study seeking to pinpoint the determinants of multiple aspects of GBS including the onset, course, and outcome (113). Little is known about the factors that influence GBS heterogeneity and treatment decisions based on customization. Prior research has discovered correlations among acute phase biomarkers such as genetic polymorphisms, serum IgG levels, electrophysiological subtypes, and anti-ganglioside antibodies with clinical course (114,115). Controlling for a number of significant variables is crucial when investigating the connection between maternal stress and childhood GBS. For instance, it has been demonstrated that maternal infections during gestation affect fetal development and may raise the likelihood that the fetus would acquire autoimmune diseases (66). Furthermore, genetic susceptibility is important since some genetic predispositions might influence the way the child’s immune system is impacted by maternal stress (32). The association between maternal stress and GBS can be further complicated by the fact that lower socioeconomic situations are frequently linked to increased stress levels and unfavorable pregnancy outcomes (68).

To further grasp the intricacies of this connection between maternal stress and pediatric GBS, future research should take into account additional confounding factors like maternal socio-demographics (e.g., age, race, ethnicity, parity, educational level, lifestyle, income, occupation), maternal comorbidities, pregnancy complications, mode of delivery, birth difficulties, fetus characteristics (e.g., sex, birthweight, gestational age), or postnatal factors such as stressful early experiences, such as trauma, unfavorable family dynamics, exposure to environmental factors, diet, parental care which may exacerbate the consequences of prenatal stress (8).

However, the Brighton Collaboration criteria for GBS have been capturing GBS cases very effectively in either retrospective or prospective studies (116). A new promising biomarker for pediatric GBS is being used, called cerebrospinal fluid neurofilament light chain (CSF-NfL). Increased CSF-NfL indicates deterioration of motor functions and poor prognosis in the short term (117). There are also other emerging biomarkers like serum neurofilament light chain (NfL) and anti-ganglioside antibodies. Infection, immune, and blood-nerve barrier biomarkers are also being explored (117,118). Despite all the promising options currently being explored, it is still a challenging endeavor to find a reliable biomarker because GBS is a heterogeneous disease. Therefore, more research is needed to identify a biomarker with clinical significance for early diagnosis and prognosis (118,119).

Future research directions

Further research should be focused on identifying the biomarkers of maternal stress in pregnancy through prospective cohort studies and on the incidence of pediatric autoimmune disorders. These include determining cortisol levels, inflammatory markers, and epigenetic signatures, among others, to establish the incidence of pediatric autoimmune disorders like GBS. This will provide a temporal relationship between prenatal stress exposure, postnatal immune responses, and the onset of GBS. Experimental models are also required to explore the molecular and cellular mechanisms linking maternal stress to immune dysregulation in offspring. Moreover, it is essential in future studies to include systematic reviews with meta-analysis, including specific statistical data, such as strength of association and risk ratios, to better quantify our findings and to strengthen the evidence base. Finally, studies should look for possible interventions that may reduce risk, such as pregnancy stress management programs. Moreover, no specific effects of prenatal stress on brain regions relevant to GBS have been identified, highlighting a potential research gap for further investigation. Translating these findings into effective prevention strategies and improving maternal-fetal healthcare requires collaboration between obstetricians, pediatricians, and immunologists.

Strengths and limitations

This narrative review offers thorough details regarding the connection between maternal stress and pediatric GBS. One of its key advantages is its comprehensive analysis of the literature, which incorporates findings from multiple studies that investigate at how maternal stress affects fetal development and the autoimmune diseases that follow. The variety of research has enabled a more nuanced comprehension of the intricate nature of GBS. Additionally, this study lays a strong basis for future research by identifying several ways that maternal stress may affect immune system programming.

Despite the strengths, this review still has limitations. There are very few direct studies that specifically relate maternal stress to pediatric GBS, which is a substantial gap among the available research and could restrict the conclusions that can be made. Additionally, studies with different demographics and methodologies are used in the review, which introduces heterogeneity in the results. This variation could have an impact on how broadly the findings can be applied. To better understand causal connections and investigate the intricate details of individual risk variables, further prospective research and meta-analyses are required.

Conclusions

Maternal stress during pregnancy may be detrimental to the development of immune system of the growing fetus and thus predispose offspring to autoimmune diseases like GBS. The putative mechanisms of immune dysregulation due to stress-induced hormonal changes and inflammation provide potential pathways through which maternal stress might increase GBS risk, especially in the presence of other postnatal immune triggers such as infection.

Acknowledgments

Authors express their gratitude to Dr. Fatma E. Hassan for her invaluable guidance, supervision and critical review of this article.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-25-18/rc

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Funding: None.

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